Celiakia – Patofizjologia i mechanizm

Celiakia
Patofizjologia i mechanizm

Celiakia jest autoimmunologicznym zaburzeniem jelita cienkiego, wywołanym nieprawidłową odpowiedzią immunologiczną na gluten u osób genetycznie predysponowanych, głównie z ekspresją HLA-DQ2 (ponad 90% przypadków) lub HLA-DQ8. Gluten, szczególnie jego frakcja gliadyny bogata w prolinę i glutaminę, jest oporny na trawienie i ulega modyfikacji przez tkankową transglutaminazę (tTG), co zwiększa jego immunogenność. Deaminowane peptydy gliadyny wiążą się z cząsteczkami HLA-DQ2/8 na komórkach prezentujących antygen, aktywując limfocyty T CD4+ i indukując produkcję prozapalnych cytokin (IFN-γ, IL-21, IL-2). Równocześnie aktywuje się odpowiedź wrodzona, m.in. poprzez IL-15, która stymuluje limfocyty CD8+ śródnabłonkowe (IEL), prowadząc do uszkodzenia enterocytów i zaniku kosmków jelitowych. Charakterystyczne zmiany histopatologiczne obejmują zanik kosmków, hiperplazję krypt oraz zwiększoną liczbę IEL, co skutkuje zaburzeniami wchłaniania i objawami klinicznymi. Diagnostycznie istotne są przeciwciała przeciwko tTG, które korelują z nasileniem zapalenia. Celiakia ma charakter wielonarządowy, manifestując się także pozajelitowymi objawami, w tym neurologicznymi i dermatologicznymi (np. zapalenie skóry opryszczkowate). W patogenezie istotną rolę odgrywa także mikrobiota jelitowa, której dysbioza może wpływać na rozwój i przebieg choroby.

Patogeneza celiakii

Celiakia (choroba trzewna) to autoimmunologiczne zaburzenie charakteryzujące się nieprawidłową odpowiedzią immunologiczną na gluten – białko występujące w pszenicy, życie i jęczmieniu. Choroba ta rozwija się u osób genetycznie predysponowanych i prowadzi do zapalenia oraz uszkodzenia błony śluzowej jelita cienkiego, czego konsekwencją jest zanik kosmków jelitowych i upośledzenie wchłaniania składników odżywczych¹². Celiakia może być uważana za chorobę wielonarządową ze względu na szeroki zakres objawów klinicznych i zajęcie różnych układów organizmu³.

Czynniki genetyczne

Predyspozycja genetyczna odgrywa kluczową rolę w rozwoju celiakii. Najbardziej znanym czynnikiem ryzyka genetycznego, odpowiadającym za około 35% całkowitego ryzyka genetycznego, jest obecność genów kodujących białka MHC klasy II, w tym ludzki antygen leukocytarny (HLA) DQ2 i HLA-DQ8⁴⁵. Ponad 90% pacjentów z celiakią wykazuje ekspresję cząsteczek HLA-DQ2, a pozostali – HLA-DQ8⁶. Haplotypy te są obecne na powierzchni komórek prezentujących antygen (APC) w blaszce właściwej jelita, a wiązanie się gliadyny prowadzi do ekspresji prozapalnej cytokiny interferonu gamma i aktywacji limfocytów T CD4+⁷.

Celiakia często występuje rodzinnie – częstość występowania choroby wśród krewnych pierwszego stopnia wynosi około 10%, a wśród bliźniąt jednojajowych sięga 80%⁸⁹. Chociaż obecność HLA-DQ2 lub HLA-DQ8 jest niezbędna do rozwoju choroby, nie jest wystarczająca. Częstość występowania tych haplotypów w populacji zachodniej sięga 30-40%, podczas gdy celiakia rozwija się tylko u 1-3% osób¹⁰¹¹. Homozygotyczność HLA-DQ2 wiąże się ze zwiększonym ryzykiem celiakii i chłoniaka T-komórkowego związanego z enteropatią¹².

Badania asocjacyjne całego genomu zidentyfikowały 39 loci niezwiązanych z HLA, które również predysponują do celiakii¹³. Jednym z tych genów mogą być warianty genetyczne na chromosomie 19, w genie miozyny IXB (MYO9B), które potencjalnie mogą przewidywać odpowiedź na dietę bezglutenową¹⁴. Celiakia jest związana z wieloma innymi zaburzeniami autoimmunologicznymi, w tym cukrzycą typu 1 i chorobą autoimmunologiczną tarczycy¹⁵.

Rola glutenu w patogenezie celiakii

Gluten jest kluczowym czynnikiem środowiskowym wyzwalającym celiakię¹⁶¹⁷. Składa się on z glutenin i gliadyn, które są frakcją rozpuszczalną w mieszaninie alkoholu i wody. Gliadyny dzielą się dalej na frakcje alfa, gamma i omega na podstawie elektrogęstości¹⁸.

Gluten charakteryzuje się wysoką zawartością proliny i glutaminy, co czyni go trudnym do strawienia przez enzymy proteolityczne przewodu pokarmowego¹⁹²⁰. W rezultacie duże cząsteczki gliadyny pozostają w jelicie, gdzie są modyfikowane przez tkankową transglutaminazę (tTG), co zwiększa ich toksyczność dla osób podatnych (pozytywnych dla HLA-DQ2 lub HLA-DQ8)²¹.

Wysokie zawartości proliny umożliwiają peptydom glutenowym odporność na aktywność proteaz żołądkowych, trzustkowych i jelitowych, co zwiększa ich przeżywalność w jelicie cienkim²². Peptydy glutenowe mogą przedostawać się przez barierę nabłonkową albo przez transcytozę, albo przez zwiększenie przepuszczalności ścisłych połączeń nabłonkowych i docierać do blaszki właściwej, gdzie ulegają deaminacji przez tkankową transglutaminazę (tTG)²³.

Rola transglutaminazy tkankowej

Transglutaminaza tkankowa (tTG) odgrywa kluczową rolę w patogenezie celiakii, działając zarówno jako autoantygen, jak i modyfikując peptydy gliadyny²⁴. tTG katalitycznie deaminuje reszty glutaminy w peptydach gliadyny, przekształcając je w kwas glutaminowy, co prowadzi do powstania ujemnie naładowanych reszt, które wiążą się ze zwiększonym powinowactwem do cząsteczek HLA-DQ2 lub HLA-DQ8²⁵²⁶.

To przekształcenie glutaminy w kwas glutaminowy poprzez deaminację powoduje zwiększenie powinowactwa do HLA-DQ2/8 i umożliwia aktywację oraz ekspansję specyficznych dla peptydów glutenowych limfocytów T CD4+ typu I oraz wydzielanie przez nie prozapalnych cytokin²⁷. Konwersja glutaminy do reszt kwasu glutaminowego w wyniku deaminacji prowadzi do stosunkowo dużej liczby ujemnie naładowanych reszt w peptydach gliadyny, które wiążą się z dużym powinowactwem do cząsteczek HLA-DQ2 lub HLA-DQ8²⁸.

Warto podkreślić, że auto-przeciwciała skierowane przeciwko tTG są wysoce specyficznymi i czułymi wskaźnikami celiakii, chociaż ich pierwotna rola w patogenezie tej choroby nie jest w pełni wyjaśniona²⁹. Poziom przeciwciał wykazuje bezpośredni związek z nasileniem procesu zapalnego w jelicie³⁰.

Mechanizmy immunologiczne w celiakii

Celiakia rozwija się w wyniku aktywacji zarówno komórkowej (limfocyty T), jak i humoralnej (limfocyty B) odpowiedzi immunologicznej³¹. W patogenezie celiakii biorą udział dwa główne mechanizmy odpowiedzi immunologicznej: adaptacyjna i wrodzona.

Odpowiedź adaptacyjna

Peptydy gliadyny zmodyfikowane przez tTG są prezentowane limfocytom T CD4+ przez komórki prezentujące antygen (APC) posiadające HLA-DQ2 lub HLA-DQ8³². Aktywowane limfocyty T CD4+ wydzielają duże ilości prozapalnych cytokin, w tym interferonu gamma (IFN-γ), interleukiny-21 (IL-21) i interleukiny-2 (IL-2)³³.

Produkcja IFN-γ jest charakterystyczną cechą specyficznych dla peptydów glutenowych limfocytów T ograniczonych HLA-DQ2 i HLA-DQ8, które są izolowane z błony śluzowej jelita cienkiego pacjentów z celiakią i uważa się, że odgrywają kluczową rolę w inicjowaniu uszkodzeń błony śluzowej³⁴.

Aktywowane limfocyty T CD4+ wywołują również klonalną ekspansję limfocytów B, które następnie różnicują się w komórki plazmatyczne wydzielające przeciwciała przeciwko gliadynie i przeciwko tkankowej transglutaminazie³⁵. Ta odpowiedź humoralna prowadzi do produkcji przeciwciał przeciwko tTG, które są charakterystyczne dla celiakii³⁶.

Odpowiedź wrodzona

Równolegle z odpowiedzią adaptacyjną, w celiakii aktywowana jest również odpowiedź wrodzona. Niektóre peptydy gliadyny, które nie są rozpoznawane przez limfocyty T, aktywują zarówno APC, jak i komórki nabłonkowe jelita³⁷. W szczególności, α-gliadyna 31-43 indukuje produkcję interleukiny-15 (IL-15), kluczowej cytokiny zaangażowanej w aktywację limfocytów T³⁸.

IL-15 indukuje ekspresję cząsteczki stresu MICA (major histocompatibility complex class I-related chain A) na enterocytach i zwiększa ekspresję NKG2D (aktywujących receptorów komórek NK) na śródnabłonkowych limfocytach (IEL). Ta interakcja prowadzi do bezpośredniego zabijania enterocytów i jest prawdopodobną przyczyną zaniku kosmków³⁹.

IL-15 odgrywa wieloaspektową i kluczową rolę w patogenezie celiakii. Jest znacznie nadekspresjonowana w nieleczonej celiakii i ma zasadnicze znaczenie dla aktywacji i ekspansji limfocytów T CD8+ śródnabłonkowych (IEL), kluczowych graczy w uszkodzeniu nabłonka⁴⁰. IL-15 promuje proliferację, przeżycie i właściwości zabijania komórek przez śródnabłonkowe limfocyty⁴¹.

Zwiększona gęstość limfocytów CD8+ śródnabłonkowych jest uważana za cechę charakterystyczną celiakii⁴². Komórki te mogą być stymulowane przez IL-15, co przyczynia się bezpośrednio do śmierci enterocytów⁴³.

Rola bariery jelitowej

W patogenezie celiakii istotną rolę odgrywa również bariera nabłonkowa jelita, która fizjologicznie jest nieprzepuszczalna dla makrocząsteczek takich jak gliadyna⁴⁴. U osób z genetyczną predyspozycją do rozwoju celiakii, gliadyna wchodzi w interakcję z komórkami jelitowymi, wywołując rozłączenie ścisłych połączeń międzykomórkowych (tight junctions, TJs)⁴⁵.

Badania wykazały, że gliadyna przyspiesza dezintegrację międzykomórkowych białek połączeń ścisłych poprzez aktywację szlaku receptora naskórkowego czynnika wzrostu (EGFR) oraz przez obniżenie regulacji genu aktywowanego przez proliferatory peroksysomów γ (PPAR-γ) i białek ścisłych połączeń jelitowych zonuliny-1 (ZO-1), klaudyny-1 i okluzji⁴⁶.

Upośledzenie TJs prowadzi do up-regulacji zonuliny, peptydu zaangażowanego w regulację TJ i odpowiedzialnego za zwiększoną przepuszczalność jelit⁴⁷. Peptydy gliadyny przechodzą przez barierę nabłonkową i aktywują limfocyty T zlokalizowane w blaszce właściwej⁴⁸.

Utrata bariery jelitowej prowadzi do zwiększonego dostępu cząsteczek pochodzących z jelita (np. samego antygenu gliadyny, agregatów biomolekularnych, pęcherzyków zewnątrzkomórkowych, przeciwciał AGA, ATG2A, mediatorów zapalnych itp.) do krwiobiegu, co przyczynia się do manifestacji neurologicznych poprzez bezpośrednią toksyczność, odkładanie kompleksów immunologicznych i produkcję przeciwciał reagujących krzyżowo, wpływając na tzw. „oś mikrobiota jelitowa-mózg”⁴⁹.

Mechanizmy uszkodzenia tkankowego

Konsekwencją aktywacji odpowiedzi immunologicznej w celiakii jest charakterystyczne uszkodzenie błony śluzowej jelita cienkiego. Odpowiedź immunologiczna na gluten prowadzi do uwolnienia cytokin i uszkodzenia tkanek⁵⁰. To uszkodzenie tkanek skutkuje charakterystycznym obrazem patologicznym zaniku kosmków i stanu zapalnego⁵¹.

Kontakt limfocytów T CD4+ w blaszce właściwej z glutenem indukuje ich aktywację i proliferację, z produkcją prozapalnych cytokin, metaloproteinaz i czynnika wzrostu keratynocytów przez komórki zrębu, co indukuje hiperplazję krypt i skrócenie kosmków wtórne do śmierci komórek nabłonkowych jelita indukowanej przez śródnabłonkowe limfocyty (IEL)⁵².

Zamiast normalnej architektury wysokich kosmków i głębokich krypt, w celiakii obserwuje się spłaszczoną błonę śluzową pozbawioną kosmków. Może to znacznie zmniejszyć powierzchnię jelita cienkiego, powodując zaburzenia wchłaniania składników odżywczych, co może prowadzić do biegunki i niedożywienia⁵³. Tkanka dwunastnicy wykazuje również zwiększoną liczbę śródnabłonkowych limfocytów⁵⁴.

Przewlekły stan zapalny prowadzi do przebudowy tkanki, hiperplazji krypt i zaniku kosmków jelitowych. Te zmiany patologiczne są odwracalne po wprowadzeniu diety bezglutenowej, co stanowi wyjątkową cechę celiakii w porównaniu do innych zaburzeń autoimmunologicznych⁵⁵.

Rola mikrobioty jelitowej

Coraz więcej dowodów wskazuje na rolę mikrobioty jelitowej w patogenezie celiakii. Mikrobiota jelitowa współistnieje ze swoim gospodarzem w continuum między homeostazą a patogenicznością; górny odcinek przewodu pokarmowego zawiera mikrobiotę jelitową, która jest zmieniana kompozycyjnie i metabolicznie przez składniki pokarmowe⁵⁶.

Kilka badań wskazuje na zmiany w składzie i funkcji mikrobioty jelitowej w celiakii, z których niektóre mogą poprzedzać pojawienie się choroby i/lub utrzymywać się, gdy pacjenci są na diecie bezglutenowej⁵⁷. Istnieją również dowody na to, że mikrobiota jelitowa może promować lub zmniejszać immunopatologię związaną z celiakią⁵⁸.

Skład mikrobioty jelitowej, w tym wiromu, wpływa na aktywację jelitowego układu odpornościowego i rozwój nietolerancji glutenu. Czynniki takie jak praktyki żywieniowe, nawyki dietetyczne, stosowanie antybiotyków, częste narażenie na wirusy (wirus Coxsackie, adenowirus) przed 2 rokiem życia mogą przyczyniać się do wystąpienia celiakii poprzez zmianę składu mikrobiologicznego jelita⁵⁹.

Model patogenezy celiakii

Zaproponowany model konceptualizujący rolę odpowiedzi limfocytów T w patogenezie celiakii dzieli to zjawisko na trzy fazy: wydarzenia światła i wczesnej błony śluzowej; aktywacja patogennych limfocytów T CD4+; oraz wydarzenia prowadzące do uszkodzenia tkanek⁶⁰.

Faza patogenezy	Główne wydarzenia	Konsekwencje
Faza 1: Wydarzenia światła i wczesnej błony śluzowej	– Spożycie glutenu – Niepełne trawienie glutenu w górnym odcinku przewodu pokarmowego – Przechodzenie peptydów glutenowych przez barierę nabłonkową	– Obecność dużych cząsteczek gliadyny w jelicie – Zwiększona przepuszczalność jelit – Dotarcie peptydów do blaszki właściwej
Faza 2: Aktywacja patogennych limfocytów T CD4+	– Deaminacja peptydów glutenowych przez tTG – Prezentacja zmodyfikowanych peptydów przez APC z HLA-DQ2/8 – Aktywacja specyficznych dla glutenu limfocytów T CD4+	– Zwiększone powinowactwo peptydów do HLA-DQ2/8 – Proliferacja specyficznych limfocytów T – Produkcja prozapalnych cytokin (IFN-γ, IL-21, IL-2)
Faza 3: Uszkodzenie tkanek	– Produkcja IL-15 – Aktywacja limfocytów śródnabłonkowych CD8+ – Klonalna ekspansja limfocytów B – Produkcja przeciwciał przeciwko gliadynie i tTG	– Bezpośrednie zabijanie enterocytów – Zanik kosmków jelitowych – Hiperplazja krypt – Zaburzenia wchłaniania składników odżywczych

Podsumowując, patogeneza celiakii obejmuje złożoną interakcję między czynnikami genetycznymi (głównie HLA-DQ2/DQ8), środowiskowymi (gluten) i immunologicznymi. Proces rozpoczyna się od niepełnego trawienia i wchłaniania peptydów glutenowych, które przechodzą przez barierę jelitową i są modyfikowane przez tTG. Następnie zmodyfikowane peptydy są prezentowane limfocytom T CD4+ przez komórki APC, co prowadzi do kaskady reakcji immunologicznych, w tym produkcji prozapalnych cytokin, aktywacji limfocytów śródnabłonkowych i produkcji przeciwciał. Końcowym rezultatem jest uszkodzenie błony śluzowej jelita cienkiego, zanik kosmków i zaburzenia wchłaniania⁶¹⁶²⁶³.

Interakcje między gliadyną a cząsteczkami HLA

Powodem, dla którego geny HLA zwiększają ryzyko celiakii, jest to, że receptory utworzone przez te geny wiążą się z peptydami gliadyny silniej niż inne formy receptora prezentującego antygen⁶⁴. Większość białek w żywności odpowiedzialnych za reakcję immunologiczną w celiakii to prolaminy⁶⁵.

Peptyd oporny na proteazy z α-gliadyny zawiera region, który stymuluje limfocyty i prowadzi do uwalniania interleukiny-15⁶⁶. Tkankowa transglutaminaza modyfikuje peptydy glutenowe do formy, która może bardziej efektywnie stymulować układ odpornościowy⁶⁷.

Gliadyna specyficznie wiąże się z heterodimerami HLA-DQ2 lub HLA-DQ8 znajdującymi się w 90-95% i 5-10% pacjentów z celiakią⁶⁸. Obecne są one na powierzchni komórek prezentujących antygen w blaszce właściwej, a wiązanie gliadyny prowadzi do ekspresji prozapalnej cytokiny interferonu gamma i aktywacji limfocytów T CD4+⁶⁹.

Różnice w odpowiedzi immunologicznej

Istnieją dowody na to, że odpowiedź adaptacyjna i wrodzona na gluten mogą istnieć niezależnie i obie są wymagane do indukcji zniszczenia komórek nabłonkowych, co prowadzi do zaniku kosmków i objawów klinicznych związanych z zaburzeniami wchłaniania⁷⁰.

Celiakia charakteryzuje się małojelitowym uszkodzeniem błony śluzowej i zaburzeniami wchłaniania składników odżywczych u osób predysponowanych genetycznie w odpowiedzi na spożycie w diecie pszenicy, gliadyny i podobnych białek w jęczmieniu i życie⁷¹. Patogeneza choroby obejmuje interakcje między czynnikami środowiskowymi, genetycznymi i immunologicznymi⁷².

Szeroki zakres objawów klinicznych w celiakii, od dysfunkcji przewodu pokarmowego do ciężkich zespołów zaburzeń wchłaniania, wynika z interakcji między reakcją immunologiczną na peptydy glutenowe a bezpośrednim wpływem tych peptydów na różne tkanki i narządy⁷³.

Celiakia jako choroba wielonarządowa

Celiakia może być uważana za syndrom ze względu na szeroki zakres manifestacji klinicznych i zajęcie różnych układów organizmu⁷⁴. Choroba ta wykazuje szczególne cechy w porównaniu do innych zaburzeń autoimmunologicznych, w tym całkowite ustąpienie uszkodzenia błony śluzowej oraz odwracalność jej progresji i dynamiki przewlekłej, przy całkowitym unikaniu glutenu⁷⁵.

Celiakia jest wieloukładowym zaburzeniem autoimmunologicznym, które może powodować objawy dotyczące przewodu pokarmowego i innych układów narządowych, takich jak skóra i kości⁷⁶. Patogeneza zapalenia skóry opryszczkowatego w skórze jest powiązana z patogenezą celiakii w jelicie. Podobnie jak celiakia, zapalenie skóry opryszczkowate jest częstsze u osób genetycznie predysponowanych noszących haplotyp HLA-DQ2 lub HLA-DQ8⁷⁷.

U pacjentów z celiakią, wraz z tworzeniem przeciwciał IgA przeciwko tkankowej transglutaminazie, dochodzi również do tworzenia przeciwciał IgA przeciwko transglutaminazie naskórkowej⁷⁸.

Manifestacje neurologiczne celiakii

Celiakia jest złożoną chorobą wielonarządową z wysoką częstością występowania objawów pozajelitowych, w tym neurologicznych i psychiatrycznych, takich jak ataksja móżdżkowa, neuropatia obwodowa, padaczka, ból głowy, zaburzenia poznawcze i depresja⁷⁹.

Czynniki przyczynowe i mechanizmy patofizjologiczne zaangażowania neurologicznego w celiakii pozostają kontrowersyjne. Zgodnie z najnowszymi dowodami, mogą być one związane z patogenezą mediowaną przez gluten, w tym reakcją krzyżową przeciwciał, odkładaniem kompleksów immunologicznych, bezpośrednią neurotoksycznością, a w ciężkich przypadkach niedoborem witamin lub składników odżywczych⁸⁰.

Produkty pochodzące z mikrobioty jelitowej (takie jak antygeny, toksyny, miRNA itp.) mogą być znajdowane w przedziałach mózgowych u osób z celiakią⁸¹.

Inne manifestacje systemowe

Powikłania przewlekłego zapalenia mogą obejmować osłabioną odporność. Gdy układ odpornościowy jest chronicznie nadaktywny, ma mniej zasobów do zwalczania ostrego ataku, takiego jak infekcja⁸².

Przewlekłe zapalenie prowadzi do zwiększonego ryzyka raka w jelicie cienkim. Badania pokazują, że około 7% osób z celiakią rozwija chłoniaki jelitowe, zwykle po kilku dekadach⁸³.

Uszkodzenie jelita cienkiego może mieć poważne konsekwencje. Jelito cienkie wchłania składniki odżywcze z pożywienia przez błonę śluzową. Jeśli błona śluzowa jest uszkodzona, nie będzie w stanie wchłaniać składników odżywczych tak, jak powinna. Jest to nazywane zaburzeniami wchłaniania⁸⁴.

Nowe kierunki badań nad patogenezą celiakii

Ostatnie badania poszerzyły naszą wiedzę na temat patogenezy celiakii, identyfikując nowe geny i szlaki potencjalnie zaangażowane w wczesne etapy rozwoju choroby⁸⁵.

Badania genomowe i transkryptomiczne

Sekwencjonowanie RNA błony śluzowej dwunastnicy u pacjentów z aktywną celiakią, celiakią w remisji i kontrolami bez celiakii pozwoliło zidentyfikować nowe geny zaangażowane w patogenezę⁸⁶. Zidentyfikowano nadregulację nowych genów, w tym IL12R, ITGAM i IGSF4, zaangażowanych w maszynerię odpowiedzi immunologicznej i proces adhezji komórkowej w błonie śluzowej osób z aktywną celiakią w porównaniu do osób w remisji⁸⁷.

Badania te potwierdziły wcześniejsze odkrycia oparte na GWAS i badaniach immunologicznych istotnych dla patogenezy celiakii i opisują nowe geny i szlaki, które po dalszej walidacji mogą przyczyniać się do wczesnych etapów patogenezy celiakii, trwającego zapalenia i chorób współistniejących związanych z celiakią⁸⁸.

Analiza zidentyfikowała nadregulację cząsteczek adhezji komórkowej, takich jak IGSF4, i innych zaangażowanych w migrację przeznabłonkową leukocytów, takich jak ITAGAM, w aktywnej celiakii⁸⁹. Nadregulacja szlaków spliceosomu nie była wcześniej opisywana w celiakii⁹⁰.

Dysregulacja metaboliczna w celiakii

Badania metabolizmu komórek nabłonkowych jelita cienkiego (sIECs) w celiakii wykazały znaczące zmiany w aktywności 28 podstawowych zadań metabolicznych, wpływając na krytyczne procesy integralne dla funkcji sIECs, takie jak regulacja stresu oksydacyjnego, synteza nukleotydów i naprawa DNA, produkcja energii oraz metabolizm poliamin i aminokwasów⁹¹.

Krytyczne funkcje sIECs opierają się na złożonej, precyzyjnie dostosowanej sieci procesów metabolicznych, które wspierają produkcję energii, wzrost komórek i syntezę niezbędnych związków bioaktywnych. Przewlekłe zapalenie i niszczenie tkanek w celiakii zakłócają te sieci metaboliczne w sIECs⁹².

Te zakłócenia metaboliczne znacząco zaburzają kilka aspektów zdrowia jelit istotnych dla celiakii, takich jak wchłanianie i trawienie składników odżywczych, integralność bariery jelitowej, interakcje komórek odpornościowych i ogólna odpowiedź zapalna na gluten⁹³.

Rola wirusów w patogenezie celiakii

Centralne celem niektórych badań jest określenie mechanizmów, poprzez które infekcje wirusowe prowadzą do utraty tolerancji na antygen pokarmowy i indukują celiakię, oraz opracowanie strategii zapobiegania utracie tolerancji wywołanej przez wirusy i wystąpieniu celiakii⁹⁴.

Reowirusy to ludzkie wirusy dsRNA ostatnio powiązane z celiakią⁹⁵. Odkryto, że szczep reowirusa T1L znosi tolerancję na antygeny pokarmowe, w tym gluten, wykorzystując szlak zależny od IRF1, podczas gdy szczep T3D-RV tego nie robi⁹⁶.

Organoidowe modele badań nad celiakią

Ostatnie postępy w inżynierii tkankowej zaowocowały potężnym narzędziem do badania złożonych chorób: organoidami⁹⁷. W kontekście celiakii, organoidy jelitowe wyłoniły się jako cenny system modelowy do wyjaśnienia mechanizmów choroby⁹⁸.

Dane sugerują kluczową rolę IL-7 w organizowaniu kaskady zapalnej, która leży u podstaw patogenezy celiakii⁹⁹. Rozwój technologii organoidów stanowi znaczący krok naprzód w badaniach nad celiakią. Zapewniając bardziej fizjologicznie odpowiedni model w porównaniu do tradycyjnych hodowli komórkowych lub badań na zwierzętach, organoidy umożliwiają precyzyjną analizę mechanizmów choroby i ułatwiają ocenę nowych strategii terapeutycznych¹⁰⁰.

Implikacje terapeutyczne wynikające z patogenezy

Głębsze zrozumienie dokładnej roli mikroorganizmów w patogenezie celiakii pomoże w opracowaniu strategii modulujących mikrobiotę, takich jak probiotyki, aby zapobiegać lub pomagać w leczeniu tej choroby¹⁰¹.

Identyfikacja mechanizmów rozwoju celiakii może prowadzić do alternatywnych podejść w leczeniu celiakii¹⁰². Postępy w zrozumieniu immunopatogenezy celiakii mogą prowadzić do alternatywnych metod leczenia tej choroby¹⁰³.

Potrzeba opracowania metod leczenia niedietetycznego jest powszechnie uznana, ale jest to utrudnione przez brak patofizjologicznie istotnego modelu przedklinicznego. Niemniej jednak, modele in vitro i in vivo umożliwiły badanie mechanizmów choroby i opracowanie nowych podejść do leczenia: stosowanie żywności z neutralizowanym glutenem, korekcja mikrobioty, koktajle specyficznych endoproteinaz, polimerowe substancje wiążące gluten, specyficzne inhibitory transglutaminaz i prozapalnych cytokin oraz szczepionka oparta na terapii swoistej dla alergenu¹⁰⁴.

Badacze z Uniwersytetu Kalifornijskiego w Davis usunęli klaster genów w pszenicy, który generuje białka glutenowe, które mogą wyzwalać reakcje immunologiczne, bez szkody dla jakości chleba z tego globalnie odżywczego zboża¹⁰⁵. Zespół badawczy użył promieniowania gamma do celowania i usunięcia alfa-gliadyn, które mogą powodować ciężkie reakcje u osób z celiakią¹⁰⁶.

Lepsza znajomość składu toksycznych peptydów glutenowych poprawiła sposoby ich wykrywania w żywności i napojach oraz możliwości monitorowania zgodności z dietą bezglutenową za pomocą podejść nieinwazyjnych¹⁰⁷.

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#2 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#3 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#4 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
It has been shown that the Saharawi, an Algerian population has the highest prevalence of celiac disease (nearly, 6%) among all of the worldwide populations. The best-characterized genetic risk factor for celiac disease, accounting for 35% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen (HLA) DQ 2 and HLA-DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes is about 30%, whereas only 1%-3% develops the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins. Recently, genome-wide association studies have identified 39 non-HLA loci that also predispose to celiac disease. One of these genes may relate to genetic variants on chromosome 19, in the myosin IXB gene (i.e., MYO9B), and may potentially predict responsiveness to a gluten-free diet (GFD). Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs). It has been ascertained that they present gluten peptides to antigen-specific T-lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, tTG2 may transform non-charged glutamine into negatively charged glutamic acid.
#5 Celiac disease: a comprehensive current review | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z
Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options. […] A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). […] CD is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well defined.
#6 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
It has been shown that the Saharawi, an Algerian population has the highest prevalence of celiac disease (nearly, 6%) among all of the worldwide populations. The best-characterized genetic risk factor for celiac disease, accounting for 35% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen (HLA) DQ 2 and HLA-DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes is about 30%, whereas only 1%-3% develops the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins. Recently, genome-wide association studies have identified 39 non-HLA loci that also predispose to celiac disease. One of these genes may relate to genetic variants on chromosome 19, in the myosin IXB gene (i.e., MYO9B), and may potentially predict responsiveness to a gluten-free diet (GFD). Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs). It has been ascertained that they present gluten peptides to antigen-specific T-lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, tTG2 may transform non-charged glutamine into negatively charged glutamic acid.
#7 Celiac Disease (Sprue): Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/171805-overview
The interaction of alcohol-soluble gliadin in wheat, barley, and rye with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in the enteric epithelial cells, stimulating the proliferation of the natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes. […] Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium. […] Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.
#8 Pathogenesis of celiac disease – Dr. SchÃ¤r Institute
https://www.drschaer.com/us/institute/a/pathogenesis-celiac-disease
Celiac disease has a complex pathology resulting from interaction between a number of genetic and exogenous factors. […] A high incidence of celiac disease within affected families (approximately 10% among first-degree relatives and 80% among twins) suggests a genetic involvement in the pathogenesis of celiac disease. […] An important genetic factor is the human leukocyte antigen (HLA) system, a gene complex whose task is to recognize foreign molecules. […] 90% of celiac patients carry genes encoding HLA DQ2, while most of the remainder carry the HLA DQ8 haplotype. […] Although these are necessary for the disease to develop, they are not solely responsible for it. […] It is known that these genes are also present in up to 40% of individuals in Western populations, however, the frequency is population dependent.
#9 Celiac Disease (Sprue): Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/171805-overview
Celiac disease has a strong hereditary component. The prevalence of the condition in first-degree relatives is approximately 10%. […] A strong association exists between celiac disease and two human leukocyte antigen (HLA) haplotypes (DQ2 and DQ8). Damage to the small intestinal mucosa occurs with the presentation of gluten-derived peptide gliadin, consisting of 33 amino acids, by the HLA molecules to helper T cells. Helper T cells mediate the inflammatory response. Endogenous tissue transglutaminase deamidates gliadin into a negatively charged protein, increasing its immunogenicity. Autoantibodies to type 2 transglutaminase (TG2) is a hallmark of celiac disease. […] Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.
#10 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
It has been shown that the Saharawi, an Algerian population has the highest prevalence of celiac disease (nearly, 6%) among all of the worldwide populations. The best-characterized genetic risk factor for celiac disease, accounting for 35% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen (HLA) DQ 2 and HLA-DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes is about 30%, whereas only 1%-3% develops the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins. Recently, genome-wide association studies have identified 39 non-HLA loci that also predispose to celiac disease. One of these genes may relate to genetic variants on chromosome 19, in the myosin IXB gene (i.e., MYO9B), and may potentially predict responsiveness to a gluten-free diet (GFD). Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs). It has been ascertained that they present gluten peptides to antigen-specific T-lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, tTG2 may transform non-charged glutamine into negatively charged glutamic acid.
#11 Emergence of Celiac disease and Gluten-related disorders in Asia
https://www.jnmjournal.org/journal/view.html?uid=1675&vmd=Full
Celiac disease (CeD) is a systemic, immune-mediated enteropathy, which is triggered by gluten protein in genetically susceptible individuals. […] The pathogenesis of CeD involves a complex interplay of environmental and genetic factors. […] The HLA alleles which have been shown to pose the highest risk for CeD and are found in more than 95% of CeD are HLA-DQ2 (HLA-DQA1*0501 and HLA-DQB1*0201) and HLA-DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302). […] The biological plausibility of this predisposition is explained by the high affinity of deamidated gliadin peptides to HLA-DQ2 and HLA-DQ8 molecules. […] Homozygosity of HLA-DQ2 depicts a gene-dose effect and is a predictor of complicated CeD like refractory disease or malignant transformation. […] It must be noted though, that approximately 40% of the Western population also carry these haplotypes without ever developing CeD, and thus HLA-DQ2 and DQ8 are necessary but not sufficient for CeD to develop.
#12 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate
https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults
Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. […] Celiac disease is an immune disorder triggered by an environmental agent (the gluten component of wheat and related cereals) in genetically predisposed individuals. […] The genetic basis of celiac disease is supported by the frequent intrafamilial occurrence and the remarkably close association with the human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8 gene locus. […] Homozygosity for HLA DQ2 has been associated with an increased risk for celiac disease and enteropathy-associated T-cell lymphoma. […] It has been estimated that the HLA contribution to the development of celiac disease among siblings is 36 percent.
#13 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
It has been shown that the Saharawi, an Algerian population has the highest prevalence of celiac disease (nearly, 6%) among all of the worldwide populations. The best-characterized genetic risk factor for celiac disease, accounting for 35% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen (HLA) DQ 2 and HLA-DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes is about 30%, whereas only 1%-3% develops the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins. Recently, genome-wide association studies have identified 39 non-HLA loci that also predispose to celiac disease. One of these genes may relate to genetic variants on chromosome 19, in the myosin IXB gene (i.e., MYO9B), and may potentially predict responsiveness to a gluten-free diet (GFD). Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs). It has been ascertained that they present gluten peptides to antigen-specific T-lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, tTG2 may transform non-charged glutamine into negatively charged glutamic acid.
#14 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
It has been shown that the Saharawi, an Algerian population has the highest prevalence of celiac disease (nearly, 6%) among all of the worldwide populations. The best-characterized genetic risk factor for celiac disease, accounting for 35% of the total genetic risk, is the presence of genes encoding for MHC class II proteins including human leukocyte antigen (HLA) DQ 2 and HLA-DQ8. Over 90% of affected subjects express HLA-DQ2 molecules; the remainder express HLA-DQ8. The frequency of celiac disease risk HLA genotypes is about 30%, whereas only 1%-3% develops the disease. It is now accepted that HLA is one of the main but not sufficient factors involved in the onset of celiac disease, but a multitude of genetic factors are responsible in celiac disease susceptibility, as demonstrated by studies on monozygotic twins. Recently, genome-wide association studies have identified 39 non-HLA loci that also predispose to celiac disease. One of these genes may relate to genetic variants on chromosome 19, in the myosin IXB gene (i.e., MYO9B), and may potentially predict responsiveness to a gluten-free diet (GFD). Both HLA-DQ2 and HLA-DQ8 codified for heterodimers located on Antigen-Presenting Cells (APCs). It has been ascertained that they present gluten peptides to antigen-specific T-lymphocytes in the intestinal mucosa, inducing their proliferation as well as cytokine production. In particular, tTG2 may transform non-charged glutamine into negatively charged glutamic acid.
#15 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate
https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults
Thus, another gene or genes at an HLA-unlinked locus must also participate. […] Moreover, novel genetic and especially epigenetic factors that increase the risk or severity of celiac disease have been identified. […] Celiac disease is associated with a number of autoimmune disorders, including type 1 diabetes mellitus and autoimmune thyroid disease. […] In patients with celiac disease, immune responses to gliadin fractions promote an inflammatory reaction, characterized by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. […] This response is mediated by both the innate and adaptive immune systems.
#16 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#17 Pathogenesis of celiac disease – Dr. SchÃ¤r Institute
https://www.drschaer.com/us/institute/a/pathogenesis-celiac-disease
The presence of gluten in the diet is clearly a pre-requisite for the development of celiac disease. […] Data from such studies appears to indicate that exclusive or any breastfeeding, including breastfeeding at the time of gluten introduction does not reduce the risk of developing coeliac disease during childhood. […] Moreover, for infants at higher risk of developing celiac disease, gluten introduction at 4 months of age, or at 6-12 months of age results in similar rates of celiac disease diagnosis in early childhood.
#18 Pediatric Celiac Disease (Sprue): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/932104-overview
The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrated in specific binding to HLA-DQ2 or DQ8 molecules and in stimulating gluten-specific CD4 T cells. These T cells express / TCR, and can be isolated from the lamina propria and cultivated. In vitro, they have been shown to recognize specific gluten peptides presented through interaction with DQ2 or DQ8 molecules. […] Gluten is a complex macromolecule that contains abundant proline and glutamine residues, rendering it largely indigestible. Under usual circumstances, gluten is left (in part) unabsorbed by the GI tract. Gluten is composed of glutenins and gliadins, the alcohol-water soluble fraction. These gliadins are further divided into alpha, gamma, and omega fractions based on electrodensity.
#19
https://www.jci.org/articles/view/30253
Gliadins, glutenins, hordeins, and secalins have a high proline and glutamine content. […] The production of IFN- is a signature of gluten peptide-specific HLA-DQ2 and HLA-DQ8-restricted T cells that are isolated from the mucosa of the small intestine of CD patients, and it is considered to have a key role in the downstream initiation of mucosal damage. […] Why is disease limited to those with HLA-DQ2 or HLA-DQ8? […] Activation of CD4+ T cells specific for gluten peptides in the lamina propria clearly requires that those peptides be presented by APCs (probably DCs) that express HLA-DQ2 or HLA-DQ8. […] Recent studies suggest that activation of the innate immune system is important in the pathogenesis of CD and in some of the complications of this disease, namely in refractory CD and in the development of EATLs.
#20 Development of Celiac Disease; Pathogenesis and Strategies to Con
https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html
HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD. […] High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. […] Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] tTG catalyzes selective crosslinking or deamidation of protein-bound specific glutamine residues whereas acidic pH in the stomach results in random deamidation of numerous peptides. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity.
#21 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#22 Development of Celiac Disease; Pathogenesis and Strategies to Con
https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html
HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD. […] High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. […] Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] tTG catalyzes selective crosslinking or deamidation of protein-bound specific glutamine residues whereas acidic pH in the stomach results in random deamidation of numerous peptides. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity.
#23 Development of Celiac Disease; Pathogenesis and Strategies to Con
https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html
HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD. […] High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. […] Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] tTG catalyzes selective crosslinking or deamidation of protein-bound specific glutamine residues whereas acidic pH in the stomach results in random deamidation of numerous peptides. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity.
#24 Celiac Disease by Dr ASHUTOSH CHANDAN DUBEY/Dr STRANGE .pptx
https://www.slideshare.net/slideshow/celiac-disease-by-dr-ashutosh-chandan-dubey-dr-strange-pptx/278782445
These modified peptides can be presented by HLA-DQ2/DQ8 molecules on APCs and thereby activate and expand gluten peptide specific CD4+T cells and induce their secretion of pro-inflammatory cytokines like IFN- Y, IL-21 IL-2. The interaction between IL-15 and gluten induced CD4+T cells in active CD is required for CD8+ IELs to mediate tissue destruction by acquiring a fully toxic phenotype. These inflammatory response lead to villous atrophy, crypt hyperplasia, B cell differentiation with Ab production. […] TG2 also plays a key role in CD pathogenesis, acting both as autoantigen and by generating immunogenic, deamidated gliadin peptides that are recognized by T-cells. TG2 modifies immunogenic gluten peptides by means of deamidation, which leads to increased HLA-DQ2/8 affinity and enables activation and expansion of gluten peptide specific CD4+ type I helper T-cells and their secretion of pro-inflammatory cytokines.
#25 Development of Celiac Disease; Pathogenesis and Strategies to Con
https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html
HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD. […] High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. […] Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] tTG catalyzes selective crosslinking or deamidation of protein-bound specific glutamine residues whereas acidic pH in the stomach results in random deamidation of numerous peptides. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity.
#26 Azthena logo with the word Azthena
https://www.news-medical.net/health/Celiac-Disease-Pathogenesis.aspx
Celiac disease is an autoimmune condition where the body responds to gluten in the diet by the immune system going in an overdrive and affecting the inner walls of the small intestines. […] Celiac disease results from activation of both a cell-mediated (T-cell) and humoral (B-cell) immune response. This activation results from exposure to the glutens. […] The target of these autoantibodies is enzyme tissue transglutaminase (tTG). This enzyme plays an important role in pathogenesis of celiac disease. It works by deamidating gliadin which results in greater proliferative response of gliadin-specific T-cells that lead to mucosal inflammation and further B-cell activation in patients with HLA-DQ2 or -DQ8.
#27 Celiac Disease by Dr ASHUTOSH CHANDAN DUBEY/Dr STRANGE .pptx
https://www.slideshare.net/slideshow/celiac-disease-by-dr-ashutosh-chandan-dubey-dr-strange-pptx/278782445
These modified peptides can be presented by HLA-DQ2/DQ8 molecules on APCs and thereby activate and expand gluten peptide specific CD4+T cells and induce their secretion of pro-inflammatory cytokines like IFN- Y, IL-21 IL-2. The interaction between IL-15 and gluten induced CD4+T cells in active CD is required for CD8+ IELs to mediate tissue destruction by acquiring a fully toxic phenotype. These inflammatory response lead to villous atrophy, crypt hyperplasia, B cell differentiation with Ab production. […] TG2 also plays a key role in CD pathogenesis, acting both as autoantigen and by generating immunogenic, deamidated gliadin peptides that are recognized by T-cells. TG2 modifies immunogenic gluten peptides by means of deamidation, which leads to increased HLA-DQ2/8 affinity and enables activation and expansion of gluten peptide specific CD4+ type I helper T-cells and their secretion of pro-inflammatory cytokines.
#28 Development of Celiac Disease; Pathogenesis and Strategies to Con
https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html
HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD. […] High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. […] Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] tTG catalyzes selective crosslinking or deamidation of protein-bound specific glutamine residues whereas acidic pH in the stomach results in random deamidation of numerous peptides. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity.
#29
https://haematologica.org/article/view/5094
The role of the human leukocyte antigen region (HLA) in celiac disease has been suggested by the observation that nearly all patients with celiac disease possess either the HLA-DQ2 (90%) or HLA-DQ8 heterodimer. However, HLA-DQ2 is also found in 30% of the healthy Caucasian population indicating that it is a necessary but not sufficient component for the development of celiac disease. […] The participation of HLA-DQ2 in the pathogenesis of celiac disease is described schematically. In addition to the role of A-gliadin p3143 described above, a second gluten peptide p5773 is presented to mesenteric lymph node T cells by HLA-DQ2 on antigen presenting dendritic cells (DC). HLA-DQ2 preferentially binds peptides with negatively charged amino acids. Tissue transglutaminase (TTG), the target of antiendomysial antibodies in celiac disease, has an important role in converting glutamine to glutamate residues generating negatively charged amino acids that are better bound by HLA-DQ2. Although anti-TTG antibodies are highly specific and sensitive indicators of celiac disease, the primary role of such antibodies in the pathogenesis of this disease is unclear. Antigen specific mesenteric T cells subsequently migrate to the peripheral blood and home back to the intestine employing specific cell adhesion molecules, inducing cell death by cytokine release, mainly interferon-.
#30 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism
https://journals.eco-vector.com/2658-4433/article/view/90770
The contribution of TG2 (transglutaminase-2) in celiac disease development is not limited to the deamination of gluten-like peptides but to the role of the enzyme as a target for antibody production. Typically, antibodies against TG2 are not produced; however, there are specific B-lymphocytes against TG2. The production of antibodies is encouraged by the gliadin-specific CD4+ T-lymphocytes, especially when the gliadin and TG2 are bound to the small intestinal mucosa. IgA and, to a lesser extent, IgM and IgG mainly represent antibodies against TG2. The level of antibodies does not reduce the enzyme activity despite their high affinity to TG2. Additionally, there is evidence that antibodies encourage the mobilization of Ca2+, which induces intracellular activation of TG2. Although the final role of antibodies to TG2 in celiac disease development is unclear, a direct relationship has been established between the level of autoantibodies and the severity of the inflammatory process in the intestine. Moreover, anti-TG2 IgA represents a specific and sensitive marker of celiac disease usually detected in almost all patients. […] Identifying the mechanisms of gluten-associated disease development will provide a fundamental understanding of the adverse reactions of gluten in different groups of patients and allow the development of more precise recommendations for treatment selection and new drug development.
#31 Azthena logo with the word Azthena
https://www.news-medical.net/health/Celiac-Disease-Pathogenesis.aspx
Celiac disease is an autoimmune condition where the body responds to gluten in the diet by the immune system going in an overdrive and affecting the inner walls of the small intestines. […] Celiac disease results from activation of both a cell-mediated (T-cell) and humoral (B-cell) immune response. This activation results from exposure to the glutens. […] The target of these autoantibodies is enzyme tissue transglutaminase (tTG). This enzyme plays an important role in pathogenesis of celiac disease. It works by deamidating gliadin which results in greater proliferative response of gliadin-specific T-cells that lead to mucosal inflammation and further B-cell activation in patients with HLA-DQ2 or -DQ8.
#32
https://www.jci.org/articles/view/30253
Gliadins, glutenins, hordeins, and secalins have a high proline and glutamine content. […] The production of IFN- is a signature of gluten peptide-specific HLA-DQ2 and HLA-DQ8-restricted T cells that are isolated from the mucosa of the small intestine of CD patients, and it is considered to have a key role in the downstream initiation of mucosal damage. […] Why is disease limited to those with HLA-DQ2 or HLA-DQ8? […] Activation of CD4+ T cells specific for gluten peptides in the lamina propria clearly requires that those peptides be presented by APCs (probably DCs) that express HLA-DQ2 or HLA-DQ8. […] Recent studies suggest that activation of the innate immune system is important in the pathogenesis of CD and in some of the complications of this disease, namely in refractory CD and in the development of EATLs.
#33 Celiac Disease by Dr ASHUTOSH CHANDAN DUBEY/Dr STRANGE .pptx
https://www.slideshare.net/slideshow/celiac-disease-by-dr-ashutosh-chandan-dubey-dr-strange-pptx/278782445
These modified peptides can be presented by HLA-DQ2/DQ8 molecules on APCs and thereby activate and expand gluten peptide specific CD4+T cells and induce their secretion of pro-inflammatory cytokines like IFN- Y, IL-21 IL-2. The interaction between IL-15 and gluten induced CD4+T cells in active CD is required for CD8+ IELs to mediate tissue destruction by acquiring a fully toxic phenotype. These inflammatory response lead to villous atrophy, crypt hyperplasia, B cell differentiation with Ab production. […] TG2 also plays a key role in CD pathogenesis, acting both as autoantigen and by generating immunogenic, deamidated gliadin peptides that are recognized by T-cells. TG2 modifies immunogenic gluten peptides by means of deamidation, which leads to increased HLA-DQ2/8 affinity and enables activation and expansion of gluten peptide specific CD4+ type I helper T-cells and their secretion of pro-inflammatory cytokines.
#34
https://www.jci.org/articles/view/30253
Gliadins, glutenins, hordeins, and secalins have a high proline and glutamine content. […] The production of IFN- is a signature of gluten peptide-specific HLA-DQ2 and HLA-DQ8-restricted T cells that are isolated from the mucosa of the small intestine of CD patients, and it is considered to have a key role in the downstream initiation of mucosal damage. […] Why is disease limited to those with HLA-DQ2 or HLA-DQ8? […] Activation of CD4+ T cells specific for gluten peptides in the lamina propria clearly requires that those peptides be presented by APCs (probably DCs) that express HLA-DQ2 or HLA-DQ8. […] Recent studies suggest that activation of the innate immune system is important in the pathogenesis of CD and in some of the complications of this disease, namely in refractory CD and in the development of EATLs.
#35 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#36 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism
https://journals.eco-vector.com/2658-4433/article/view/90770
The contribution of TG2 (transglutaminase-2) in celiac disease development is not limited to the deamination of gluten-like peptides but to the role of the enzyme as a target for antibody production. Typically, antibodies against TG2 are not produced; however, there are specific B-lymphocytes against TG2. The production of antibodies is encouraged by the gliadin-specific CD4+ T-lymphocytes, especially when the gliadin and TG2 are bound to the small intestinal mucosa. IgA and, to a lesser extent, IgM and IgG mainly represent antibodies against TG2. The level of antibodies does not reduce the enzyme activity despite their high affinity to TG2. Additionally, there is evidence that antibodies encourage the mobilization of Ca2+, which induces intracellular activation of TG2. Although the final role of antibodies to TG2 in celiac disease development is unclear, a direct relationship has been established between the level of autoantibodies and the severity of the inflammatory process in the intestine. Moreover, anti-TG2 IgA represents a specific and sensitive marker of celiac disease usually detected in almost all patients. […] Identifying the mechanisms of gluten-associated disease development will provide a fundamental understanding of the adverse reactions of gluten in different groups of patients and allow the development of more precise recommendations for treatment selection and new drug development.
#37 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#38
https://haematologica.org/article/view/5094
The key steps underlying the intestinal inflammatory response in celiac disease have been reviewed recently by van Heel and West. The toxic fractions of wheat proteins relevant to celiac disease have now been well characterized. Because of their high proline and glutamine content, gluten peptides are hydrophobic and resistant to degradation by gastric, pancreatic and intestinal brush border membrane proteases. Several peptides of key importance have been identified. A-gliadin p3143 induces interleukin 15, a key cytokine involved in T-cell activation. Interleukin 15 induces the expression of a stress molecule, MICA (major histocompatibility complex class I-related chain A) on enterocytes and upregulates NKG2D (activating natural killer cell receptors) on intraepithelial lymphocytes (IEL). This interaction results in direct enterocyte killing and is a likely cause of villous atrophy.
#39
https://haematologica.org/article/view/5094
The key steps underlying the intestinal inflammatory response in celiac disease have been reviewed recently by van Heel and West. The toxic fractions of wheat proteins relevant to celiac disease have now been well characterized. Because of their high proline and glutamine content, gluten peptides are hydrophobic and resistant to degradation by gastric, pancreatic and intestinal brush border membrane proteases. Several peptides of key importance have been identified. A-gliadin p3143 induces interleukin 15, a key cytokine involved in T-cell activation. Interleukin 15 induces the expression of a stress molecule, MICA (major histocompatibility complex class I-related chain A) on enterocytes and upregulates NKG2D (activating natural killer cell receptors) on intraepithelial lymphocytes (IEL). This interaction results in direct enterocyte killing and is a likely cause of villous atrophy.
#40 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review
https://www.mdpi.com/1422-0067/24/20/15482
Despite considerable advances in understanding celiac disease, numerous questions regarding its exact mechanisms and immune-pathophysiology remain unanswered. […] The activation of GALT by these gluten-derived peptides precipitates an inflammatory response, which is the crux of the pathogenesis in celiac disease. […] Following the ingestion of gluten, gliadin binds to the chemokine receptor CXCR3 on the luminal aspect of the intestinal epithelium. This binding prompts enterocytes to release the protein Zonulin. […] Type I IFN potentially provokes the release of IFN-Î³ and interleukin-15 (IL-15) by dendritic cells (DCs). The role of IL-15 within this pathogenic framework is multifaceted and instrumental. […] IL-15 production is notably upregulated in untreated celiac disease and plays a crucial role in the activation and expansion of CD8+ T intraepithelial lymphocytes (IELs), the key players in epithelial damage.
#41 Celiac Disease
http://courses.washington.edu/pbio376/celiac/celiacdisease-376.html
Once in the lamina propria, an enzyme modifies these peptides, making them even more antigenic. They are engulfed by antigen presenting cells (APC’s) which display them on their surface bound to MHC II molecules. They stimulate helper T cells, which secrete cytokines that orchestrate the inflammatory response that leads to tissue damage. One cytokine in particular (IL-15) stimulates intraepithelial lymphocytes. IL-15 promotes their proliferation, survival, and cell-killing properties. […] The consequence of the tissue damage is a change in the mucosa in the small intestine. Instead of the normal architecture of tall villi and deep crypts, what is observed in celiac disease is a flattened mucosa lacking villi. This can greatly decrease the surface area of the small intestine, causing malabsorption of nutrients, which can cause diarrhea and malnutrition. Duodenal tissue also shows increased numbers of intraepithelial lymphocytes.
#42 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#43 Celiac Disease by Dr ASHUTOSH CHANDAN DUBEY/Dr STRANGE .pptx
https://www.slideshare.net/slideshow/celiac-disease-by-dr-ashutosh-chandan-dubey-dr-strange-pptx/278782445
These modified peptides can be presented by HLA-DQ2/DQ8 molecules on APCs and thereby activate and expand gluten peptide specific CD4+T cells and induce their secretion of pro-inflammatory cytokines like IFN- Y, IL-21 IL-2. The interaction between IL-15 and gluten induced CD4+T cells in active CD is required for CD8+ IELs to mediate tissue destruction by acquiring a fully toxic phenotype. These inflammatory response lead to villous atrophy, crypt hyperplasia, B cell differentiation with Ab production. […] TG2 also plays a key role in CD pathogenesis, acting both as autoantigen and by generating immunogenic, deamidated gliadin peptides that are recognized by T-cells. TG2 modifies immunogenic gluten peptides by means of deamidation, which leads to increased HLA-DQ2/8 affinity and enables activation and expansion of gluten peptide specific CD4+ type I helper T-cells and their secretion of pro-inflammatory cytokines.
#44 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#45 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#46 Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation
https://www.mdpi.com/1422-0067/23/24/15564
Following the ingestion of gluten-containing food, proline-rich gliadin peptides (the antigenic component of gluten) are deamidated by intestinal issue transglutaminases 2 (TG2), a family of enzymes widely expressed in the body, as shown in Figure 1. This results in a gliadin-modified epitope with a greater affinity for human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 pockets in the antigen-presenting cells (APCs). The subsequent CD4 + T-cell activation leads to cytokines release and activation of metalloproteinases (MMP), eventually resulting in mucosal remodeling, intestinal villus atrophy, activation of lymphocytes B, and the production of antibodies to gluten (AGA) and autoantibodies to TG2 (ATG2A). […] Moreover, studies have demonstrated that gliadin accelerates the disassembling of intercellular junctional proteins via the epidermal growth factor receptor (EGFR) pathway activation and by the downregulation of peroxisome proliferation activated receptor Î³ (PPAR-Î³) gene and intestinal tight junctions (TJ) proteins zonulin-1 (ZO-1), claudin-1, and occluding. The loss of the intestinal barrier leads to increased access for gut-derived molecules (e.g., gliadin antigen itself, biomolecular aggregates, extracellular vesicles, AGA, ATG2A, inflammatory mediators, etc.) to enter the blood circulation and contribute to neurological manifestations by direct toxicity, immune complex deposition, and production of cross-reacting antibodies, all affecting the so-called âgut microbiota-brain axisâ. […] Intestinal microbiota-derived products (such as antigens, toxins, miRNA, etc.), indeed, can be found in the brain compartments of CD subjects.
#47 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#48 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#49 Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation
https://www.mdpi.com/1422-0067/23/24/15564
Following the ingestion of gluten-containing food, proline-rich gliadin peptides (the antigenic component of gluten) are deamidated by intestinal issue transglutaminases 2 (TG2), a family of enzymes widely expressed in the body, as shown in Figure 1. This results in a gliadin-modified epitope with a greater affinity for human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 pockets in the antigen-presenting cells (APCs). The subsequent CD4 + T-cell activation leads to cytokines release and activation of metalloproteinases (MMP), eventually resulting in mucosal remodeling, intestinal villus atrophy, activation of lymphocytes B, and the production of antibodies to gluten (AGA) and autoantibodies to TG2 (ATG2A). […] Moreover, studies have demonstrated that gliadin accelerates the disassembling of intercellular junctional proteins via the epidermal growth factor receptor (EGFR) pathway activation and by the downregulation of peroxisome proliferation activated receptor Î³ (PPAR-Î³) gene and intestinal tight junctions (TJ) proteins zonulin-1 (ZO-1), claudin-1, and occluding. The loss of the intestinal barrier leads to increased access for gut-derived molecules (e.g., gliadin antigen itself, biomolecular aggregates, extracellular vesicles, AGA, ATG2A, inflammatory mediators, etc.) to enter the blood circulation and contribute to neurological manifestations by direct toxicity, immune complex deposition, and production of cross-reacting antibodies, all affecting the so-called âgut microbiota-brain axisâ. […] Intestinal microbiota-derived products (such as antigens, toxins, miRNA, etc.), indeed, can be found in the brain compartments of CD subjects.
#50 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#51 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#52 Celiac disease: a comprehensive current review | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z
The contact of CD4+ T cells in the lamina propria with gluten induces their activation and proliferation, with production of proinflammatory cytokines, metalloproteases, and keratinocyte growth factor by stromal cells, which induces cryptal hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by intraepithelial lymphocytes (IELs). […] These data shed light on the molecular mechanisms underlying CD histopathology and illuminate the reason for the lack of enteropathy in the mouse models for CD.
#53 Celiac Disease
http://courses.washington.edu/pbio376/celiac/celiacdisease-376.html
Once in the lamina propria, an enzyme modifies these peptides, making them even more antigenic. They are engulfed by antigen presenting cells (APC’s) which display them on their surface bound to MHC II molecules. They stimulate helper T cells, which secrete cytokines that orchestrate the inflammatory response that leads to tissue damage. One cytokine in particular (IL-15) stimulates intraepithelial lymphocytes. IL-15 promotes their proliferation, survival, and cell-killing properties. […] The consequence of the tissue damage is a change in the mucosa in the small intestine. Instead of the normal architecture of tall villi and deep crypts, what is observed in celiac disease is a flattened mucosa lacking villi. This can greatly decrease the surface area of the small intestine, causing malabsorption of nutrients, which can cause diarrhea and malnutrition. Duodenal tissue also shows increased numbers of intraepithelial lymphocytes.
#54 Celiac Disease
http://courses.washington.edu/pbio376/celiac/celiacdisease-376.html
Once in the lamina propria, an enzyme modifies these peptides, making them even more antigenic. They are engulfed by antigen presenting cells (APC’s) which display them on their surface bound to MHC II molecules. They stimulate helper T cells, which secrete cytokines that orchestrate the inflammatory response that leads to tissue damage. One cytokine in particular (IL-15) stimulates intraepithelial lymphocytes. IL-15 promotes their proliferation, survival, and cell-killing properties. […] The consequence of the tissue damage is a change in the mucosa in the small intestine. Instead of the normal architecture of tall villi and deep crypts, what is observed in celiac disease is a flattened mucosa lacking villi. This can greatly decrease the surface area of the small intestine, causing malabsorption of nutrients, which can cause diarrhea and malnutrition. Duodenal tissue also shows increased numbers of intraepithelial lymphocytes.
#55 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#56 Novel players in coeliac disease pathogenesis: role of the gut microbiota | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/nrgastro.2015.90
The intestinal microbiota coexists with its host in a continuum between homeostasis and pathogenicity; the upper gastrointestinal tract harbours a gut microbiota that is affected compositionally and metabolically by food components. […] Coeliac disease is a chronic immune-mediated enteropathy caused by dietary gluten in genetically susceptible individuals. […] The role of microbial factors in coeliac disease pathogenesis has been suggested. […] Although clinical studies demonstrate that microbial changes are associated with coeliac disease, the individual microbes involved and underlying mechanisms remain elusive. […] Emerging data in gnotobiotic models indicate that the intestinal microbiota has a complex modulatory role in host immune responses to gluten. […] A deeper understanding of the precise role of microbes in coeliac disease pathogenesis will aid in the development of microbiota-modulating strategies, such as probiotics, to prevent or help treat the disease.
#57 Novel players in coeliac disease pathogenesis: role of the gut microbiota | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/nrgastro.2015.90
Several studies point towards alteration in gut microbiota composition and function in coeliac disease, some of which can precede the onset of disease and/or persist when patients are on a gluten-free diet. […] Evidence also exists that the gut microbiota might promote or reduce coeliac-disease-associated immunopathology. […] However, additional studies are required in humans and in mice (using gnotobiotic technology) to determine cause-effect relationships and to identify agents for modulating the gut microbiota as a therapeutic or preventative approach for coeliac disease. […] In this Review, we summarize the current evidence for altered gut microbiota composition in coeliac disease and discuss how the interplay between host genetics, environmental factors and the intestinal microbiota might contribute to its pathogenesis. […] Moreover, we highlight the importance of utilizing animal models and long-term clinical studies to gain insight into the mechanisms through which host-microbial interactions can influence host responses to gluten.
#58 Novel players in coeliac disease pathogenesis: role of the gut microbiota | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/nrgastro.2015.90
Several studies point towards alteration in gut microbiota composition and function in coeliac disease, some of which can precede the onset of disease and/or persist when patients are on a gluten-free diet. […] Evidence also exists that the gut microbiota might promote or reduce coeliac-disease-associated immunopathology. […] However, additional studies are required in humans and in mice (using gnotobiotic technology) to determine cause-effect relationships and to identify agents for modulating the gut microbiota as a therapeutic or preventative approach for coeliac disease. […] In this Review, we summarize the current evidence for altered gut microbiota composition in coeliac disease and discuss how the interplay between host genetics, environmental factors and the intestinal microbiota might contribute to its pathogenesis. […] Moreover, we highlight the importance of utilizing animal models and long-term clinical studies to gain insight into the mechanisms through which host-microbial interactions can influence host responses to gluten.
#59 Celiac Disease by Dr ASHUTOSH CHANDAN DUBEY/Dr STRANGE .pptx
https://www.slideshare.net/slideshow/celiac-disease-by-dr-ashutosh-chandan-dubey-dr-strange-pptx/278782445
The composition of the gut microbiota, including the virome affects the activation of intestinal immune system and development of gluten intolerance. Factors like feeding practices, dietary habits, antibiotic use, frequent viral exposures (coxsackie virus, adenovirus) before 2 years of age could contribute to the onset of CD by altering the microbial composition of the gut.
#60
https://www.jci.org/articles/view/30253
A model that I have proposed to conceptualize the role of the adaptive T cell response in CD pathogenesis divides pathogenesis into 3 phases: luminal and early mucosal events; activation of pathogenic CD4+ T cells; and events leading to tissue damage. […] Does knowledge of the immunopathogenesis of CD suggest alternative or adjunctive therapeutic approaches?
#61 Pathogenesis | Celiac Disease Center at Columbia University Medical Center
https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/
Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. […] As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.
#62 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#63 Celiac disease: a comprehensive current review | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z
Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options. […] A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). […] CD is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well defined.
#64 Coeliac disease – Wikipedia
https://en.wikipedia.org/wiki/Coeliac_disease
The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. […] The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. […] One protease-resistant peptide from -gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. […] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. […] The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel’s mucosal lining and causes malabsorption as it impairs the body’s ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food.
#65 Coeliac disease – Wikipedia
https://en.wikipedia.org/wiki/Coeliac_disease
The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. […] The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. […] One protease-resistant peptide from -gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. […] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. […] The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel’s mucosal lining and causes malabsorption as it impairs the body’s ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food.
#66 Coeliac disease – Wikipedia
https://en.wikipedia.org/wiki/Coeliac_disease
The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. […] The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. […] One protease-resistant peptide from -gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. […] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. […] The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel’s mucosal lining and causes malabsorption as it impairs the body’s ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food.
#67 Coeliac disease – Wikipedia
https://en.wikipedia.org/wiki/Coeliac_disease
The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. […] The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. […] One protease-resistant peptide from -gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. […] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. […] The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel’s mucosal lining and causes malabsorption as it impairs the body’s ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food.
#68 Celiac Disease (Sprue): Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/171805-overview
The interaction of alcohol-soluble gliadin in wheat, barley, and rye with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in the enteric epithelial cells, stimulating the proliferation of the natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes. […] Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium. […] Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.
#69 Celiac Disease (Sprue): Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/171805-overview
The interaction of alcohol-soluble gliadin in wheat, barley, and rye with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in the enteric epithelial cells, stimulating the proliferation of the natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes. […] Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium. […] Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.
#70 Mechanisms of Disease: immunopathogenesis of celiac disease | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/ncpgasthep0582
Celiac disease is a genetic inflammatory disorder with autoimmune components that is induced by the ingestion of dietary gluten. […] Although the importance of the adaptive immune response to gluten has been well established, observations now also point towards a central role for the gluten-induced innate stress response in the pathogenesis of celiac disease and its malignant complications. […] There is emerging evidence that the adaptive and innate immune responses to gluten might exist independently and are both required to induce epithelial cell destruction, which results in villous atrophy and clinical symptoms related to malabsorption.
#71 Celiac disease: pathogenesis of a model immunogenetic disease. – Document – Gale Academic OneFile
https://go.gale.com/ps/i.do?id=GALE%7CA157592730&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=00219738&p=AONE&sw=w
Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] As is discussed in this article, acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] Recent advances in our understanding of the immunopathogenesis of CD might lead to alternative treatments for this disease.
#72 Celiac disease: pathogenesis of a model immunogenetic disease. – Document – Gale Academic OneFile
https://go.gale.com/ps/i.do?id=GALE%7CA157592730&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=00219738&p=AONE&sw=w
Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] As is discussed in this article, acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] Recent advances in our understanding of the immunopathogenesis of CD might lead to alternative treatments for this disease.
#73 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review
https://www.mdpi.com/1422-0067/24/20/15482
Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. […] The immune response in celiac disease triggers inflammation and damage to the mucosa of the small intestine, leading to a range of impacts from gastrointestinal (GI) discomfort to severe malabsorption syndromes. […] As an autoimmune disease with a well-defined environmental trigger (gluten), a strong genetic linkage with HLA-DQ2 and DQ8 haplotypes, and a specific autoantigen, celiac disease presents a compelling model for investigating the cellular and molecular mechanisms of autoimmunity.
#74 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#75 Celiac disease: From pathophysiology to treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/
Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease. Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.
#76 Celiac disease: Managing a multisystem disorder | Cleveland Clinic Journal of Medicine
https://www.ccjm.org/content/83/3/217
Celiac disease is a multisystem autoimmune disorder that can cause symptoms involving the gastrointestinal tract and other organ systems such as the skin and bones. This paper reviews the pathogenesis, diagnosis, and management of celiac disease and associated diseases. […] Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population. […] The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor). […] Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain.
#77 Celiac disease: Managing a multisystem disorder | Cleveland Clinic Journal of Medicine
https://www.ccjm.org/content/83/3/217
Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia. […] Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process. […] The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. […] In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase.
#78 Celiac disease: Managing a multisystem disorder | Cleveland Clinic Journal of Medicine
https://www.ccjm.org/content/83/3/217
Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia. […] Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process. […] The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. […] In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase.
#79 Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation
https://www.mdpi.com/1422-0067/23/24/15564
Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. […] The causal factors and pathophysiological mechanisms of neurological involvement in CD remain controversial. According to recent evidence, these can be related to a gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and, in severe cases, vitamins or nutrients deficiency, as shown in Figure 1.
#80 Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation
https://www.mdpi.com/1422-0067/23/24/15564
Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. […] The causal factors and pathophysiological mechanisms of neurological involvement in CD remain controversial. According to recent evidence, these can be related to a gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and, in severe cases, vitamins or nutrients deficiency, as shown in Figure 1.
#81 Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation
https://www.mdpi.com/1422-0067/23/24/15564
Following the ingestion of gluten-containing food, proline-rich gliadin peptides (the antigenic component of gluten) are deamidated by intestinal issue transglutaminases 2 (TG2), a family of enzymes widely expressed in the body, as shown in Figure 1. This results in a gliadin-modified epitope with a greater affinity for human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 pockets in the antigen-presenting cells (APCs). The subsequent CD4 + T-cell activation leads to cytokines release and activation of metalloproteinases (MMP), eventually resulting in mucosal remodeling, intestinal villus atrophy, activation of lymphocytes B, and the production of antibodies to gluten (AGA) and autoantibodies to TG2 (ATG2A). […] Moreover, studies have demonstrated that gliadin accelerates the disassembling of intercellular junctional proteins via the epidermal growth factor receptor (EGFR) pathway activation and by the downregulation of peroxisome proliferation activated receptor Î³ (PPAR-Î³) gene and intestinal tight junctions (TJ) proteins zonulin-1 (ZO-1), claudin-1, and occluding. The loss of the intestinal barrier leads to increased access for gut-derived molecules (e.g., gliadin antigen itself, biomolecular aggregates, extracellular vesicles, AGA, ATG2A, inflammatory mediators, etc.) to enter the blood circulation and contribute to neurological manifestations by direct toxicity, immune complex deposition, and production of cross-reacting antibodies, all affecting the so-called âgut microbiota-brain axisâ. […] Intestinal microbiota-derived products (such as antigens, toxins, miRNA, etc.), indeed, can be found in the brain compartments of CD subjects.
#82 Celiac Disease: Symptoms & How It’s Treated
https://my.clevelandclinic.org/health/diseases/14240-celiac-disease
Complications of chronic inflammation can include: Compromised immunity. When your immune system is chronically overactive, it’s left with fewer resources to address an acute attack, such as an infection. […] Chronic inflammation leads to an increased risk of cancer in your small intestine. Studies show about 7% of people with celiac disease develop intestinal lymphomas, usually after several decades.
#83 Celiac Disease: Symptoms & How It’s Treated
https://my.clevelandclinic.org/health/diseases/14240-celiac-disease
Complications of chronic inflammation can include: Compromised immunity. When your immune system is chronically overactive, it’s left with fewer resources to address an acute attack, such as an infection. […] Chronic inflammation leads to an increased risk of cancer in your small intestine. Studies show about 7% of people with celiac disease develop intestinal lymphomas, usually after several decades.
#84 Celiac Disease: Symptoms & How It’s Treated
https://my.clevelandclinic.org/health/diseases/14240-celiac-disease
Damage to your small intestine can have serious consequences. Your small intestine absorbs nutrients from your food through the mucosa. If the mucosa is damaged, it won’t be able to absorb nutrients as it should. This is called malabsorption. […] Many autoimmune diseases, like celiac disease, are at least partly inherited (genetic disorders). That means a particular gene variant that’s passed down through family lines makes you more susceptible to developing it. […] One theory is that it’s triggered by some type of significant physical stress that overextends your immune system. […] Celiac disease can appear at any age after you or your child has begun eating gluten. […] If you go many years before being diagnosed or you don’t succeed in avoiding gluten afterward, the effects of celiac disease can be more severe and long-lasting. Malnutrition can affect your nervous system and skeletal system and some of these effects are hard to reverse, especially when they occur during childhood development. Chronic inflammation (enteritis) can also lead to other problems in your intestine.
#85 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. […] Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. […] We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. […] We highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity.
#86 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. […] Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. […] We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. […] We highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity.
#87 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. […] Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. […] We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. […] We highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity.
#88 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
Our study confirmed previous findings based on GWAS and immunological studies pertinent to CD pathogenesis and describes novel genes and pathways that with further validation may be found to contribute to the early steps in the pathogenesis of CD, ongoing inflammation, and comorbidities associated with CD. […] Despite the well described pathogenic role of the adaptive immune response in CD, a complete understanding of the pathophysiology of CD, particularly concerning the early steps leading to loss of tolerance to gluten, are poorly defined. […] Our work provides a base from which further investigation may validate and mechanistically link these findings to previously unknown aspects of the pathogenesis of CD. […] Our findings support a possible link between the microbiome, innate immune response, and the development of CD and highlight possible associations that with future validation may lead to crucial knowledge of the steps leading to loss of tolerance to gluten.
#89 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
Our findings that patients with active CD had an upregulation in cytokine-cytokine receptor interaction and the chemokine signaling pathway is expected given our understanding of CD pathogenesis and the inflammation associated with active CD. […] Our analysis identified the upregulation of cell adhesion molecules such as IGSF4 and others involved in leukocyte transendothelial migration such as ITAGAM in active CD. […] An upregulation of spliceosome pathways has not been described before in CD. […] Our data shows an upregulation of IL-17. […] Our findings are supported by previous studies suggesting the early diagnosis of CD prevents the development of further autoimmune disease and that comorbid autoimmune conditions improve with CD treatment.
#90 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132
Our findings that patients with active CD had an upregulation in cytokine-cytokine receptor interaction and the chemokine signaling pathway is expected given our understanding of CD pathogenesis and the inflammation associated with active CD. […] Our analysis identified the upregulation of cell adhesion molecules such as IGSF4 and others involved in leukocyte transendothelial migration such as ITAGAM in active CD. […] An upregulation of spliceosome pathways has not been described before in CD. […] Our data shows an upregulation of IL-17. […] Our findings are supported by previous studies suggesting the early diagnosis of CD prevents the development of further autoimmune disease and that comorbid autoimmune conditions improve with CD treatment.
#91 Investigating intestinal epithelium metabolic dysfunction in celiac disease using personalized genome-scale models | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03854-0
Celiac disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Chronic inflammation and tissue damage associated with CeD disrupt the intricate network of metabolic processes in sIECs that support these functions, impairing their ability to perform their essential roles. However, the specific disrupted metabolic processes underlying sIECs dysfunction in CeD remain largely undefined. […] Significant alterations in the activity of 28 essential metabolic tasks were observed in active CeD and remission CeD, impacting critical processes integral to sIECs function such as oxidative stress regulation, nucleotide synthesis and DNA repair, energy production, and polyamine and amino acid metabolism.
#92 Investigating intestinal epithelium metabolic dysfunction in celiac disease using personalized genome-scale models | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03854-0
These findings offer a foundation for developing therapeutic interventions targeting impaired metabolic processes in CeD. […] The critical functions of sIECs rely on a complex, finely tuned network of metabolic processes that support energy production, cell growth, and synthesis of essential bioactive compounds. Chronic inflammation and tissue destruction in CeD disrupt these metabolic networks in sIECs. These metabolic disruptions significantly compromise several aspects of gut health relevant to CeD such as nutrient absorption and digestion, gut barrier integrity, immune cell interactions, and the overall inflammatory response to gluten. […] This study presents a rigorous and quantitative exploration of sIECs metabolic dysfunction in CeD by leveraging highly personalized GEMs of metabolism that incorporate patient-specific transcriptional data and sex-specific parameters. Our findings provide new insights into the dysregulation of specific metabolic processes within sIECs in CeD, shedding light on novel avenues for therapeutic intervention and personalized treatment strategies.
#93 Investigating intestinal epithelium metabolic dysfunction in celiac disease using personalized genome-scale models | BMC Medicine | Full Text
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03854-0
These findings offer a foundation for developing therapeutic interventions targeting impaired metabolic processes in CeD. […] The critical functions of sIECs rely on a complex, finely tuned network of metabolic processes that support energy production, cell growth, and synthesis of essential bioactive compounds. Chronic inflammation and tissue destruction in CeD disrupt these metabolic networks in sIECs. These metabolic disruptions significantly compromise several aspects of gut health relevant to CeD such as nutrient absorption and digestion, gut barrier integrity, immune cell interactions, and the overall inflammatory response to gluten. […] This study presents a rigorous and quantitative exploration of sIECs metabolic dysfunction in CeD by leveraging highly personalized GEMs of metabolism that incorporate patient-specific transcriptional data and sex-specific parameters. Our findings provide new insights into the dysregulation of specific metabolic processes within sIECs in CeD, shedding light on novel avenues for therapeutic intervention and personalized treatment strategies.
#94
https://grantome.com/grant/NIH/R01-DK098435-06
The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of tolerance (LOT) to oral antigen and induce celiac disease (CD) and to design strategies to prevent virus-induced LOT and CD onset. […] CD is a T cell-mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. […] Reoviruses are human dsRNA viruses recently linked to CD. […] We discovered that reovirus strain T1L abrogates tolerance to dietary antigens including gluten using a pathway dependent on IRF1, whereas strain T3D-RV does not. […] We propose to enhance an understanding of how viruses influence the development of autoimmune inflammatory disorders and prevent CD by identifying virus and host factors that influence LOT to dietary antigen and defining strategies to block virus-induced LOT and CD development. […] Knowledge gained through these efforts will enhance an understanding of how viral infections lead to the development of gastrointestinal inflammatory disorders and foster new strategies to prevent CD in genetically vulnerable individuals.
#95
https://grantome.com/grant/NIH/R01-DK098435-06
The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of tolerance (LOT) to oral antigen and induce celiac disease (CD) and to design strategies to prevent virus-induced LOT and CD onset. […] CD is a T cell-mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. […] Reoviruses are human dsRNA viruses recently linked to CD. […] We discovered that reovirus strain T1L abrogates tolerance to dietary antigens including gluten using a pathway dependent on IRF1, whereas strain T3D-RV does not. […] We propose to enhance an understanding of how viruses influence the development of autoimmune inflammatory disorders and prevent CD by identifying virus and host factors that influence LOT to dietary antigen and defining strategies to block virus-induced LOT and CD development. […] Knowledge gained through these efforts will enhance an understanding of how viral infections lead to the development of gastrointestinal inflammatory disorders and foster new strategies to prevent CD in genetically vulnerable individuals.
#96
https://grantome.com/grant/NIH/R01-DK098435-06
The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of tolerance (LOT) to oral antigen and induce celiac disease (CD) and to design strategies to prevent virus-induced LOT and CD onset. […] CD is a T cell-mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. […] Reoviruses are human dsRNA viruses recently linked to CD. […] We discovered that reovirus strain T1L abrogates tolerance to dietary antigens including gluten using a pathway dependent on IRF1, whereas strain T3D-RV does not. […] We propose to enhance an understanding of how viruses influence the development of autoimmune inflammatory disorders and prevent CD by identifying virus and host factors that influence LOT to dietary antigen and defining strategies to block virus-induced LOT and CD development. […] Knowledge gained through these efforts will enhance an understanding of how viral infections lead to the development of gastrointestinal inflammatory disorders and foster new strategies to prevent CD in genetically vulnerable individuals.
#97 Organoid models elucidate Celiac disease pathogenesis | Immunopaedia
https://www.immunopaedia.org.za/breaking-news/organoid-models-elucidate-celiac-disease-pathogenesis/
Recent advancements in tissue engineering have yielded a powerful tool for investigating complex diseases: organoids. […] In the context of celiac disease, intestinal organoids have emerged as a valuable model system to elucidate disease mechanisms. […] The data suggest a pivotal role for IL-7 in orchestrating the inflammatory cascade that underlies celiac disease pathogenesis. […] The development of organoid technology represents a significant leap forward in celiac disease research. By providing a more physiologically relevant model compared to traditional cell culture or animal studies, organoids enable precise dissection of disease mechanisms and facilitate the evaluation of novel therapeutic strategies.
#98 Organoid models elucidate Celiac disease pathogenesis | Immunopaedia
https://www.immunopaedia.org.za/breaking-news/organoid-models-elucidate-celiac-disease-pathogenesis/
Recent advancements in tissue engineering have yielded a powerful tool for investigating complex diseases: organoids. […] In the context of celiac disease, intestinal organoids have emerged as a valuable model system to elucidate disease mechanisms. […] The data suggest a pivotal role for IL-7 in orchestrating the inflammatory cascade that underlies celiac disease pathogenesis. […] The development of organoid technology represents a significant leap forward in celiac disease research. By providing a more physiologically relevant model compared to traditional cell culture or animal studies, organoids enable precise dissection of disease mechanisms and facilitate the evaluation of novel therapeutic strategies.
#99 Organoid models elucidate Celiac disease pathogenesis | Immunopaedia
https://www.immunopaedia.org.za/breaking-news/organoid-models-elucidate-celiac-disease-pathogenesis/
Recent advancements in tissue engineering have yielded a powerful tool for investigating complex diseases: organoids. […] In the context of celiac disease, intestinal organoids have emerged as a valuable model system to elucidate disease mechanisms. […] The data suggest a pivotal role for IL-7 in orchestrating the inflammatory cascade that underlies celiac disease pathogenesis. […] The development of organoid technology represents a significant leap forward in celiac disease research. By providing a more physiologically relevant model compared to traditional cell culture or animal studies, organoids enable precise dissection of disease mechanisms and facilitate the evaluation of novel therapeutic strategies.
#100 Organoid models elucidate Celiac disease pathogenesis | Immunopaedia
https://www.immunopaedia.org.za/breaking-news/organoid-models-elucidate-celiac-disease-pathogenesis/
Recent advancements in tissue engineering have yielded a powerful tool for investigating complex diseases: organoids. […] In the context of celiac disease, intestinal organoids have emerged as a valuable model system to elucidate disease mechanisms. […] The data suggest a pivotal role for IL-7 in orchestrating the inflammatory cascade that underlies celiac disease pathogenesis. […] The development of organoid technology represents a significant leap forward in celiac disease research. By providing a more physiologically relevant model compared to traditional cell culture or animal studies, organoids enable precise dissection of disease mechanisms and facilitate the evaluation of novel therapeutic strategies.
#101 Novel players in coeliac disease pathogenesis: role of the gut microbiota | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/nrgastro.2015.90
The intestinal microbiota coexists with its host in a continuum between homeostasis and pathogenicity; the upper gastrointestinal tract harbours a gut microbiota that is affected compositionally and metabolically by food components. […] Coeliac disease is a chronic immune-mediated enteropathy caused by dietary gluten in genetically susceptible individuals. […] The role of microbial factors in coeliac disease pathogenesis has been suggested. […] Although clinical studies demonstrate that microbial changes are associated with coeliac disease, the individual microbes involved and underlying mechanisms remain elusive. […] Emerging data in gnotobiotic models indicate that the intestinal microbiota has a complex modulatory role in host immune responses to gluten. […] A deeper understanding of the precise role of microbes in coeliac disease pathogenesis will aid in the development of microbiota-modulating strategies, such as probiotics, to prevent or help treat the disease.
#102 Celiac disease: pathogenesis of a model immunogenetic disease. – Document – Gale Academic OneFile
https://go.gale.com/ps/i.do?id=GALE%7CA157592730&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=00219738&p=AONE&sw=w
Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] As is discussed in this article, acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] Recent advances in our understanding of the immunopathogenesis of CD might lead to alternative treatments for this disease.
#103
https://www.jci.org/articles/view/30253/citations
Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. […] Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] This article focuses on the role of adaptive and innate immune mechanisms in the pathogenesis of celiac disease and how current concepts of immunopathogenesis might provide alternative approaches for treating celiac disease.
#104 Open Access Macedonian Journal of Medical Sciences (OAMJMS).
https://oamjms.eu/index.php/mjms/article/view/11024
Celiac disease is a complex polygenic systemic disorder caused by dietary gluten exposure that selectively occurs in genetically susceptible people. […] The need to develop non-dietary treatment methods is widely recognized, but this is prevented by the absence of a pathophysiologically relevant preclinical model. Nonetheless, in vitro and in vivo models have made it possible to investigate the mechanisms of the disease and develop new treatment approaches: The use of foods with neutralized gluten, microbiota correction, cocktails of specific endoproteinase, polymer gluten binders, specific inhibitors of transglutaminases and inflammatory cytokines, and a vaccine based on allergen-specific therapy. […] Celiac disease pathophysiology. […] Modern ideas about the pathogenetic mechanisms of celiac disease: A decisive role in the clinical course.
#105 Targeting gluten: Researchers delete proteins in wheat harmful to people with celiac disease
https://phys.org/news/2025-05-gluten-delete-proteins-wheat-people.html
Wheat is a major source of calories, carbohydrates and protein worldwide, and its distinctive gluten proteins are what gives bread and pasta dough texture and elasticity. But it also can cause autoimmune reactions such as celiac disease, which is growing in prevalence worldwide. […] Researchers at the University of California, Davis, have deleted a cluster of genes in wheat that generates gluten proteins that can trigger immune reactions without harming the breadmaking quality of this globally nutritious crop. […] „The gluten proteins we eliminated are the ones that trigger the strongest response in people with celiac disease, and their elimination can reduce the risk of triggering the disease in people without celiac disease,” Dubcovsky said. […] The research team used gamma radiation to target and delete alpha-gliadins, which can cause severe reactions in people with celiac disease.
#106 Targeting gluten: Researchers delete proteins in wheat harmful to people with celiac disease
https://phys.org/news/2025-05-gluten-delete-proteins-wheat-people.html
Wheat is a major source of calories, carbohydrates and protein worldwide, and its distinctive gluten proteins are what gives bread and pasta dough texture and elasticity. But it also can cause autoimmune reactions such as celiac disease, which is growing in prevalence worldwide. […] Researchers at the University of California, Davis, have deleted a cluster of genes in wheat that generates gluten proteins that can trigger immune reactions without harming the breadmaking quality of this globally nutritious crop. […] „The gluten proteins we eliminated are the ones that trigger the strongest response in people with celiac disease, and their elimination can reduce the risk of triggering the disease in people without celiac disease,” Dubcovsky said. […] The research team used gamma radiation to target and delete alpha-gliadins, which can cause severe reactions in people with celiac disease.
#107
https://link.springer.com/article/10.1007/s11894-016-0512-2
Celiac disease is the most common oral intolerance in Western countries. It results from an immune response towards gluten proteins from certain cereals in genetically predisposed individuals (HLA-DQ2 and/or HLA-DQ8). Its pathogenesis involves the adaptive (HLA molecules, transglutaminase 2, dendritic cells, and CD4+ T-cells) and the innate immunity with an IL-15-mediated response elicited in the intraepithelial compartment. […] Multidisciplinary studies have provided a deeper insight of the genetic and immunological factors and their interaction with the microbiota in the pathogenesis of the disease. […] A better understanding of the composition of the toxic gluten peptides has improved the ways to detect them in food and drinks and how to monitor GFD compliance via non-invasive approaches. […] Integration of genetic and immunological insights into a model of celiac disease pathogenesis. […] IL-15: a central regulator of celiac disease immunopathology. […] Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.