Autoimmunologiczne zapalenie trzustki – Patofizjologia i mechanizm

Autoimmunologiczne zapalenie trzustki
Patofizjologia i mechanizm

Autoimmunologiczne zapalenie trzustki (AIP) to choroba o podłożu autoimmunologicznym, charakteryzująca się naciekiem komórek immunologicznych w tkance trzustkowej i dobrą odpowiedzią na terapię steroidową. Wyróżnia się trzy typy AIP: typ 1 (AIP-1), związany z IgG4 i chorobą wielonarządową; typ 2 (AIP-2), niezwiązany z IgG4, z naciekiem neutrofilowym i możliwą rolą limfocytów Th17; oraz typ 3 (AIP-3), indukowany inhibitorami punktów kontrolnych układu immunologicznego. Patogeneza AIP-1 obejmuje aktywację receptorów Toll-podobnych (TLR), plazmacytoidalnych komórek dendrytycznych (pDC) oraz cytokiny IL-33, która stymuluje odpowiedź Th2 i produkcję cytokin fibrogennych (IL-4, IL-13). W AIP-2 obserwuje się nadekspresję IL-8 i nacieki neutrofilowe, a w AIP-3 dominują limfocyty T CD8+. Genetyczne czynniki ryzyka obejmują haplotypy HLA DRB1*0405 i DQB1*0401 oraz polimorfizmy CTLA4. W diagnostyce istotne są podwyższone stężenia IgG4 oraz obecność autoprzeciwciał, takich jak ALF i CA-II, a także immunofenotyp limfocytów T CD4+ i CD8+ z ekspresją HLA-DR.

Patogeneza autoimmunologicznego zapalenia trzustki

Typy autoimmunologicznego zapalenia trzustki

Mechanizmy immunologiczne w autoimmunologicznym zapaleniu trzustki

Patogeneza AIP typu 1
Patogeneza AIP typu 2
Patogeneza AIP typu 3

Mechanizmy autoimmunologiczne

Odpowiedź immunologiczna komórkowa
Odpowiedź immunologiczna humoralna

Rola mikrobioty jelitowej
Czynniki genetyczne
Progresja do przewlekłego zapalenia trzustki
Podsumowanie

Kolejne rozdziały

Patogeneza autoimmunologicznego zapalenia trzustki

Autoimmunologiczne zapalenie trzustki (AIP) to stosunkowo niedawno odkryta forma zapalenia trzustki, która wyróżnia się jako choroba, którą można wyleczyć farmakologicznie. Sklasyfikowanie AIP jako zaburzenia autoimmunologicznego opiera się na obserwacji, że choroba związana jest z naciekiem komórek immunologicznych w tkance trzustkowej oraz wykazuje dramatyczną odpowiedź na terapię steroidową ¹². Mimo postępów w diagnostyce i leczeniu, dokładna patogeneza AIP wciąż pozostaje niewyjaśniona, a rozpoznanie wymaga kompleksowej oceny klinicznej, radiologicznej, serologicznej i patologicznej ³.

Typy autoimmunologicznego zapalenia trzustki

Wyróżniamy dwa główne typy autoimmunologicznego zapalenia trzustki, które różnią się patofizjologicznie:

Typ 1 (AIP-1) – nazywany również limfoplazmocytowym stwardniającym zapaleniem trzustki (LPSP), uważany jest za trzustkową manifestację choroby wielonarządowej związanej z IgG4. Jest częstszy w krajach azjatyckich ⁴⁵.
Typ 2 (AIP-2) – znany również jako idiopatyczne zapalenie trzustki z naciekiem przewodowym (IDCP), jest częstszy w krajach zachodnich i nie wykazuje predylekcji płciowej. Jest to choroba specyficzna dla trzustki, niezwiązana z IgG4 ⁶⁷.
Typ 3 (AIP-3) – wywoływany jest przez terapię inhibitorami punktów kontrolnych układu immunologicznego i zwykle jest bezobjawowy lub daje łagodne objawy ⁸.

Mechanizmy immunologiczne w autoimmunologicznym zapaleniu trzustki

Patogeneza AIP typu 1

Patogeneza AIP-1 nie jest jeszcze w pełni poznana, a wiele szczegółów pozostaje niejasnych. W rozwój IgG4-RD (choroby związanej z IgG4) zaangażowany jest zarówno wrodzony, jak i adaptacyjny układ odpornościowy ⁹.

Receptory Toll-podobne (TLR) są receptorami rozpoznającymi wzorce molekularne (PRR), które aktywowane są przez antygeny, takie jak bakterie jelitowe, i stanowią istotny składnik odporności wrodzonej. Nadekspresja niektórych typów receptorów TLR w trzustce i gruczołach ślinowych pacjentów z AIP i IgG4-RD podkreśla centralną rolę wrodzonego układu odpornościowego w rozwoju AIP-1 ¹⁰¹¹.

Plazmacytoidalne komórki dendrytyczne (pDC) również odgrywają kluczową rolę w patogenezie AIP u myszy i ludzi. pDC stanowią niewielki odsetek ludzkich komórek immunologicznych, ale są głównym komórkowym źródłem interferonów typu I (IFN-I) i odgrywają kluczową rolę w obronie gospodarza przed zakażeniami mikrobiologicznymi ¹². W mysim modelu AIP wykazano, że pDC wytwarzają IL-33 pod wpływem stymulacji interferonami typu I. Blokowanie sygnalizacji zależnej od IL-33 za pomocą przeciwciała neutralizującego jego receptor (ST2) wiązało się ze zmniejszeniem zapalenia trzustki i rozwoju włóknienia ¹³.

Patogenna rola IL-33 odzwierciedla się w jej zdolności do stymulowania nieprawidłowej odpowiedzi Th2 z następczą produkcją cytokin fibrogennych, takich jak interleukina 4 (IL-4) i interleukina 13 (IL-13). Stężenia IFN typu I i IL-33 wydają się być podwyższone zarówno w tkankach, jak i surowicy pacjentów z IgG4-RD, co sugeruje możliwość wykorzystania IL-33 jako nowego biomarkera IgG4-RD ¹⁴. IL-33 jest bezpośrednio związana z mechanizmami odporności adaptacyjnej zaangażowanymi w patogenezę AIP-1, ponieważ jest w stanie promować aktywację komórek Th2, komórek T pomocniczych typu 1 (Th1), wrodzonych limfoidalnych komórek grupy 2 (ILC2s), a także regulatorowych limfocytów T (Tregs) ¹⁵.

Dodatkowo do aktywacji limfocytów T pomocniczych i regulatorowych CD4+, która następuje po interakcji między TLR a MHC-II, również interakcja między komórkami T helper pęcherzykowych (Tfh), zwłaszcza krążącymi komórkami Tfh typu 1, a SLAMF7, członkiem rodziny receptorów Signaling Lymphocyte Activation Molecule, promuje uwalnianie IgG4 ¹⁶. Najnowsze badania wykazały, że SLAMF7+ CD4+ CTLs są zwiększone we krwi obwodowej osób z aktywną IgG4-RD, co wskazuje na ich kluczową rolę patologiczną w chorobie ¹⁷.

Patogeneza AIP typu 2

Patogeneza AIP-2 jest mniej poznana w porównaniu do AIP-1. AIP-2 charakteryzuje się zapaleniem bogatym w neutrofile. Szczególnie zmiany nabłonkowe granulocytowe (GEL), składające się z nacieków neutrofilowych w przewodach, są głównym histologicznym objawem choroby ¹⁸¹⁹.

Zasugerowano możliwą rolę Th-17 w rozwoju choroby. Podfrakcja efektorowych limfocytów T CD4+ Th-17 odgrywa kluczową rolę w infiltracji okołoprzewodowej tkanki trzustkowej, gdzie uwalniają cytokiny zapalne, głównie IL-17, IL-21, IL-22 i IL-23 ²⁰.

Hipotezę genetyczną zaproponowali Dong i wsp., którzy stwierdzili obecność mutacji genów wielogruczołowego zespołu endokrynnego typu 1 (MEN1) i wielotorbielowatości nerek i wątroby 1 (PKHD1) w AIP-2 ²¹.

Niedawno wykryto nadekspresję IL-8 w tkankach trzustkowych pacjentów z AIP-2. Główne funkcje IL-8 to angiogeneza i chemotaksja neutrofilów, umożliwiająca im migrację do miejsca zapalenia ²².

Patogeneza AIP typu 3

Etiopatogeneza AIP-3 jest ściśle związana z podawaniem inhibitorów punktów kontrolnych układu immunologicznego, które wyzwalają niespecyficzną zapalną odpowiedź immunologiczną mediowaną przez limfocyty T, głównie limfocyty T CD8+, co prowadzi do zwiększonego stosunku limfocytów T CD8+/CD4+ ²³.

Mechanizmy autoimmunologiczne

Odpowiedź immunologiczna komórkowa

Trzustka pacjenta z AIP często jest infiltrowana przez różne typy komórek immunologicznych, w tym limfocyty T CD4-dodatnie i granulocyty w typie 2 AIP lub komórki plazmatyczne produkujące IgG4 i antygen limfocytów B CD20 w typie 1 AIP. Limfocyty T CD4 lub CD8 i komórki plazmatyczne niosące IgG4 zostały znalezione w miąższu trzustki i innych zajętych narządach w AIP ²⁴.

Wydaje się, że czynniki regulujące funkcję komórek T wpływają na rozwój AIP. Antygen 4 związany z cytotoksycznymi limfocytami T (CTLA4) jest receptorem hamującym ekspresję na powierzchni komórek aktywowanych pamięciowych limfocytów T i na regulatorowych limfocytach T CD4+ CD25+, i działa w dużej mierze jako negatywny regulator odpowiedzi limfocytów T ²⁵.

CTLA4 może modulować pozytywne sygnały kostymulujące komórki T, konkurując z cząsteczką CD28 o wiązanie z cząsteczkami B7 CD80 i CD86 zlokalizowanymi na komórkach prezentujących antygen. Polimorfizm pojedynczego nukleotydu (SNP) + 6230G/A w regionie 3′ niepodlegającym translacji genu CTLA4 został również znaleziony w chorobie Gravesa, cukrzycy typu 1, a Umemura i wsp. wykazali, że AIP jest ściśle związane z polimorfizmem CTLA4 + 6230 i poziomami sCTLA4 w surowicy, oraz że gen CTLA4 odgrywa ważną rolę w patogenezie AIP ²⁶²⁷.

Badania pokazują, że równowaga immunologiczna Th1/Th2 jest ważnym czynnikiem w patogenezie AIP. W IgG4-RD (w tym AIP typu 1), równowaga immunologiczna typu Th2 odgrywa istotną rolę. Produkcja IgG4 może odzwierciedlać nadekspresję cytokin przeciwzapalnych, takich jak IL-10. Te odkrycia sugerują, że IgG4 nie działa jako czynnik patogenny, ani jako czynnik przeciwzapalny w AIP typu 1 ²⁸.

W początkowej fazie AIP typu 1, z powodu zmniejszenia naiwnych Tregs i CD19+CD24highCD27+ Bregs, komórki T efektorowe uczestniczą w uszkodzeniu tkanki. IL-10 i TGF-β z indukowanych Tregs powodują przełączenie komórek B do komórek plazmatycznych produkujących IgG4 oraz włóknienie. Bazofile prowadzą do różnicowania zapalnych monocytów w makrofagi M2, wpływają na produkcję IgG4 poprzez sygnalizację TLR i oddziałują na środowisko immunologiczne Th2. Makrofagi M2 przyczyniają się również do włóknienia i reakcji immunologicznej Th2. Neutrofile także wpływają na produkcję IgG4 poprzez NETs (neutrophil extracellular traps) ²⁹.

Odpowiedź immunologiczna humoralna

Okazjonalne współistnienie AIP z innymi chorobami autoimmunologicznymi sugeruje, że mogą istnieć wspólne antygeny docelowe w trzustce i innych narządach wydzielniczych, takich jak gruczoły ślinowe, drogi żółciowe i kanaliki nerkowe ³⁰³¹.

Zgłoszono szereg autoprzeciwciał, takich jak czynnik reumatoidalny (RF), p-ANCA, ANA, ASMA, AMA, przeciwciała przeciwtarczycowe i przeciwmikrosomalne. Inne autoprzeciwciała, takie jak przeciwciało przeciwlaktoferrynowe (ALF) i przeciwko anhydrazie węglanowej II (CA-II), również zostały zgłoszone. CA-II i ALF są rozpowszechnione w komórkach kilku gruczołów wydzielniczych, a wysoka częstość występowania tych przeciwciał sugeruje, że mogą one być antygenami docelowymi w AIP ³²³³.

Immunohistochemiczne barwienie pokazuje głównie limfocyty T CD3-dodatnie w nacieku okołoprzewodowym, który obejmuje kombinację komórek CD4 i CD8. Komórki CD4 i CD8 zawierają HLA-DR. Antygeny HLA-DR są wyrażane na komórkach przewodów trzustkowych i komórkach T CD4-dodatnich, co sugeruje, że proces autoimmunologiczny jest zaangażowany w zapalenie ³⁴.

Aktywowane limfocyty T CD4+ i CD8+ niosące HLA-DR i CD45RO były podwyższone w obwodowych limfocytach krwi (PBL), jak również w trzustce w AIP w porównaniu do innych przyczyn zapalenia trzustki, takich jak zapalenie związane z alkoholem lub kamicą żółciową ³⁵.

Podobnie jak w zespole Sjögrena czy pierwotnym stwardniającym zapaleniu dróg żółciowych, komórki T CD4+ wykazujące odpowiedź immunologiczną typu Th1 są głównie zaangażowane w rozwój AIP jako komórki efektorowe w porównaniu do komórek T CD4+ typu Th2 ³⁶.

Rola mikrobioty jelitowej

Rosnąca świadomość związku między specyficznymi zmianami w składzie mikrobioty jelitowej a wrodzoną odpowiedzią immunologiczną, a tym samym rozwojem chorób autoimmunologicznych, doprowadziła do hipotezy o możliwej roli mikrobioty w etiopatogenezie AIP, szczególnie K. Pneumoniae ³⁷.

Ostatnie odkrycia wskazują, że aktywacja plazmacytoidalnych komórek dendrytycznych, a następnie intensywna produkcja interferonu typu I i interleukiny-33, odgrywa kluczową rolę w napędzaniu przewlekłych odpowiedzi fibrozapalnych zarówno w mysim, jak i ludzkim AIP ³⁸.

Co więcej, zmiany kompozycyjne w mikrobiocie jelitowej, znane jako dysbioza jelitowa, wywoływały patogenne odpowiedzi interferonu typu I napędzane przez plazmacytoidalne komórki dendrytyczne. Dysbioza jelitowa jest związana z załamaniem funkcji bariery jelitowej ³⁹.

Niedawne badania ujawniły, że zaburzenie bariery jelitowej pogarsza eksperymentalne AIP, ułatwiając translokację patogennych bakterii, takich jak Staphylococcus sciuri, do trzustki z jelit. Wyniki te wskazują, że oś jelito-trzustka leży u podstaw immunopatogenezy AIP, a utrzymanie integralności bariery jelitowej może zapobiec pogorszeniu AIP, hamując kolonizację trzustki przez szkodliwe bakterie jelitowe ⁴⁰⁴¹.

Czynniki genetyczne

Zidentyfikowano kilka genetycznych czynników podatności na AIP typu 1. Odkrycia uzyskane w jednej grupie etnicznej nie zawsze są potwierdzane u pacjentów w innych grupach, co rodzi możliwość, że genetyczne czynniki podatności mogą różnić się między grupami etnicznymi ⁴².

Zgłoszono ścisłe skojarzenie z haplotypami ludzkiego antygenu leukocytowego (HLA) DRB1*0405 i DQB1*0401 u pacjentów z AIP. Zatem prezentacja antygenu wspólnego peptydu limfocytom T przez HLA DRB1*0405 lub HLA DQB1*0401 może wywołać AIP ⁴³.

Odkryto również, że polimorficzne geny (polimorfizm CTLA-4 49A i haplotyp -318C/+ 49A/CT60G) kodujące antygen 4 związany z cytotoksycznymi limfocytami T, kluczowy negatywny regulator odpowiedzi immunologicznej limfocytów T, są związane z AIP w populacji chińskiej ⁴⁴.

Zaobserwowano również, że mutacje DRB1*0405 i DQB1*0401 są znacznie częstsze u pacjentów z AIP w porównaniu do pacjentów z przewlekłym zwapniającym zapaleniem trzustki, nawet jeśli te początkowe i obiecujące odkrycia nie zostały potwierdzone przez dwa niedawne badania. Park i wsp. stwierdzili, że tylko DQB1*0302 miał istotny związek z nawrotem AIP ⁴⁵⁴⁶.

Progresja do przewlekłego zapalenia trzustki

Wyniki kumulatywnych badań sugerują, że AIP może prowadzić do ciężkiego tworzenia kamieni trzustkowych i postępować do potwierdzonego przewlekłego zapalenia trzustki w długim okresie, co może być najprawdopodobniej spowodowane nawrotami choroby i zastojem soku trzustkowego ⁴⁷.

Postulowane są dwa mechanizmy powstawania kamieni trzustkowych w AIP: 1) ciężkie uszkodzenie tkanki przypisywane specyficznym procesom zapalnym choroby; i 2) zastój soku trzustkowego spowodowany zwężeniem przewodu trzustkowego ⁴⁸.

Na podstawie wyników badań zaproponowano hipotezę sekwencyjnego mechanizmu progresji AIP do przewlekłego zapalenia trzustki: wiele przypadków AIP obejmuje obrzęk głowy trzustki w ostrej fazie, z których część prowadzi do długotrwałego zwężenia zarówno przewodu Wirsungu, jak i Santoryniego w tym regionie, co może następnie powodować zastój soku trzustkowego w przewodzie trzustkowym powyżej zwężenia ⁴⁹.

Podsumowanie

Autoimmunologiczne zapalenie trzustki to złożone schorzenie, którego patogeneza nie jest jeszcze w pełni poznana. Badania wskazują na zaangażowanie zarówno wrodzonej, jak i adaptacyjnej odpowiedzi immunologicznej, z kluczową rolą cytokin, komórek prezentujących antygen, limfocytów T i B oraz czynników genetycznych. Mikrobiota jelitowa i oś jelito-trzustka także odgrywają znaczącą rolę w patogenezie AIP.

Lepsze zrozumienie mechanizmów leżących u podstaw AIP może prowadzić do rozwoju nowych strategii terapeutycznych ukierunkowanych na specyficzne szlaki immunologiczne, co może poprawić wyniki leczenia i zmniejszyć ryzyko nawrotów tej choroby. Obecne badania skupiają się na identyfikacji biomarkerów diagnostycznych i predykcyjnych dla AIP, co może ułatwić wczesne rozpoznanie i lepsze monitorowanie odpowiedzi na leczenie.

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Materiały źródłowe

#1 Pathophysiology of autoimmune pancreatitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4024516/
Autoimmune pancreatitis (AIP) is a recently discovered form of pancreatitis and represents one of the diseases of the pancreas which can be cured and healed medically. […] The categorization of AIP as an autoimmune disorder is based on the observation that the disease is associated with the infiltration of immune cells into pancreatic tissue, and that the disease dramatically responds to steroid therapy. […] The pancreas of a patient with AIP is often infiltrated by various types of immune cells, including cluster of differentiation (CD) 4-positive T cells and granulocytes in type 2 AIP or IgG4-producing plasma cells and B-lymphocyte antigen CD20 in type 1 AIP. […] CD4 or CD8 T lymphocytes and IgG4-bearing plasma cells have been found in the pancreatic parenchyma and other involved organs in AIP.
#2 Pathophysiology of autoimmune pancreatitis
https://www.wjgnet.com/2150-5330/full/v5/i1/11.htm
Autoimmune pancreatitis (AIP) is a recently discovered form of pancreatitis and represents one of the diseases of the pancreas which can be cured and healed medically. […] The categorization of AIP as an autoimmune disorder is based on the observation that the disease is associated with the infiltration of immune cells into pancreatic tissue, and that the disease dramatically responds to steroid therapy. […] The pancreas of a patient with AIP is often infiltrated by various types of immune cells, including cluster of differentiation (CD) 4-positive T cells and granulocytes in type 2 AIP or IgG4-producing plasma cells and B-lymphocyte antigen CD20 in type 1 AIP. […] It has also been reported that DRB1*0405 and DQB1*0401 mutations are significantly more frequent in patients with AIP when compared to those with chronic calcifying pancreatitis, even if these initial and promising findings were not confirmed by two recent studies.
#3 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis.
#4 Autoimmune pancreatitis | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/autoimmune-pancreatitis?lang=us
Autoimmune pancreatitis is a type of chronic pancreatitis characterized by a heterogeneous autoimmune inflammatory process in which prominent lymphocytic infiltration with associated fibrosis of the pancreas causes organ dysfunction. […] Three types of autoimmune pancreatitis have been described: type 1 autoimmune pancreatitis (AIP-1), also known as lymphoplasmacytic sclerosing pancreatitis (LPSP), is associated with IgG4-related disease and is more common in Asian countries. […] Type 2 autoimmune pancreatitis (AIP-2), also known as idiopathic ductal centric pancreatitis (IDCP), is more common in Western countries and has no gender predilection. […] Type 3 autoimmune pancreatitis (AIP-3) is caused by immune checkpoint inhibitor therapy and is usually asymptomatic or mildly symptomatic. […] Elevated IgG4 levels in 50% of AIP-1 cases are typically normal in AIP-2 cases, although p-ANCA and c-ANCA autoantibodies are often positive. […] Autoimmune pancreatitis accounts for 2-6% of patients who undergo pancreatic resection because they are suspected of having pancreatic cancer.
#5 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis.
#6 Autoimmune pancreatitis | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/autoimmune-pancreatitis?lang=us
Autoimmune pancreatitis is a type of chronic pancreatitis characterized by a heterogeneous autoimmune inflammatory process in which prominent lymphocytic infiltration with associated fibrosis of the pancreas causes organ dysfunction. […] Three types of autoimmune pancreatitis have been described: type 1 autoimmune pancreatitis (AIP-1), also known as lymphoplasmacytic sclerosing pancreatitis (LPSP), is associated with IgG4-related disease and is more common in Asian countries. […] Type 2 autoimmune pancreatitis (AIP-2), also known as idiopathic ductal centric pancreatitis (IDCP), is more common in Western countries and has no gender predilection. […] Type 3 autoimmune pancreatitis (AIP-3) is caused by immune checkpoint inhibitor therapy and is usually asymptomatic or mildly symptomatic. […] Elevated IgG4 levels in 50% of AIP-1 cases are typically normal in AIP-2 cases, although p-ANCA and c-ANCA autoantibodies are often positive. […] Autoimmune pancreatitis accounts for 2-6% of patients who undergo pancreatic resection because they are suspected of having pancreatic cancer.
#7 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis.
#8 Autoimmune pancreatitis | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/autoimmune-pancreatitis?lang=us
Autoimmune pancreatitis is a type of chronic pancreatitis characterized by a heterogeneous autoimmune inflammatory process in which prominent lymphocytic infiltration with associated fibrosis of the pancreas causes organ dysfunction. […] Three types of autoimmune pancreatitis have been described: type 1 autoimmune pancreatitis (AIP-1), also known as lymphoplasmacytic sclerosing pancreatitis (LPSP), is associated with IgG4-related disease and is more common in Asian countries. […] Type 2 autoimmune pancreatitis (AIP-2), also known as idiopathic ductal centric pancreatitis (IDCP), is more common in Western countries and has no gender predilection. […] Type 3 autoimmune pancreatitis (AIP-3) is caused by immune checkpoint inhibitor therapy and is usually asymptomatic or mildly symptomatic. […] Elevated IgG4 levels in 50% of AIP-1 cases are typically normal in AIP-2 cases, although p-ANCA and c-ANCA autoantibodies are often positive. […] Autoimmune pancreatitis accounts for 2-6% of patients who undergo pancreatic resection because they are suspected of having pancreatic cancer.
#9 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-1 is not yet fully understood, and many details are still unclear. The innate and adaptive immune systems are involved in the development of IgG4-RD. Toll-like receptors are pattern recognition receptors (PRRs) that are activated by antigens such as intestinal bacteria and are an essential component of innate immunity. Overexpression of certain types of Toll-like receptors (TLRs) in the pancreas and salivary glands of patients with AIP and IgG4-RD underscores the central role of the innate immune system in the development of AIP-1. The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. […] In a mouse model of AIP, pDCs were shown to produce IL-33 by stimulation with type I interferons (IFN-I). Blocking IL-33-mediated signaling by a neutralizing antibody (Ab) to its receptor interleukin 1 receptor-like (also called ST2) was associated with a reduction in pancreatic inflammation and fibrosis development. The pathogenic role of IL-33 is reflected in its ability to stimulate an aberrant Th2 response with subsequent production of fibrogenic cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13); concentrations of type 1 IFN and IL-33 appear to be increased in both tissue and serum from patients with IgG4-RD, suggesting the use of IL-33 as a novel IgG4-RD biomarker.
#10 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://www.mdpi.com/1422-0067/23/20/12667
Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. […] The pathogenesis of AIP-1 is not yet fully understood, and many details are still unclear. The innate and adaptive immune systems are involved in the development of IgG4-RD. Toll-like receptors are pattern recognition receptors (PRRs) that are activated by antigens such as intestinal bacteria and are an essential component of innate immunity. Overexpression of certain types of Toll-like receptors (TLRs) in the pancreas and salivary glands of patients with AIP and IgG4-RD underscores the central role of the innate immune system in the development of AIP-1.
#11 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
Autoimmune pancreatitis (AIP) is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas, leading to inflammation and fibrosis. […] Despite numerous attempts, the pathogenesis of AIP-1 is still unclear. As it is the pancreatic manifestation of IgG4-RD, it is a multifactorial disease in which both genetic and environmental factors play a pivotal role. […] The overexpression of certain types of TLRs in the pancreas highlights the central role of the innate immune system in the development of AIP-1. […] The unregulated production of IFN-I and, consequently, of interleukine (IL)-33 by pDCs could underlie AIP-1. […] The role of IgG4 in the development of AIP-1 and IgG4-RD is still unclear, but it is hypothesized that IgG4 may play a role in the activation of the complement system after the presence of immune complexes has been demonstrated in IgG4-RD-affected tissues.
#12 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://www.mdpi.com/1422-0067/23/20/12667
The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. pDCs represent a small percentage of human immune cells but are the major cellular source of type 1 interferons (IFN-I) and play a key role in host defense against microbial infections. […] IL-33 is directly related to the mechanisms of adaptive immunity involved in the pathogenesis of AIP 1, as it is able to promote the activation of Th2 cells, type 1 helper T cells (Th1), innate group 2 lymphoid cells (ILC2s), but also regulatory T cells (Tregs). […] The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested.
#13 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-1 is not yet fully understood, and many details are still unclear. The innate and adaptive immune systems are involved in the development of IgG4-RD. Toll-like receptors are pattern recognition receptors (PRRs) that are activated by antigens such as intestinal bacteria and are an essential component of innate immunity. Overexpression of certain types of Toll-like receptors (TLRs) in the pancreas and salivary glands of patients with AIP and IgG4-RD underscores the central role of the innate immune system in the development of AIP-1. The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. […] In a mouse model of AIP, pDCs were shown to produce IL-33 by stimulation with type I interferons (IFN-I). Blocking IL-33-mediated signaling by a neutralizing antibody (Ab) to its receptor interleukin 1 receptor-like (also called ST2) was associated with a reduction in pancreatic inflammation and fibrosis development. The pathogenic role of IL-33 is reflected in its ability to stimulate an aberrant Th2 response with subsequent production of fibrogenic cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13); concentrations of type 1 IFN and IL-33 appear to be increased in both tissue and serum from patients with IgG4-RD, suggesting the use of IL-33 as a novel IgG4-RD biomarker.
#14 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-1 is not yet fully understood, and many details are still unclear. The innate and adaptive immune systems are involved in the development of IgG4-RD. Toll-like receptors are pattern recognition receptors (PRRs) that are activated by antigens such as intestinal bacteria and are an essential component of innate immunity. Overexpression of certain types of Toll-like receptors (TLRs) in the pancreas and salivary glands of patients with AIP and IgG4-RD underscores the central role of the innate immune system in the development of AIP-1. The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. […] In a mouse model of AIP, pDCs were shown to produce IL-33 by stimulation with type I interferons (IFN-I). Blocking IL-33-mediated signaling by a neutralizing antibody (Ab) to its receptor interleukin 1 receptor-like (also called ST2) was associated with a reduction in pancreatic inflammation and fibrosis development. The pathogenic role of IL-33 is reflected in its ability to stimulate an aberrant Th2 response with subsequent production of fibrogenic cytokines, such as interleukin 4 (IL-4) and interleukin 13 (IL-13); concentrations of type 1 IFN and IL-33 appear to be increased in both tissue and serum from patients with IgG4-RD, suggesting the use of IL-33 as a novel IgG4-RD biomarker.
#15 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://www.mdpi.com/1422-0067/23/20/12667
The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. pDCs represent a small percentage of human immune cells but are the major cellular source of type 1 interferons (IFN-I) and play a key role in host defense against microbial infections. […] IL-33 is directly related to the mechanisms of adaptive immunity involved in the pathogenesis of AIP 1, as it is able to promote the activation of Th2 cells, type 1 helper T cells (Th1), innate group 2 lymphoid cells (ILC2s), but also regulatory T cells (Tregs). […] The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested.
#16 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
In addition to the activation of T helper and T reg CD4+ lymphocytes that follows the interaction between TLRs and MHC-II, also the interaction between T follicular helper (Tfh) cells, especially circulating type 1 Tfh cells, and SLAMF7, a member of the Signaling Lymphocyte Activation Molecule family receptors, promotes IgG4 release. […] Recent studies have shown that SLAMF7+ CD4+ CTLs are increased in the peripheral blood of subjects with active IgG4-RD, and thus represent a key pathological factor in the disease. […] The Th-17 subset of CD4+ effector T cells plays a crucial role in infiltrating the periductal pancreatic tissue, where they release inflammatory cytokines, mainly IL-17, IL-21, IL-22, and IL-23. […] The increasing awareness of the relationship between specific alterations in the composition of the gut microbiota and the innate immunological response, and thus the development of autoimmune diseases, led to the hypothesis of a possible role of the microbiota in the etiopathogenesis of AIP, particularly K. Pneumoniae. […] Finally, the etiopathogenesis of AIP-3 is closely related to the administration of checkpoint inhibitors, which trigger a non-specific inflammatory immune response mediated by T cells, mainly CD8+ T cells, resulting in an increased ratio of CD8+/CD4+ T lymphocytes.
#17 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
In addition to the activation of T helper and T reg CD4+ lymphocytes that follows the interaction between TLRs and MHC-II, also the interaction between T follicular helper (Tfh) cells, especially circulating type 1 Tfh cells, and SLAMF7, a member of the Signaling Lymphocyte Activation Molecule family receptors, promotes IgG4 release. […] Recent studies have shown that SLAMF7+ CD4+ CTLs are increased in the peripheral blood of subjects with active IgG4-RD, and thus represent a key pathological factor in the disease. […] The Th-17 subset of CD4+ effector T cells plays a crucial role in infiltrating the periductal pancreatic tissue, where they release inflammatory cytokines, mainly IL-17, IL-21, IL-22, and IL-23. […] The increasing awareness of the relationship between specific alterations in the composition of the gut microbiota and the innate immunological response, and thus the development of autoimmune diseases, led to the hypothesis of a possible role of the microbiota in the etiopathogenesis of AIP, particularly K. Pneumoniae. […] Finally, the etiopathogenesis of AIP-3 is closely related to the administration of checkpoint inhibitors, which trigger a non-specific inflammatory immune response mediated by T cells, mainly CD8+ T cells, resulting in an increased ratio of CD8+/CD4+ T lymphocytes.
#18 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration, are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested. A genetic hypothesis is proposed by Dong et al., who found the presence of mutations of the multiple endocrine neoplasia 1 (MEN1) and polycystic kidney and liver disease 1 (PKHD1) gene in AIP-2. Recently, overexpression of IL-8 was detected in the affected pancreatic tissues of patients with AIP-2. The main functions of IL-8 are angiogenesis and chemotaxis of neutrophils, allowing them to migrate to the site of inflammation.
#19 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://www.mdpi.com/1422-0067/23/20/12667
The plasmacytoid dendritic cells (pDCs) may also play a key role in the pathogenesis of murine AIP and also human AIP/IgG4-RD. pDCs represent a small percentage of human immune cells but are the major cellular source of type 1 interferons (IFN-I) and play a key role in host defense against microbial infections. […] IL-33 is directly related to the mechanisms of adaptive immunity involved in the pathogenesis of AIP 1, as it is able to promote the activation of Th2 cells, type 1 helper T cells (Th1), innate group 2 lymphoid cells (ILC2s), but also regulatory T cells (Tregs). […] The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested.
#20 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
In addition to the activation of T helper and T reg CD4+ lymphocytes that follows the interaction between TLRs and MHC-II, also the interaction between T follicular helper (Tfh) cells, especially circulating type 1 Tfh cells, and SLAMF7, a member of the Signaling Lymphocyte Activation Molecule family receptors, promotes IgG4 release. […] Recent studies have shown that SLAMF7+ CD4+ CTLs are increased in the peripheral blood of subjects with active IgG4-RD, and thus represent a key pathological factor in the disease. […] The Th-17 subset of CD4+ effector T cells plays a crucial role in infiltrating the periductal pancreatic tissue, where they release inflammatory cytokines, mainly IL-17, IL-21, IL-22, and IL-23. […] The increasing awareness of the relationship between specific alterations in the composition of the gut microbiota and the innate immunological response, and thus the development of autoimmune diseases, led to the hypothesis of a possible role of the microbiota in the etiopathogenesis of AIP, particularly K. Pneumoniae. […] Finally, the etiopathogenesis of AIP-3 is closely related to the administration of checkpoint inhibitors, which trigger a non-specific inflammatory immune response mediated by T cells, mainly CD8+ T cells, resulting in an increased ratio of CD8+/CD4+ T lymphocytes.
#21 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration, are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested. A genetic hypothesis is proposed by Dong et al., who found the presence of mutations of the multiple endocrine neoplasia 1 (MEN1) and polycystic kidney and liver disease 1 (PKHD1) gene in AIP-2. Recently, overexpression of IL-8 was detected in the affected pancreatic tissues of patients with AIP-2. The main functions of IL-8 are angiogenesis and chemotaxis of neutrophils, allowing them to migrate to the site of inflammation.
#22 Autoimmune Pancreatitis: From Pathogenesis to Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9604056/
The pathogenesis of AIP-2 is less known compared to AIP-1. AIP-2 is characterized by neutrophil-rich inflammation. In particular, granulocytic epithelial lesions (GELs), consisting of neutrophilic ductal infiltration, are the major histologic finding of the disease. A possible role of Th-17 in the development of the disease was suggested. A genetic hypothesis is proposed by Dong et al., who found the presence of mutations of the multiple endocrine neoplasia 1 (MEN1) and polycystic kidney and liver disease 1 (PKHD1) gene in AIP-2. Recently, overexpression of IL-8 was detected in the affected pancreatic tissues of patients with AIP-2. The main functions of IL-8 are angiogenesis and chemotaxis of neutrophils, allowing them to migrate to the site of inflammation.
#23 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
In addition to the activation of T helper and T reg CD4+ lymphocytes that follows the interaction between TLRs and MHC-II, also the interaction between T follicular helper (Tfh) cells, especially circulating type 1 Tfh cells, and SLAMF7, a member of the Signaling Lymphocyte Activation Molecule family receptors, promotes IgG4 release. […] Recent studies have shown that SLAMF7+ CD4+ CTLs are increased in the peripheral blood of subjects with active IgG4-RD, and thus represent a key pathological factor in the disease. […] The Th-17 subset of CD4+ effector T cells plays a crucial role in infiltrating the periductal pancreatic tissue, where they release inflammatory cytokines, mainly IL-17, IL-21, IL-22, and IL-23. […] The increasing awareness of the relationship between specific alterations in the composition of the gut microbiota and the innate immunological response, and thus the development of autoimmune diseases, led to the hypothesis of a possible role of the microbiota in the etiopathogenesis of AIP, particularly K. Pneumoniae. […] Finally, the etiopathogenesis of AIP-3 is closely related to the administration of checkpoint inhibitors, which trigger a non-specific inflammatory immune response mediated by T cells, mainly CD8+ T cells, resulting in an increased ratio of CD8+/CD4+ T lymphocytes.
#24 Pathophysiology of autoimmune pancreatitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4024516/
Autoimmune pancreatitis (AIP) is a recently discovered form of pancreatitis and represents one of the diseases of the pancreas which can be cured and healed medically. […] The categorization of AIP as an autoimmune disorder is based on the observation that the disease is associated with the infiltration of immune cells into pancreatic tissue, and that the disease dramatically responds to steroid therapy. […] The pancreas of a patient with AIP is often infiltrated by various types of immune cells, including cluster of differentiation (CD) 4-positive T cells and granulocytes in type 2 AIP or IgG4-producing plasma cells and B-lymphocyte antigen CD20 in type 1 AIP. […] CD4 or CD8 T lymphocytes and IgG4-bearing plasma cells have been found in the pancreatic parenchyma and other involved organs in AIP.
#25 Pathophysiology of autoimmune pancreatitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4024516/
It seems that factors regulating T-cell function influence the development of AIP. […] The cytotoxic T-lymphocyte antigen 4 gene is an inhibitory receptor expressed on the cell surface of activated memory T cells and on CD4+ CD25+ regulatory T cells, and acts largely as a negative regulator of T-cell responses. […] CTLA4 may modulate positive T-cell costimulatory signals by competing with the CD28 molecule for engagement with the B7 molecules CD80 and CD86 localized on antigen-presenting cells. […] The + 6230G/A SNP in the 3 untranslated region of CTLA4 has been also found in Graves disease, type 1 diabetes and Umemura et al have demonstrated that AIP is closely associated with the CTLA4 + 6230 SNP and serum sCTLA4 levels and that CTLA4 gene plays an important role in the pathogenesis of AIP. […] Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells.
#26 Pathophysiology of autoimmune pancreatitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4024516/
It seems that factors regulating T-cell function influence the development of AIP. […] The cytotoxic T-lymphocyte antigen 4 gene is an inhibitory receptor expressed on the cell surface of activated memory T cells and on CD4+ CD25+ regulatory T cells, and acts largely as a negative regulator of T-cell responses. […] CTLA4 may modulate positive T-cell costimulatory signals by competing with the CD28 molecule for engagement with the B7 molecules CD80 and CD86 localized on antigen-presenting cells. […] The + 6230G/A SNP in the 3 untranslated region of CTLA4 has been also found in Graves disease, type 1 diabetes and Umemura et al have demonstrated that AIP is closely associated with the CTLA4 + 6230 SNP and serum sCTLA4 levels and that CTLA4 gene plays an important role in the pathogenesis of AIP. […] Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells.
#27 Pathophysiology of autoimmune pancreatitis
https://www.wjgnet.com/2150-5330/full/v5/i1/11.htm
Furthermore, Park et al found that only DQB1*0302 had a significant association with the relapse of AIP. […] Finally, it has been found that the polymorphic genes (CTLA-4 49A polymorphism and -318C/+ 49A/CT60G haplotype) encoding cytotoxic T lymphocyte-associated antigen 4, a key negative regulator of the T-cell immune response, are associated with AIP in a Chinese population. […] Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells. […] The cytotoxic T-lymphocyte antigen 4 gene is an inhibitory receptor expressed on the cell surface of activated memory T cells and on CD4+ CD25+ regulatory T cells, and acts largely as a negative regulator of T-cell responses. […] The + 6230G/A SNP in the 3 untranslated region of CTLA4 has been also found in Graves disease, type 1 diabetes and Umemura et al have demonstrated that AIP is closely associated with the CTLA4+ 6230 SNP and serum sCTLA4 levels and that CTLA4 gene plays an important role in the pathogenesis of AIP.
#28
https://link.springer.com/article/10.1007/s00535-018-1440-8
In 1995, Yoshida and colleagues proposed the concept of autoimmune pancreatitis (AIP), which has recently been recognized as a new pancreatic inflammatory disease. […] Recent research has described the clinical and pathophysiological features of type 1 AIP, but some details remain unclear. […] The pathogenic mechanism of type 1 AIP remains unclear. From the viewpoint of acquired immunity, the Th1/Th2 immune balance is an important consideration. In IgG4-RD (include type 1 AIP), Th2 type immune balance has an important role in the pathogenesis of IgG4-RD. […] Production of IgG4 may reflect over expression of anti-inflammatory cytokines, such as IL-10. These findings suggest that IgG4 does not act as a pathogenic factor, nor is it an anti-inflammatory factor in type 1 AIP. Further studies are necessary to clarify the precise role of IgG4 in IgG4-RD and include type 1 AIP.
#29
https://link.springer.com/article/10.1007/s00535-018-1440-8
We suggest the following pathophysiology of type 1 AIP. In the initial stage of type 1 AIP, because of decreased nave Tregs and CD19+CD24highCD27+ Bregs, effector T-cells are involved in the tissue damage. IL-10 and TGF- from increased inducible Tregs induce the switch from B-cells to IgG4-producing plasma cells and fibrosis, respectively. Basophils lead to differentiation of inflammatory monocytes into M2 macrophages, affect production of IgG4 via TLR signaling, and influence the Th2 immune environment. M2 macrophages also contribute to the fibrosis and Th2 immune reaction. Neutrophils also influence IgG4 production via NETs.
#30 Autoimmune Pancreatitis: Case Series and Review of the Literature.
http://www.annclinlabsci.org/content/39/2/167.long
Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. […] The pathogenesis of AuP remains a mystery. The occasional coexistence of AuP with other auto-immune diseases suggests that there may be common target antigens in the pancreas and the other exocrine organs, such as the salivary glands, biliary tract, and renal tubules. […] A number of autoantibodies such as rheumatoid factor (RF), p-ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II (CA-II) have also been reported. CA-II and ALF are distributed in cells of several exocrine glands and the high prevalence of these antibodies suggests that they might be target antigens in AuP.
#31 Autoimmune Pancreatitis: Case Series and Review of the Literature.
https://www.annclinlabsci.org/content/39/2/167.full
Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. […] The pathogenesis of AuP remains a mystery. The occasional coexistence of AuP with other auto-immune diseases suggests that there may be common target antigens in the pancreas and the other exocrine organs, such as the salivary glands, biliary tract, and renal tubules. […] A number of autoantibodies such as rheumatoid factor (RF), p-ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II (CA-II) have also been reported. CA-II and ALF are distributed in cells of several exocrine glands and the high prevalence of these antibodies suggests that they might be target antigens in AuP.
#32 Autoimmune Pancreatitis: Case Series and Review of the Literature.
http://www.annclinlabsci.org/content/39/2/167.long
Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. […] The pathogenesis of AuP remains a mystery. The occasional coexistence of AuP with other auto-immune diseases suggests that there may be common target antigens in the pancreas and the other exocrine organs, such as the salivary glands, biliary tract, and renal tubules. […] A number of autoantibodies such as rheumatoid factor (RF), p-ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II (CA-II) have also been reported. CA-II and ALF are distributed in cells of several exocrine glands and the high prevalence of these antibodies suggests that they might be target antigens in AuP.
#33 Autoimmune Pancreatitis: Case Series and Review of the Literature.
https://www.annclinlabsci.org/content/39/2/167.full
Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. […] The pathogenesis of AuP remains a mystery. The occasional coexistence of AuP with other auto-immune diseases suggests that there may be common target antigens in the pancreas and the other exocrine organs, such as the salivary glands, biliary tract, and renal tubules. […] A number of autoantibodies such as rheumatoid factor (RF), p-ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II (CA-II) have also been reported. CA-II and ALF are distributed in cells of several exocrine glands and the high prevalence of these antibodies suggests that they might be target antigens in AuP.
#34 Autoimmune Pancreatitis: Case Series and Review of the Literature.
http://www.annclinlabsci.org/content/39/2/167.long
Microscopic findings in AuP show lymphoplasmacytic sclerosing pancreatitis with diffuse lymphoplasmacytic infiltration and pronounced acinar atrophy. […] The histologic hallmark in the pancreas is an intense inflammatory cell infiltrate around medium and large sized interlobular ducts. […] Immunohistochemical staining shows mainly CD3 positive T-lymphocytes in the periductal infiltrate, which includes a combination of CD4 and CD8 cells. The CD4 and CD8 cells contain HLA-DR. The HLA-DR antigens are expressed on pancreatic duct cells and CD4 positive T cells, which suggests that an autoimmune process is involved in the inflammation.
#35 Autoimmune Pancreatitis: Etiology, Pathogenesis, Clinical Finding
https://www.primescholars.com/articles/autoimmune-pancreatitis-etiology-pathogenesis-clinical-findings-and-treatment-the-japanese-experience-98724.html
The occasional coexistence of pancreatitis with other lesions suggests that there may be common target antigens in the pancreas and other exocrine organs such as the salivary gland, biliary tract and renal tubules. […] The activated CD4+ and CD8+ T-cells bearing HLA-DR and CD45RO were elevated in the peripheral blood lymphocytes (PBLs) as well as in the pancreas in AIP as compared to other causes of pancreatitis such as alcoholic or gallstone-related pancreatitis. […] Similar to SjS or PSC, CD4+ T-cells showing the Th1 type of immune response are predominantly involved in the development of AIP as effector cells over Th2 type CD4+ T-cells. […] Although the pathogenesis of AIP is still unknown, several hypotheses have been proposed from the clinical and animal experimental aspects. […] The first step in the disease may be an antigenic alteration at the pancreatic duct or acinar cells such as an aberrant expression of HLA-DR. […] The long-term prognosis of AIP is unknown.
#36 Autoimmune Pancreatitis: Etiology, Pathogenesis, Clinical Finding
https://www.primescholars.com/articles/autoimmune-pancreatitis-etiology-pathogenesis-clinical-findings-and-treatment-the-japanese-experience-98724.html
The occasional coexistence of pancreatitis with other lesions suggests that there may be common target antigens in the pancreas and other exocrine organs such as the salivary gland, biliary tract and renal tubules. […] The activated CD4+ and CD8+ T-cells bearing HLA-DR and CD45RO were elevated in the peripheral blood lymphocytes (PBLs) as well as in the pancreas in AIP as compared to other causes of pancreatitis such as alcoholic or gallstone-related pancreatitis. […] Similar to SjS or PSC, CD4+ T-cells showing the Th1 type of immune response are predominantly involved in the development of AIP as effector cells over Th2 type CD4+ T-cells. […] Although the pathogenesis of AIP is still unknown, several hypotheses have been proposed from the clinical and animal experimental aspects. […] The first step in the disease may be an antigenic alteration at the pancreatic duct or acinar cells such as an aberrant expression of HLA-DR. […] The long-term prognosis of AIP is unknown.
#37 Autoimmune pancreatitis: Cornerstones and future perspectives
https://www.wjgnet.com/1007-9327/full/v30/i8/817.htm
In addition to the activation of T helper and T reg CD4+ lymphocytes that follows the interaction between TLRs and MHC-II, also the interaction between T follicular helper (Tfh) cells, especially circulating type 1 Tfh cells, and SLAMF7, a member of the Signaling Lymphocyte Activation Molecule family receptors, promotes IgG4 release. […] Recent studies have shown that SLAMF7+ CD4+ CTLs are increased in the peripheral blood of subjects with active IgG4-RD, and thus represent a key pathological factor in the disease. […] The Th-17 subset of CD4+ effector T cells plays a crucial role in infiltrating the periductal pancreatic tissue, where they release inflammatory cytokines, mainly IL-17, IL-21, IL-22, and IL-23. […] The increasing awareness of the relationship between specific alterations in the composition of the gut microbiota and the innate immunological response, and thus the development of autoimmune diseases, led to the hypothesis of a possible role of the microbiota in the etiopathogenesis of AIP, particularly K. Pneumoniae. […] Finally, the etiopathogenesis of AIP-3 is closely related to the administration of checkpoint inhibitors, which trigger a non-specific inflammatory immune response mediated by T cells, mainly CD8+ T cells, resulting in an increased ratio of CD8+/CD4+ T lymphocytes.
#38 Gut Microbiota Involved in the Immunopathogenesis of Autoimmune Pancreatitis
https://www.gutnliver.org/journal/view.html?volume=19&number=2&spage=171
Autoimmune pancreatitis (AIP), which is considered the pancreatic expression of a systemic immunoglobulin G4-related disease, is characterized by excessive infiltration of plasmacytes bearing immunoglobulin G4 and a unique form of fibrosis in multiple organs. This relatively new disease entity has garnered great attention from clinicians, but its pathophysiology remains poorly understood. Recent discoveries indicate that plasmacytoid dendritic cell activation followed by robust production of type I interferon and interleukin-33 plays a key role in driving chronic fibro-inflammatory responses in both murine and human AIP. […] Furthermore, the compositional alterations in the gut microbiota, known as intestinal dysbiosis, triggered plasmacytoid dendritic cell-driven pathogenic type I interferon responses. Intestinal dysbiosis is associated with a breakdown in intestinal barrier function; thus, we examined whether the latter condition affects the development of experimental AIP. Our recent research has revealed that intestinal barrier disruption worsens experimental AIP by facilitating the translocation of pathogenic bacteria, such as Staphylococcus sciuri, to the pancreas from the gut. These results indicate the gut-pancreas axis underlies the immunopathogenesis of AIP, and the maintenance of intestinal barrier integrity can prevent the worsening of AIP by inhibiting pancreatic colonization by harmful gut bacteria.
#39 Gut Microbiota Involved in the Immunopathogenesis of Autoimmune Pancreatitis
https://www.gutnliver.org/journal/view.html?volume=19&number=2&spage=171
Autoimmune pancreatitis (AIP), which is considered the pancreatic expression of a systemic immunoglobulin G4-related disease, is characterized by excessive infiltration of plasmacytes bearing immunoglobulin G4 and a unique form of fibrosis in multiple organs. This relatively new disease entity has garnered great attention from clinicians, but its pathophysiology remains poorly understood. Recent discoveries indicate that plasmacytoid dendritic cell activation followed by robust production of type I interferon and interleukin-33 plays a key role in driving chronic fibro-inflammatory responses in both murine and human AIP. […] Furthermore, the compositional alterations in the gut microbiota, known as intestinal dysbiosis, triggered plasmacytoid dendritic cell-driven pathogenic type I interferon responses. Intestinal dysbiosis is associated with a breakdown in intestinal barrier function; thus, we examined whether the latter condition affects the development of experimental AIP. Our recent research has revealed that intestinal barrier disruption worsens experimental AIP by facilitating the translocation of pathogenic bacteria, such as Staphylococcus sciuri, to the pancreas from the gut. These results indicate the gut-pancreas axis underlies the immunopathogenesis of AIP, and the maintenance of intestinal barrier integrity can prevent the worsening of AIP by inhibiting pancreatic colonization by harmful gut bacteria.
#40 Gut Microbiota Involved in the Immunopathogenesis of Autoimmune Pancreatitis
https://www.gutnliver.org/journal/view.html?volume=19&number=2&spage=171
Autoimmune pancreatitis (AIP), which is considered the pancreatic expression of a systemic immunoglobulin G4-related disease, is characterized by excessive infiltration of plasmacytes bearing immunoglobulin G4 and a unique form of fibrosis in multiple organs. This relatively new disease entity has garnered great attention from clinicians, but its pathophysiology remains poorly understood. Recent discoveries indicate that plasmacytoid dendritic cell activation followed by robust production of type I interferon and interleukin-33 plays a key role in driving chronic fibro-inflammatory responses in both murine and human AIP. […] Furthermore, the compositional alterations in the gut microbiota, known as intestinal dysbiosis, triggered plasmacytoid dendritic cell-driven pathogenic type I interferon responses. Intestinal dysbiosis is associated with a breakdown in intestinal barrier function; thus, we examined whether the latter condition affects the development of experimental AIP. Our recent research has revealed that intestinal barrier disruption worsens experimental AIP by facilitating the translocation of pathogenic bacteria, such as Staphylococcus sciuri, to the pancreas from the gut. These results indicate the gut-pancreas axis underlies the immunopathogenesis of AIP, and the maintenance of intestinal barrier integrity can prevent the worsening of AIP by inhibiting pancreatic colonization by harmful gut bacteria.
#41 Gut Microbiota Involved in the Immunopathogenesis of Autoimmune Pancreatitis
https://www.gutnliver.org/journal/view.html?volume=19&number=2&spage=171
Thus, accumulations of pDCs that produce both type I IFN and IL-33 underlie the pathogenic innate immune responses in both murine and human AIP. […] Intestinal dysbiosis is a significant factor contributing to the immunopathogenesis of AIP and IgG4-RD, emphasizing the potential of maintaining a healthy gut microbiota for disease prevention and treatment. The pathophysiology targeting the gut-pancreas axis may help in developing novel treatments for AIP and IgG4-RD.
#42 Type 1 autoimmune pancreatitis | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-82
Several genetic susceptibility factors for type 1 AIP have been identified as summarized in Table 3. Findings obtained in one ethnic group are not always confirmed in patients in other groups, which raises the possibility that genetic susceptibility factors may be different among ethnic groups. […] In view of the autoimmune hypothesis surrounding IgG4-related disease, a series of studies have investigated the specificity of autoantibody responses in patients with type 1 AIP leading to the identification of several autoantigens. Antibodies against lactoferrin and carbonic anhydrase (CA) II are most frequently detected in type 1 AIP (73% and 54%, respectively). Anti-CA-IV antibodies were also detected in 34% of patients. Other potential autoantigens include pancreatic secretory trypsin inhibitor and trypsinogens. However, it remains to be seen whether IgG4 is an autoantibody in type 1 AIP or is over-expressed secondary in response to an unknown primary inflammatory stimulus.
#43 A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria | Laboratory Investigation
https://www.nature.com/articles/labinvest2010153
The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. […] We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. […] The concept of a syndrome complex or autoimmune exocrinopathy suggests that the pancreas and other organs may possess common target antigens. […] A close association with the human leukocyte antigen (HLA) haplotypes DRB1*0405 and DQB1*0401 has been reported in AIP patients.
#44 Pathophysiology of autoimmune pancreatitis
https://www.wjgnet.com/2150-5330/full/v5/i1/11.htm
Furthermore, Park et al found that only DQB1*0302 had a significant association with the relapse of AIP. […] Finally, it has been found that the polymorphic genes (CTLA-4 49A polymorphism and -318C/+ 49A/CT60G haplotype) encoding cytotoxic T lymphocyte-associated antigen 4, a key negative regulator of the T-cell immune response, are associated with AIP in a Chinese population. […] Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells. […] The cytotoxic T-lymphocyte antigen 4 gene is an inhibitory receptor expressed on the cell surface of activated memory T cells and on CD4+ CD25+ regulatory T cells, and acts largely as a negative regulator of T-cell responses. […] The + 6230G/A SNP in the 3 untranslated region of CTLA4 has been also found in Graves disease, type 1 diabetes and Umemura et al have demonstrated that AIP is closely associated with the CTLA4+ 6230 SNP and serum sCTLA4 levels and that CTLA4 gene plays an important role in the pathogenesis of AIP.
#45 Pathophysiology of autoimmune pancreatitis
https://www.wjgnet.com/2150-5330/full/v5/i1/11.htm
Autoimmune pancreatitis (AIP) is a recently discovered form of pancreatitis and represents one of the diseases of the pancreas which can be cured and healed medically. […] The categorization of AIP as an autoimmune disorder is based on the observation that the disease is associated with the infiltration of immune cells into pancreatic tissue, and that the disease dramatically responds to steroid therapy. […] The pancreas of a patient with AIP is often infiltrated by various types of immune cells, including cluster of differentiation (CD) 4-positive T cells and granulocytes in type 2 AIP or IgG4-producing plasma cells and B-lymphocyte antigen CD20 in type 1 AIP. […] It has also been reported that DRB1*0405 and DQB1*0401 mutations are significantly more frequent in patients with AIP when compared to those with chronic calcifying pancreatitis, even if these initial and promising findings were not confirmed by two recent studies.
#46 Pathophysiology of autoimmune pancreatitis
https://www.wjgnet.com/2150-5330/full/v5/i1/11.htm
Furthermore, Park et al found that only DQB1*0302 had a significant association with the relapse of AIP. […] Finally, it has been found that the polymorphic genes (CTLA-4 49A polymorphism and -318C/+ 49A/CT60G haplotype) encoding cytotoxic T lymphocyte-associated antigen 4, a key negative regulator of the T-cell immune response, are associated with AIP in a Chinese population. […] Even if these data are not concordant, it is possible that physiological IgG4 responses are induced by prolonged antigen exposure and controlled by type 2 helper T cells. […] The cytotoxic T-lymphocyte antigen 4 gene is an inhibitory receptor expressed on the cell surface of activated memory T cells and on CD4+ CD25+ regulatory T cells, and acts largely as a negative regulator of T-cell responses. […] The + 6230G/A SNP in the 3 untranslated region of CTLA4 has been also found in Graves disease, type 1 diabetes and Umemura et al have demonstrated that AIP is closely associated with the CTLA4+ 6230 SNP and serum sCTLA4 levels and that CTLA4 gene plays an important role in the pathogenesis of AIP.
#47 Autoimmune pancreatitis can develop into chronic pancreatitis | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-9-77
Based on our cumulative study outcomes, we have proposed the hypothesis of a sequential progression mechanism of AIP to chronic pancreatitis: many cases of AIP include pancreatic head swelling during the acute stage, some of which lead to long-standing narrowing of both Wirsungs and Santorinis ducts in this region, which may then cause pancreatic juice stasis in the upstream pancreatic duct. […] This cumulative study has clarified the following points: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of patients with AIP experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsungs and Santorinis ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised JCDC, with independent risk factors of pancreatic head swelling and MPD non-narrowing in the pancreatic body. Finally, AIP can lead to severe pancreatic stone formation and progress to confirmed chronic pancreatitis over a long-term period, which may be most presumably caused by disease recurrence and pancreatic juice stasis.
#48 Autoimmune pancreatitis can develop into chronic pancreatitis | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-9-77
We evaluated the long-term outcomes of patients with AIP and observed that some individuals experienced pancreatic calcification. […] Such imaging findings mimicked those of chronic pancreatitis, suggesting that patients with AIP could progress to this state. […] These studies suggested that pancreatic calcification was closely associated with relapse and that AIP could transform into ordinary chronic pancreatitis after multiple recurrences. […] We have postulated two mechanisms for pancreatic stone formation in AIP: 1) severe tissue injury attributed to the specific inflammatory disease processes; and 2) pancreatic juice stasis due to pancreatic duct narrowing. […] We could therefore recommend careful follow-up of patients with AIP having these 2 risk factors to prevent progression to chronic pancreatitis.
#49 Autoimmune pancreatitis can develop into chronic pancreatitis | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-9-77
Based on our cumulative study outcomes, we have proposed the hypothesis of a sequential progression mechanism of AIP to chronic pancreatitis: many cases of AIP include pancreatic head swelling during the acute stage, some of which lead to long-standing narrowing of both Wirsungs and Santorinis ducts in this region, which may then cause pancreatic juice stasis in the upstream pancreatic duct. […] This cumulative study has clarified the following points: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of patients with AIP experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsungs and Santorinis ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised JCDC, with independent risk factors of pancreatic head swelling and MPD non-narrowing in the pancreatic body. Finally, AIP can lead to severe pancreatic stone formation and progress to confirmed chronic pancreatitis over a long-term period, which may be most presumably caused by disease recurrence and pancreatic juice stasis.