Przewlekła choroba ziarniniakowa
Patofizjologia i mechanizm

Przewlekła choroba ziarniakowa (CGD) jest pierwotnym niedoborem odporności spowodowanym mutacjami w genach kodujących podjednostki kompleksu oksydazy NADPH fagocytów, co prowadzi do defektu w produkcji reaktywnych form tlenu (ROS), w tym anionów ponadtlenkowych i nadtlenku wodoru. W efekcie fagocyty (neutrofile, monocyty, makrofagi) nie są zdolne do skutecznego zabijania bakterii i grzybów, zwłaszcza katalazo-dodatnich, co skutkuje nawracającymi, ciężkimi zakażeniami oraz tworzeniem ziarniniaków w różnych narządach. CGD dzieli się na formę sprzężoną z chromosomem X (mutacje w genie CYBB kodującym gp91phox, 65-70% przypadków) oraz autosomalną recesywną (mutacje w genach NCF1, NCF2, CYBA, NCF4, CYBC1, 30-35% przypadków). Diagnostyka opiera się na ocenie produkcji ponadtlenku przez fagocyty za pomocą testów takich jak redukcja błękitu nitrotetrazolowego (NBT) i cytometria przepływowa z dihydrorodaminą 123 (DHR). Przebieg kliniczny i przeżywalność korelują z resztkową aktywnością NADPH oksydazy, niezależnie od konkretnego genu.

  1. Patogeneza przewlekłej choroby ziarniakowej
    1. Rola oksydazy NADPH w patogenezie CGD
    2. Molekularny mechanizm dysfunkcji oksydazy NADPH
    3. Defekty genetyczne w CGD
  2. Mechanizm dysfunkcji fagocytów w CGD
    1. Zaburzony wybuch tlenowy
    2. Nieprawidłowe zabijanie drobnoustrojów
    3. Rola drobnoustrojów katalazo-dodatnich
  3. Procesy zapalne i tworzenie ziarniniaków
    1. Patofizjologia stanu zapalnego
    2. Mechanizm tworzenia ziarniniaków
    3. Apoptoza neutrofili i procesy zapalne
    4. Dysfunkcja regulacji zapalnej
  4. Różnice między typami genetycznymi CGD
    1. Różnice w przebiegu klinicznym
    2. Wpływ genów modyfikujących na obraz kliniczny
  5. Diagnostyka CGD
    1. Testy funkcji neutrofili
    2. Badania genetyczne
  6. Konsekwencje kliniczne dysfunkcji oksydazy NADPH
    1. Podatność na zakażenia
    2. Powikłania zapalne i tworzenie ziarniniaków
    3. Podłoże molekularne wzmożonej rekcji zapalnej
  7. Aktualne kierunki badań nad patogenezą CGD
    1. Badania nad ekspresją genów i transkryptomika
    2. Aktywacja inflamasomu IL-1beta niezależna od ROS
    3. Rola neutrofili NOS2high i makrofagów w tworzeniu ziarniniaków
    4. Rola czynnika NCF2 w patogenezie CGD
    5. Kolejne rozdziały

Patogeneza przewlekłej choroby ziarniakowej

Przewlekła choroba ziarniakowa (CGD – Chronic Granulomatous Disease) jest rzadkim pierwotnym niedoborem odporności, który wynika z defektów w kompleksie oksydazy NADPH (fosforanu dinukleotydu nikotynamido-adeninowego) fagocytów, nazywanym również oksydazą fagocytarną (phox). Te genetyczne defekty prowadzą do niezdolności fagocytów (neutrofili, monocytów i makrofagów) do niszczenia określonych drobnoustrojów.123

Rola oksydazy NADPH w patogenezie CGD

Podstawowy defekt w CGD polega na niezdolności neutrofili, monocytów, makrofagów i eozynofili do wytworzenia wybuchu tlenowego (respiratory burst), a w konsekwencji do generowania anionów ponadtlenkowych i innych reaktywnych form tlenu pochodzących z ponadtlenku, takich jak nadtlenek wodoru. To sprawia, że pacjenci są podatni na ciężkie, nawracające zakażenia bakteryjne i grzybicze.123

Kompleks NADPH oksydazy składa się z wielu podjednostek i odpowiada za produkcję reaktywnych form tlenu (ROS), które są wykorzystywane do zabijania patogenów. Mutacje w którymkolwiek z 6 genów, które kodują różne części NADPH oksydazy, mogą zmniejszyć zdolność neutrofili do produkcji ROS. Ta niewydolność prowadzi do CGD, z powodu niezdolności neutrofili do zabijania określonych bakterii i grzybów.12

Molekularny mechanizm dysfunkcji oksydazy NADPH

Aktywny kompleks NADPH oksydazy jest strukturą składającą się z sześciu białek. W stanie podstawowym ma dwa komponenty: kompleks związany z błoną komórkową osadzony w ścianach ziarnistości wtórnych oraz oddzielne składniki cytozolowe.1 Enzym NADH oksydaza jest enzymem wieloskładnikowym, który zawiera związany z błoną, heterodimetryczny cytochrom typu b, składający się z podjednostek gp91phox (znanej również jako Nox2) i p22phox. Wszystkie te elementy są niezbędne do prawidłowej produkcji ponadtlenku.2

W procesie aktywacji komórkowej, rozpuszczalne składniki cytozolowe – p67phox, p47phox i p40phox – przemieszczają się do błony komórkowej i wiążą się z komponentami heterodimeru cytochromu-b558. To katalizuje transfer elektronów z NADPH do tlenu, powodując powstawanie ponadtlenku w składniku zewnątrzkomórkowym. Następne reakcje za pośrednictwem dysmutazy ponadtlenkowej (SOD), katalazy lub mieloperoksydazy (MPO), zachodzące w fagolizosomie, mogą prowadzić do powstania H2O2, H2O lub HOCl- odpowiednio.1

Defekty genetyczne w CGD

CGD jest chorobą heterogenną genetycznie, wywoływaną przez mutacje w genach kodujących podjednostki kompleksu oksydazy NADPH fagocytów. Wyróżniamy dwa podstawowe typy dziedziczenia:1

  • Forma sprzężona z chromosomem X (X-linked) – powodowana przez mutacje w genie CYBB (znajdującym się na chromosomie Xp21.1), który koduje podjednostkę gp91phox (Nox2). Jest to najczęstsza forma CGD, występująca u około 65-70% pacjentów.23
  • Forma autosomalna recesywna (AR-CGD) – stanowi około 30-35% przypadków i dotyka w równym stopniu mężczyzn i kobiety. Występuje w wyniku mutacji w genach kodujących:4
    • p47phox (gen NCF1 na chromosomie 7q11.23)
    • p67phox (gen NCF2 na chromosomie 1q25)
    • p22phox (gen CYBA na chromosomie 16q24)
    • p40phox (gen NCF4 na chromosomie 22q13.1)
    • CYBC1/EROS (gen na chromosomie 17q25.3) – niedawno zidentyfikowany jako istotny regulator obfitości heterodimeru gp91phox-p22phox kompleksu NADPH oksydazy fagocytów w komórkach ludzkich1

Mutacje w genie CYBB mają różny zakres – od zmian pojedynczych nukleotydów do delecji megabazowych. Mutacje nonsensowne, typu missense (bezpośrednio lub przez przesunięcie ramki odczytu) powodują powstanie kodonu stop dalej w dół sekwencji, co prowadzi do przedwczesnego zakończenia syntezy białka.1

Istotne jest, że cechy kliniczne i nasilenie choroby, a także przeżywalność pacjentów, w znacznym stopniu zależą od genu, typu i pozycji mutacji.1 Wykazano, że przeżywalność pacjentów z CGD jest silnie związana z resztkową produkcją ponadtlenku, niezależnie od konkretnego zmutowanego genu.1

Mechanizm dysfunkcji fagocytów w CGD

W przebiegu przewlekłej choroby ziarniakowej podstawowy defekt dotyczy procesu fagocytozy, który jest kluczowym mechanizmem obrony przeciw patogenom.

Zaburzony wybuch tlenowy

W warunkach prawidłowych, podczas fagocytozy, neutrofile przechodzą tzw. „wybuch tlenowy” (respiratory burst), który jest odpowiedzią oksydacyjną, w której wewnątrz nienaruszonych fagocytów powstają wysoce reaktywne bakteriobójcze metabolity oksydacyjne, w tym ponadtlenek (O2–), nadtlenek wodoru (H2O2), kwas podchlorawy (HOCl) i rodnik hydroksylowy (·OH). Te pochodne tlenu odgrywają kluczową rolę w zabijaniu określonych patogennych bakterii i grzybów.12

W CGD, fagocyty nie mogą wytworzyć bakteriobójczych anionów ponadtlenkowych (O2–), co w konsekwencji zaburza produkcję rodnika hydroksylowego (OH–), nadtlenku wodoru (H2O2), anionu nadtlenoazotynowego (ONOO–) i oksyhalidów – produktów, które odgrywają kluczową rolę w zabijaniu określonych patogennych bakterii i grzybów.1

Nieprawidłowe zabijanie drobnoustrojów

W CGD fagocyty prawidłowo pochłaniają bakterie, ale nie mogą ich zabić. Przeżycie wewnątrzkomórkowe pochłoniętych bakterii prowadzi do rozwoju ziarniniaków w węzłach chłonnych, skórze, płucach, wątrobie, przewodzie pokarmowym i/lub kościach.1

Fagocyty CGD mogą zabijać liczne mikroorganizmy mimo swoich defektów, ponieważ większość mikroorganizmów endogennie produkuje nadtlenek wodoru, który fagocyt dotknięty CGD może modyfikować i wykorzystywać przeciwko organizmowi w fagosomie. Bakterie i grzyby, które powodują większość infekcji w CGD, to organizmy katalazo-dodatnie.1

Rola drobnoustrojów katalazo-dodatnich

Zakażenia u pacjentów z CGD są zazwyczaj wywoływane przez mikroorganizmy katalazo-dodatnie (większość bakterii i wszystkie patogeny grzybicze są katalazo-dodatnie), ale katalaza nie jest ani konieczna, ani wystarczająca do patogenności w CGD.1 Niedobór NADPH oksydazy skutkuje niezdolnością do produkcji ponadtlenku, co zmniejsza zdolność komórek do niszczenia mikroorganizmów katalazo-dodatnich.1

Diagnoza CGD powinna być rozważona u każdego pacjenta z nawracającymi zakażeniami organizmami katalazo-dodatnimi; zakażeniami nietypowymi organizmami, takimi jak Serratia marcescens, Aspergillus nidulans lub Burkholderia cepacia; lub zakażeniami w miejscach zazwyczaj uważanych za rzadkie u dzieci, takich jak ropień wątroby wywołany przez Staphylococcus aureus.2

Procesy zapalne i tworzenie ziarniniaków

Powikłania zapalne w CGD, takie jak tworzenie ziarniniaków, są szczególnie problematyczne w płucach oraz przewodzie pokarmowym i moczowo-płciowym.12 Stan zapalny jest częsty u pacjentów z CGD i w niektórych przypadkach może być pierwszą manifestacją kliniczną.1

Patofizjologia stanu zapalnego

Obecne dane wskazują, że zarówno zwiększona, jak i zmniejszona aktywność NOX2 (podjednostki NADPH oksydazy) może prowadzić do powikłań zapalnych.2 Niedobór NADPH oksydazy był postrzegany głównie jako niedobór odporności, charakteryzujący się niezdolnością do wywołania odpowiedzi zapalnej. Jednakże istnieją obecnie dowody na powikłania związane z nadmiernym stanem zapalnym w CGD.1

Główne manifestacje są reprezentowane głównie przez ziarniniaki, a także zapalenie okrężnicy, które jest częste i prowadzi do znacznej chorobowości. Defekty aktywności przeciwdrobnoustrojowej mogą ułatwiać utrzymywanie się patogenów i zwiększać odpowiedź zapalną u niektórych pacjentów.2

Mechanizm tworzenia ziarniniaków

Ziarniniaki mogą wystąpić w większości przypadków bez obecności patogenu zakaźnego.3 Uważa się, że powstają one w miejscach, gdzie drobnoustroje nie zostały wyeliminowane, lub występuje utrzymująca się dysregulowana lokalna produkcja cytokin po sterylizacji mikrobiologicznej.1

Brak ROS w leukocytach CGD tworzy zmiany w sygnalizacji, które sprzyjają odpowiedziom prozapalnym. Fagocyty CGD produkują wysokie poziomy czynnika martwicy nowotworu-alfa i interleukiny-8, prawdopodobnie poprzez hiperaktywację NF-kappa B, przyczyniając się do odpowiedzi zapalnej.1

Apoptoza neutrofili i procesy zapalne

Istnieją dowody sugerujące, że ROS mogą indukować apoptozę neutrofili. Niepowodzenie w pochłanianiu komórek apoptotycznych jest hipotetycznie związane z immunizacją na antygeny własne, prowadząc na przykład do wyższej częstości występowania tocznia u pacjentów z CGD.2

Niedobór systemu NADPH oksydazy w fagocytach pacjentów z CGD prowadzi do zmniejszonej degradacji pochłoniętego materiału lub komórek apoptotycznych, co implikuje albo pozostały pochłonięty patogen, albo neutrofile apoptotyczne pochłonięte przez makrofagi, takie jak patognomoniczne kryształy eozynofiliowe. Główną konsekwencją jest uporczywa aktywacja i nadmierny stan zapalny na poziomie komórkowym.3

Dysfunkcja regulacji zapalnej

Dysfunkcja oksydazy NADPH prowadzi nie tylko do defektów w zabijaniu drobnoustrojów przez fagocytozę, neutrofilowe pułapki zewnątrzkomórkowe i inne formy regulowanej śmierci komórkowej, ale także do defektów regulacji zapalenia związanego z ROS i innych szlaków odporności wrodzonej, które są odpowiedzialne za manifestacje nadmiernego stanu zapalnego w CGD.2

Niezdolność do generowania ROS w fagocytach z CGD prowadzi do zmian w szlakach sygnałowych, co sprzyja odpowiedziom prozapalnym. Dysfunkcja ROS prowadzi do niewydolnej autofagii, fenotypu prozapalnego ze zwiększonym wydzielaniem cytokin prozapalnych (TNFα, IL1β, IL6) i autoimmunizacji, co przyczynia się do nadmiernego stanu zapalnego związanego z CGD.1

Różnice między typami genetycznymi CGD

Dane wykazują wyraźną, statystycznie istotną różnicę w długości życia między dwoma głównymi typami CGD (związaną z chromosomem X i autosomalną recesywną), chociaż ważne jest, aby pamiętać, że u poszczególnych pacjentów z AR-CGD występowała wczesna i wyjątkowo ciężka ekspresja choroby.1

Różnice w przebiegu klinicznym

Nie jest jasne, dlaczego AR-CGD generalnie ma łagodniejszy przebieg, chociaż wykazano resztkową aktywność NADPH-oksydazy w niedoborze p47phox.2 Mechanistycznie, przeżywalność pacjentów z CGD jest silnie związana z resztkową produkcją ponadtlenku, niezależnie od konkretnego zmutowanego genu.2

Forma CGD związana z chromosomem X zwykle objawia się zakażeniem lub IBD (nieswoistym zapaleniem jelit) wcześniej niż forma związana z NCF1. Do tej pory forma związana z NCF4 była kojarzona tylko z IBD, ale bez ciężkich zakażeń.1

Wpływ genów modyfikujących na obraz kliniczny

Tendencja do rozwijania powikłań ziarniniakowatych u pacjentów z CGD wydaje się być pod wpływem modyfikatorów genetycznych. Tym samym, subtelne różnice genetyczne w cząsteczkach odporności wrodzonej wydają się przyczyniać do specyficznych odpowiedzi zapalnych u pacjentów z CGD.1

Pacjenci z CGD zwykle wykazują odpowiedź zapalną charakteryzującą się niskim poziomem ROS, silną aktywacją niezależnych od tlenu mechanizmów zabijania i zwiększonym napływem neutrofili. Ponadto, ten rodzaj odpowiedzi może być związany z chorobą autoimmunologiczną, co często obserwuje się u pacjentów z CGD.2

W przypadku formy X-linked, nosiciele, którzy doświadczyli ciężkich zakażeń, mieli co najmniej 1 przypadek zapalenia płuc spowodowanego przez powszechny patogen związany z CGD. Aż 48% wszystkich nosicieli CGD sprzężonej z chromosomem X zgłaszało zakażenia, objawy autoimmunologiczne lub oba te stany.1

Diagnostyka CGD

Diagnoza CGD opiera się na badaniach funkcji neutrofili w kierunku produkcji ponadtlenku. Wykorzystuje się testy takie jak redukcja błękitu nitrotetrazolowego (NBT) lub cytometrię przepływową z dihydrorodaminą 123 (DHR).11

Testy funkcji neutrofili

Najbardziej dokładny test dla CGD mierzy nadtlenek wodoru w fagocytach przy użyciu substancji chemicznej zwanej dihydrorodaminą.1 Diagnoza jest stawiana na podstawie cytometrii przepływowej do wykrywania produkcji rodników tlenowych przy użyciu dihydrorodaminy 123 (DHR) lub błękitu nitrotetrazolowego (NBT). Ten test może również identyfikować kobiety nosicielki formy związanej z chromosomem X i formy recesywne. W tych formach, test z użyciem DHR wykazuje 2 populacje fagocytów, normalne i zmienione chorobowo.2

Laboratoryjna diagnoza CGD opiera się na wykazaniu braku aktywności utleniającej fagocytów. Opracowano wiele różnych testów diagnostycznych w tym celu (bezpośredni pomiar produkcji ponadtlenku, redukcja ferrocytochromu, test błękitu nitrotetrazolowego (NBT) i test utleniania za pomocą cytometrii przepływowej). Cytometria przepływowa jest obecnie najczęściej stosowaną techniką ze względu na jej większą obiektywność i powtarzalność.1

Badania genetyczne

Dokładny defekt molekularny jest określany poprzez genotypowanie.2 Mutacja w którymkolwiek z 5 genów może powodować CGD. Ludzie z CGD dziedziczą zmieniony gen od rodzica. Te geny produkują białka, które tworzą enzym. Ten enzym pomaga układowi odpornościowemu właściwie działać. Enzym jest aktywny w białych krwinkach, zwanych fagocytami, które chronią przed zakażeniami, niszcząc grzyby i bakterie. Enzym jest również aktywny w komórkach układu odpornościowego, które pomagają organizmowi w gojeniu.1

Testy genetyczne są używane w celu potwierdzenia obecności specyficznej mutacji genowej, która prowadzi do CGD.1 Defekty genetyczne w NOX2 mogą powodować przewlekłą chorobę ziarniakową, charakteryzującą się zwiększoną podatnością na zakażenia i nasiloną odpowiedzią zapalną, prowadzącą do tworzenia ziarniniaków.1

Badania z zastosowaniem pojedynczego sekwencjonowania RNA komórkowego i analizy przestrzennej transkryptomu ujawniły ekspansję neutrofili i makrofagów pochodzących z monocytów w tkance płucnej, identyfikując prozapalne neutrofile NOS2high i odrębną podgrupę makrofagów pochodzących z monocytów oznaczoną przez NOS2 i ARG1.2

Defekty genetyczne w przewlekłej chorobie ziarniakowej
Typ dziedziczenia Zmutowany gen Lokalizacja chromosomowa Kodowane białko Częstość występowania
Sprzężony z chromosomem X CYBB Xp21.1 gp91phox (Nox2) 65-70%
Autosomalny recesywny CYBA 16q24 p22phox 30-35%
NCF1 7q11.23 p47phox
NCF2 1q25 p67phox
NCF4 22q13.1 p40phox
CYBC1 17q25.3 EROS

Konsekwencje kliniczne dysfunkcji oksydazy NADPH

Dysfunkcja oksydazy NADPH prowadzi do dwóch głównych zespołów klinicznych w CGD: zwiększonej podatności na zakażenia oraz tendencji do nadmiernych reakcji zapalnych i tworzenia ziarniniaków.

Podatność na zakażenia

Główną cechą kliniczną CGD jest zwiększona podatność na ciężkie i nawracające zakażenia bakteryjne i grzybicze, wraz z rozwojem ziarniniaków.1 CGD uniemożliwia układowi odpornościowemu zwalczanie niektórych zakażeń. Osoby z CGD mają wadliwy gen układu odpornościowego, co oznacza, że białe krwinki, zwane fagocytami, nie działają prawidłowo.1

U osób z CGD zakażenia, które zwykle są powstrzymywane przez zdrowy układ odpornościowy, mogą rozwinąć się do poważnych, a nawet zagrażających życiu. CGD jest chorobą przewlekłą, co oznacza, że jest to utrzymujące się schorzenie i dla pacjentów z CGD oznacza, że trwa całe życie.1

Powikłania zapalne i tworzenie ziarniniaków

Problemy zapalne mogą być poważne i obejmować zapalenie jelit (zapalenie okrężnicy), płuc, pęcherza moczowego (zapalenie pęcherza) i dziąseł (zapalenie dziąseł). Czasami problemy są spowodowane przez ziarniniaki. Są to guzki komórek odpornościowych, które tworzą ciasne struktury przypominające kulki, które mogą powodować niedrożność w tkankach ciała.2

Gdy układ odpornościowy znajduje szkodliwe rzeczy w ciele, takie jak bakterie i grzyby, wysyła komórki odpornościowe, aby je zabić. Jeśli zakażenie nie ustępuje, pojawia się więcej komórek odpornościowych, aby próbować zabić bakterie lub grzyby. Z czasem to nagromadzenie tworzy twardy guzek zwany ziarniniakiem.2

Dzieci mogą również rozwijać masy tkanki zapalnej zwane ziarniniakami w odpowiedzi na przewlekłe zakażenia. Ziarniniaki te mogą występować w skórze, przewodzie pokarmowym i układzie moczowo-płciowym.1 CGD została nazwana od tych mas zapalenia zanim odkryto genetyczne przyczyny.2

Podłoże molekularne wzmożonej rekcji zapalnej

Badania wykazały, że brak ROS w fagocytach CGD tworzy zmiany w sygnalizacji, które sprzyjają odpowiedziom prozapalnym. Fagocyty CGD produkują wysokie poziomy czynnika martwicy nowotworu-alfa i interleukiny (IL)-8, prawdopodobnie poprzez hiperaktywację NF-kappa B, przyczyniając się do odpowiedzi zapalnej.1

Czynnik hamujący migrację makrofagów (MIF) jest istotnym regulatorem w chorobach zapalnych i autoimmunologicznych, znanym z nasilania stanu zapalnego poprzez aktywację szlaków sygnałowych, takich jak MAPK, PI3K/AKT i NF-κB. Jednak rola MIF w CGD pozostaje niezbadana i stanowi potencjalny obszar dalszych badań.1

Ponadto, w odpowiednim czasie apoptoza i oczyszczanie neutrofili są kluczowe dla zakończenia odpowiedzi zapalnej. Pod wpływem cytokin zapalnych, takich jak TNF-α, IL-1 i IL-8, apoptoza neutrofili jest opóźniona, co prowadzi do zwiększonego uszkodzenia tkanek i stanu zapalnego.2

Morrbid (Myeloid RNA Regulator of Bim Induced Death) jest długim niekodującym RNA (lncRNA) specyficznie ekspresjonowanym w linii mieloidalnej, który może przedłużać przeżycie komórek poprzez obniżenie ekspresji Bim, białka związanego z apoptozą. Jednak utrzymująca się ekspresja Morrbid może skutkować nadmiernym przeżyciem komórek mieloidalnych, dodatkowo zaostrzając uszkodzenie tkanek.3

Aktualne kierunki badań nad patogenezą CGD

Badania nad patogenezą CGD koncentrują się na lepszym zrozumieniu mechanizmów molekularnych dysfunkcji oksydazy NADPH oraz poszukiwaniu nowych metod terapeutycznych.

Badania nad ekspresją genów i transkryptomika

Profilowanie ekspresji genów dostarcza wglądu w patofizjologię przewlekłej choroby ziarniakowej.1 Zastosowanie sekwencjonowania RNA pojedynczych komórek i przestrzennej transkryptomiki ujawniło ekspansję neutrofili i makrofagów pochodzących z monocytów w tkance płucnej, identyfikując prozapalne neutrofile NOS2high i odrębną podgrupę makrofagów pochodzących z monocytów oznaczoną przez NOS2 i ARG1.1

Przestrzenna transkryptomika wykazała, że neutrofile NOS2high są zlokalizowane w obszarze rdzeniowym, podczas gdy podgrupa makrofagów pochodzących z monocytów jest umiejscowiona na obwodzie, ułatwiając przebudowę macierzy pozakomórkowej.3 To badanie podkreśla, w jaki sposób kontrola środowiskowa może ustanowić naturalny model CGD, wyjaśnia mechanizmy tworzenia ziarniniaków i rozwija skuteczne interwencje terapeutyczne.2

Aktywacja inflamasomu IL-1beta niezależna od ROS

Reaktywne formy tlenu-niezależna aktywacja inflamasomu IL-1beta w komórkach pacjentów z przewlekłą chorobą ziarniakową.2 Brak ROS w leukocytach CGD tworzy zmiany w sygnalizacji, które sprzyjają odpowiedziom prozapalnym.1

Nieobecność ROS w fagocytach CGD skutkowała zwiększoną produkcją TNF- i aktywnością inflamasomu, co w pewnych warunkach może być odpowiedzialne za produkcję IL-1 w CGD.1

Rola neutrofili NOS2high i makrofagów w tworzeniu ziarniniaków

U pacjentów z CGD i w niektórych modelach zwierzęcych naśladujących CGD z określonym wyzwaniem patogennym, proliferacja i mobilizacja komórek odpornościowych linii mieloidalnej, szczególnie neutrofili, w połączeniu ze znaczną ekspresją cytokin prozapalnych, takich jak TNF-α, IL-1α i IL-1β, są uważane za głównych współtwórców indukowania stanów zapalnych.1

Tworzenie ziarniniaków jest drugą kluczową cechą w CGD, stąd jej nazwa przewlekła choroba ziarniakowa. Ziarniniaki są wysoce dynamicznymi strukturami, które, przynajmniej początkowo, koncentrują się na mikroorganizmie lub komórkach zawierających wewnątrzkomórkowy mikroorganizm, a na ich granicy składają się z bariery komórkowej. Tworzenie ziarniniaka jest szczególnie widoczne w warunkach z nieadekwatną obroną przeciwdrobnoustrojową, co może odnosić się do patogenu przyczynowego i/lub do stanu gospodarza. W tym względzie, ziarniniak może być postrzegany jako środek do powstrzymania utrzymujących się mikroorganizmów i oddzielenia ich od odpowiedzi immunologicznej gospodarza. W CGD, znalezione ziarniniaki są często sterylne, co wskazuje, że obecność ziarniniaka nie wydaje się wymagać ciągłej obecności mikroorganizmów.2

Rola czynnika NCF2 w patogenezie CGD

NCF2 (Czynnik Cytozolowy Neutrofili 2) koduje podjednostkę cytozolową p67phox holoenzymu NOX2, która jest krytyczna dla aktywności oksydazy NADPH. Mutacje zarodkowe w NCF2, podobnie jak w innych genach podjednostek NOX2, są związane z CGD.1

Co istotne, niektóre warianty genetyczne NCF2 są również powiązane ze zwiększoną podatnością na choroby autozapalne, takie jak toczeń rumieniowaty układowy i reumatoidalne zapalenie stawów, podkreślając jego kluczową rolę w regulacji zapalenia wewnętrznego.2

W badaniu zmieniono warunki hodowli z urządzeń wolnych od określonych patogenów (SPF) na warunki czystego stopnia (CL) i zaobserwowano naturalne występowanie CGD u myszy Ncf2-/-. Dokładnie rozszyfrowano patogenezę naturalnej CGD, łącząc regularne transkryptomiki pojedynczych komórek i transkryptomikę przestrzenną, oraz opracowano trzy różne, ale skorelowane zaburzenia rzadkiego stanu hipozapalenia.1

Kolejne rozdziały

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  1. 12.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis
    Chronic granulomatous disease (CGD) is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase (phox). […] These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. […] Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts. […] The diagnosis is made by neutrophil function testing for superoxide production (nitroblue tetrazolium reduction or dihydrorhodamine [DHR] 123 flow cytometry assay). […] The exact molecular defect is determined by genotyping.
  • #1 Chronic Granulomatous Disease: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/1116022-overview
    Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. […] Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them. […] The main defect in chronic granulomatous disease (CGD) is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.
  • #1 Chronic Granulomatous Disease Pathophysiology – For HCPs
    https://www.cgdpathways.com/cgd-overview/pathophysiology-of-chronic-granulomatous-disease
    CGD is a disorder that affects neutrophil function in NADPH oxidase, which is made up of multiple subunits and produces reactive oxygen species (ROS) used to kill pathogens. […] Mutations in any one of the 6 genes that make up the various parts of NADPH oxidase can reduce the neutrophils ability to produce ROS. This failure results in CGD, due to the inability of neutrophils to kill certain bacteria and fungi.
  • #1 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Chronic-Granulomatous-Disease.aspx
    CYBB mutations range from single nucleotide changes to megabase deletions. Missense, nonsense mutations (direct or by frameshift) produce a stop codon farther downstream, causing protein synthesis to be terminated prematurely. […] The active NADPH oxidase complex is a six-protein complex. It has two components in its basic state: a membrane-bound complex embedded in the walls of secondary granules and separate cytosolic components. […] The NADH oxidase enzyme is a multicomponent enzyme that consists of a membrane-bound, heterodimeric b-type cytochrome that includes the subunits gp91phox (also known as Nox2) and p22phox. All of these elements are essential for the normal production of superoxide.
  • #1 Chronic granulomatous disease: a review of the infectious and inflammatory complications | Clinical and Molecular Allergy | Full Text
    https://clinicalmolecularallergy.biomedcentral.com/articles/10.1186/1476-7961-9-10
    There are several components of NADPH oxidase: of these the cytochrome-b558 heterodimer is located in the membrane and consists of the gp91phox and p22phox units, while three cytosolic components exist- including the p67phox, p47phox, and a p40phox. Following cellular activation, the soluble cytosolic components, p67phox, p47phox, and a p40phox, move to the membrane and bind to components of the cytochrome-b558 heterodimer. […] This catalyzes the transfer of electrons from NADPH to oxygen, resulting in the formation of superoxide in the extracellular component as shown in Figure 4. Subsequent reactions via superoxide dismutase (SOD), catalase or myeloperoxidase (MPO), occurring in the phagolysome, can result in formation of H2O2, H2O, or HOCl- respectively.
  • #1 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    As a result of the failure to mount a respiratory burst in their phagocytes, the majority of CGD patients suffers from severe recurrent infections and also from dysregulated Th-17-lymphocyte-controled inflammation. […] The enzyme that catalyzes the respiratory burst, the leukocyte NADPH oxidase, consists of subunits, four of which are important for CGD (designated phox for phagocyte oxidase): gp91phox (or Nox2) and p22phox, located in membranes, as well as two cytosolic oxidase components, p47phox and p67phox. CGD is caused by a defect in any of these four components. […] Mutations in the gp91phox gene (CYBB on chromosome Xp21.1) cause the X-linked recessive form of the disease that affects the majority of CGD patients (70%). […] The remaining 30% of cases has inherited the disease in an autosomal recessive manner, in which males and females are equally affected. These patients have mutations in the genes encoding p47phox (NCF1 on chromosome 7q11.23), p67phox (NCF2 on chromosome 1q25), or p22phox (CYBA on chromosome 16q24).
  • #1 Chronic Granulomatous Disease (CGD): Commonly Associated Pathogens, Diagnosis and Treatment
    https://www.mdpi.com/2076-2607/11/9/2233
    The clinical characteristics and rigour of the disease, as well as patient survival, depend significantly on the gene, type, and position of the mutation. […] It was demonstrated for the first time that EROS (CYBC1/C17ORF62) regulates abundance of the gp91phox-p22phox heterodimer of the phagocyte NADPH OEC in human cells. Essential reactive oxygen species (EROS) mutations are a novel cause of chronic granulomatous disease.
  • #1
    https://link.springer.com/article/10.1007/s12325-017-0636-2
    Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. […] Mutations in any of the five structural subunits of the NADPH oxidase complex result in defective ROS production and the syndrome of CGD. […] Mechanistically, the survival of patients with CGD is strongly associated with residual superoxide production independent of the specific gene affected. […] CGD was initially described as a fatal granulomatous disease of childhood, and historically, most patients with CGD died by 10 years of age. […] However, improved awareness of the disease and advances in management have led to a marked improvement in life expectancy. […] Nevertheless, the median age of death remains around 30-40 years, and patients tend to become increasingly debilitated with poor quality of life with advancing age.
  • #1 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. […] Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a respiratory burst, essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. […] CGD is caused by a defect in the burst of oxygen consumption that normally accompanies phagocytosis in myeloid cells (i.e. neutrophils, eosinophils, monocytes, and macrophages). The respiratory burst involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide (O2), which in turn gives rise to hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and hydroxyl radical (.OH). These oxygen derivatives play a critical role in the killing of certain pathogenic bacteria and fungi.
  • #1 Pediatric Chronic Granulomatous Disease: Practice Essentials, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/956936-overview
    Chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-). […] This consequently interferes with the production of hydroxyl radical (OH-), hydrogen peroxide (H2O2), peroxynitrite anion (ONOO-), and oxyhalides, products that play a critical role in killing certain pathogenic bacterial and fungal agents. […] CGD is known to be caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH), reduced form, oxidase enzyme complex of phagocytes. […] The cause of chronic granulomatous disease is an inherited defect in one of the six components of phagocyte NADPH oxidase enzyme complex. […] The most common molecular defect in chronic granulomatous disease is a mutation in the CYBB (cytochrome B, b subunit) gene, which is located on the X chromosome and that encodes for gp91phox (the b subunit of flavocytochrome b558).
  • #1 Pediatric Chronic Granulomatous Disease: Practice Essentials, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/956936-overview
    The CGD phagocyte can kill numerous microorganisms despite its defects because most microorganisms endogenously produce hydrogen peroxide, which the CGD-affected phagocyte can modify and use against the organism in the phagosome. […] Bacteria and fungi that cause most infections in CGD are catalase-positive organisms. […] The diagnosis of chronic granulomatous disease should be considered in any patient with recurrent infections with catalase-positive organisms; infections with unusual organisms such as Serratia marcescens, A nidulans, or B cepacia; or infections in sites normally considered to be rare in children, such as a Staphylococcus aureus infection in a liver abscess.
  • #1 Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis/print
    Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase (phox). […] These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. […] Infections in patients with CGD are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase positive), but catalase is neither necessary nor sufficient for pathogenicity in CGD. […] Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts.
  • #1 Chronic Granulomatous Disease | Concise Medical Knowledge
    https://www.lecturio.com/concepts/chronic-granulomatous-disease/
    Chronic granulomatous disease is a defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. […] The NADPH-oxidase enzyme is impaired in phagocytic cell production of superoxide anion O2, which affects other oxidants. This enzyme is responsible for the inability to fight infections. […] Catalase-positive microorganisms are implicated in life-threatening infections. […] A deficiency in NADPH oxidase results in an inability to produce superoxide, which diminishes the cells’ ability to destroy catalase-positive microorganisms.
  • #1 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the phagocytic NADPH oxidase system. […] In this article, we systematically review the possible mechanisms of hyperinflammation in this rare primary immunodeficiency condition and their correlations with clinical aspects. […] Chronic granulomatous disease (CGD) is a fatal primary immunodeficiency caused by mutations in the genes encoding subunits of the NADPH oxidase system, which consists of five subunits. […] These defects lead to a failure of phagocytes to catalytically convert oxygen to superoxide and other reactive oxygen species (ROS) that play a key role in killing intracellular pathogens. […] Inflammation is frequent in patients with CGD, and in some instances it can be the first clinical manifestation. […] Current data indicate that either increased or decreased NOX2 activity may lead to inflammatory complications.
  • #1 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    NADPH oxidase deficiency has been seen predominantly as an immunodeficiency, characterized by an inability to mount an inflammatory response. However, there is current evidence for hyperinflammatory complications of CGD. […] The main manifestations are represented prominently by granulomas, as well as colitis, which is frequent and leads to substantial morbidity. […] Defects of microbicidal activity can facilitate the persistence of pathogens and increase the inflammatory response in some patients. […] Granulomas can occur in most instances without an infectious pathogen. […] Nevertheless, the primary mechanism of the increased inflammatory response remains poorly understood. […] A high production of ROS is usually associated with hyperinflammation. […] It is possible that ROS can modulate the inflammatory response, and the NADPH oxidase system is likely to play an important role in this resolution.
  • #1 Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era
    https://www.mdpi.com/2077-0383/13/15/4435
    Mutation of RAC2, therefore, disrupts signalling to the NADPH oxidase complex, resulting in defects in ROS production and other neutrophil and lymphocyte functions, which manifest as an autosomal dominant CGD-like syndrome. […] Overall, neutrophils deficient in the respiratory burst show defective killing of microorganisms by phagocytosis, neutrophil extracellular traps, and other forms of regulated cell death. […] However, defects of ROS-related inflammatory regulation and other innate immune pathways are thought to be responsible for the hyperinflammatory manifestations of CGD. […] Granulomas are believed to arise where microbes fail to be eliminated, or there is persistent dysregulated local cytokine production following microbial sterilisation.
  • #1 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    The absence of ROS in CGD leukocytes creates signaling alterations that favor proinflammatory responses. […] CGD phagocytes produce high levels of tumor necrosis factor-alpha and interleukin (IL)-8, probably through hyperactivation of NF-kappa B, contributing to the inflammatory response. […] There is evidence suggesting that ROS can induce neutrophil apoptosis. […] The failure to ingest apoptotic cells is hypothesized to cause immunization to self-antigens, leading, for example, to a higher prevalence of lupus in CGD patients. […] The expression of some TLRs, like TLR-5 and TLR-9, can be low in CGD patient neutrophils. […] This can contribute to impaired pathogen recognition, phagocytosis, and chemotaxis, leading to increased disease severity. […] A deficiency in the NADPH oxidase system in CGD patient phagocytes leads to reduced degradation of phagocytosed material or apoptotic cells, which implicates either the remaining phagocytosed pathogen or apoptotic neutrophils phagocytosed by macrophages, such as pathognomonic eosinophilic crystals. […] The main consequence is a persistent activation and hyperinflammation at the cellular level.
  • #1 Pathology Outlines – Chronic granulomatous disease
    https://www.pathologyoutlines.com/topic/colonchronicgran.html
    ROS dysfunction leads to inefficient autophagy, proinflammatory phenotype with increased secretion of proinflammatory cytokines (TNFα, IL1β, IL6) and autoimmunity, which contributes to the hyperinflammation associated with CGD. […] X linked recessive inheritance (65%): mutation on CYBB gene (Xp21.1). […] Autosomal recessive inheritance (35%): mutations on CYBB (16q24), NCF1 (7q11.23), NCF2 (1q25), NCF4 (22q13.1), CYBC1 (17q25.3). […] The case represents the typical clinical presentation of chronic granulomatous disease (CGD), which is characterized by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex within phagocytes (neutrophils, macrophages). […] This defect leads to an impaired oxidative burst, which is crucial for the phagocytes’ ability to generate reactive oxygen species (ROS) and effectively kill engulfed pathogens.
  • #1 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    The data presented in this paper have confirmed earlier reports and show a clear statistically significant difference in life span between the two main types of CGD, although it is important to keep in mind that there have been individual AR-CGD patients with early and extremely severe expression of the disease. […] It is not clear why AR CGD in general follows a milder course, although residual NADPH-oxidase activity has been shown in p47phox deficiency.
  • #1 Orphanet: Chronic granulomatous disease
    https://www.orpha.net/en/disease/detail/379
    A rare primary immunodeficiency, mainly affecting phagocytes, which is characterized by an increased susceptibility to severe and recurrent bacterial and fungal infections, along with the development of granulomas. […] CGD is caused by mutations in any one of the 6 genes encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits or a critical stabilizer. A mutation in the CYBB gene (Xp21.1) is seen in 65% of cases in North America and Western Europe. The other 35% of cases are due to mutations in the CYBA (16q24), NCF1 (7q11.23), NCF2 (1q25), NCF4 (22q13.1) and CYBC1 (17q25.3) genes. A deficiency in the NADPH oxidase enzyme complex leads to decreased production of reactive oxygen species (used by phagocytes to kill bacteria and fungi). […] The X-linked form of CGD typically presents with infection or IBD earlier than the NCF1-related form. To date, the NCF4-related form has only been associated with IBD but no severe infections.
  • #1 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    The trend to develop granulomatous complications in CGD patients appears to be influenced by genetic modifiers. […] Thus, subtle genetic differences in molecules of innate immunity seem to contribute to specific inflammatory responses in CGD patients. […] CGD patients usually exhibit a ROSlow inflammatory response, characterized by a strong activation of oxygen-independent killing mechanisms and an increase in neutrophil influx. […] In addition, this kind of response can be associated with autoimmune disease, as is often observed in CGD patients.
  • #1 X-Linked Chronic Granulomatous Disease Inheritance & Testing – For HCPs
    https://www.cgdpathways.com/cgd-overview/x-linked-chronic-granulomatous-disease
    X-linked CGD is an inherited disorder caused by a mutation in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which is part of neutrophils and the mechanism to kill pathogens. […] X-linked CGD accounts for approximately 65% of CGD cases. […] X-linked carriers who experienced severe infections had at least 1 case of pneumonia caused by a common CGD-associated pathogen. […] 48% of all X-linked carriers of CGD reported infections, autoimmune symptoms, or both.
  • #1 Chronic Granulomatous Disease (CGD) – Immunology; Allergic Disorders – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/chronic-granulomatous-disease-cgd
    Chronic granulomatous disease is characterized by white blood cells that cannot produce activated oxygen compounds and by defects in phagocytic cell microbicidal function. […] In CGD, white blood cells (WBCs) do not produce hydrogen peroxide, superoxide, and other activated oxygen compounds because nicotinamide adenine dinucleotide phosphate oxidase activity is deficient. Phagocytic cell microbicidal function is defective; thus, bacteria and fungi are not killed despite normal phagocytosis. […] Diagnosis of chronic granulomatous disease is by a flow cytometric oxidative (respiratory) burst assay to detect oxygen radical production using dihydrorhodamine 123 (DHR) or nitroblue tetrazolium (NBT). This test can also identify female carriers of the X-linked form and recessive forms. In these forms, the assay using DHR demonstrates 2 populations of phagocytes, normal and affected.
  • #1 Chronic granulomatous disease (CGD) and other phagocytic cell disorders | Immune Deficiency Foundation
    https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/chronic-granulomatous-disease-cgd-and-other
    Chronic granulomatous disease (CGD) is an inherited disease in which the bodys cells that eat invaders (also called phagocytes) do not make hydrogen peroxide and other chemicals. […] Chronic granulomatous disease (CGD) is a type of primary immunodeficiency (PI) in which one group of the bodys white blood cells, called neutrophils, fail to make the hydrogen peroxide, bleach, and other chemicals needed to fight bacterial and fungal infections. […] The most accurate test for chronic granulomatous disease (CGD) measures hydrogen peroxide in phagocytes using a chemical called dihydrorhodamine. […] The foundations of CGD management are early diagnosis; a combination of antibiotics and antifungal prophylaxis and interferon-gamma to reduce infections; management of exposures; and consideration for hematopoietic stem cell transplantation.
  • #1 Chronic granulomatous disease in pediatric patients: 25 years of experience | Allergologia et Immunopathologia
    https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-chronic-granulomatous-disease-in-pediatric-13106774
    The laboratory diagnosis of CGD is based on the demonstration of absence of phagocyte oxidizing activity. Many different diagnostic tests have been developed to this effect (direct measurement of superoxide production, ferrocytochrome reduction, the nitroblue tetrazolium test (NBT), and the oxidation test via flow cytometry). Flow cytometry is presently the most widely used technique, due to its greater objectiveness and reproducibility. […] The absence of phagocytic oxidative capacity in patients with CGD makes them vulnerable to bacterial and fungal infections in different locations. In any case, the increased susceptibility to infection is quite limited to a concrete range of microorganisms a fact that should contribute to suspect the diagnosis. […] The effectiveness of IFN- is subject to debate, since the exact mechanism by which it acts is not known, and the subcutaneous route of administration involved makes it more difficult to use in children. However, any mechanism capable of boosting activation of some of the other bactericidal mechanisms of phagocytic cells may be of help in eliminating intracellular infections the latter being the most frequent processes in CGD.
  • #1 Chronic granulomatous disease – Symptoms and causes – Mayo Clinic
    https://www.mayoclinic.org/diseases-conditions/chronic-granulomatous-disease/symptoms-causes/syc-20355817
    Chronic granulomatous (gran-u-LOM-uh-tus) disease (CGD) is a genetic condition in which infection-fighting white blood cells don’t work properly. […] A change in one of five genes can cause CGD. People with CGD inherit the changed gene from a parent. These genes produce proteins that form an enzyme. This enzyme helps your immune system work properly. The enzyme is active in white blood cells, called phagocytes, that protect you from infections by destroying fungi and bacteria. The enzyme also is active in immune cells that help your body heal. […] When there are changes to one of these genes, the protective proteins are not produced. Or they’re produced, but they don’t work properly.
  • #1 Chronic Granulomatous Disease (CGD) | Boston Children’s Hospital
    https://www.childrenshospital.org/conditions/chronic-granulomatous-disease-cgd
    Chronic granulomatous disease (CGD) is diagnosed through: Neutrophil function tests to determine how well these white blood cells are functioning. […] Genetic testing to confirm the presence of a specific gene mutation that results in CGD. […] The treatment involves collecting blood stem cells from the patient and treating them, in a highly specialized laboratory, using a harmless virus to insert a correct version of the faulty gp91-phox gene into the cells. […] After the transplant, the stem cells can produce new white blood cells that can fight off infection.
  • #1
    https://sciety.org/articles/activity/10.1101/2025.01.23.634507
    Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. […] Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2 high -neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. […] Spatial transcriptomics demonstrated that NOS2 high -neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. […] This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions.
  • #1 CGD – The Basics – CGDSociety
    https://cgdsociety.org/about-cgd/cgd-the-basics/
    CGD is a disorder that prevents the immune system fighting off certain infections. People with CGD carry a faulty immune system gene, which means that white blood cells, called phagocytes, don’t work properly. […] People with CGD can’t produce these attacking chemicals, because genetic mutations mean they are missing a vital protein in an enzyme called NADPH oxidase. This makes them more susceptible to fungal and bacterial infections. […] Inflammatory problems can be severe and include inflammation of the bowel (colitis), lung, bladder (cystitis) and gums (gingivitis). Sometimes problems are caused by granulomas. These are nodules of immune cells that form tight ball-like structures that can cause obstruction in body tissues.
  • #1 Chronic Granulomatous Disease Facts, Symptoms, and Treatment
    https://www.cgdconnections.com/about-cgd
    Chronic granulomatous disease, or C-G-D, is a rare disease that about 20 children are born with every year in the United States. CGD is a rare, inherited disease. It affects the immune system and makes it harder to fight off certain types of infections caused by bacteria and fungi. With CGD, infections that could typically be prevented by a healthy immune system may grow to become serious*, or even life-threatening. CGD is a chronic condition, meaning it is a persistent disease, and for CGD patients means that it is lifelong. People with CGD have an immune system that doesn’t work properly, so they are at more of a risk of getting serious, life-threatening infections that lead to hospitalization. As the immune cells try and fail to kill the fungi or bacteria, they build up and form hard lumps called granulomas. When the immune system finds harmful things in the body, like bacteria and fungi, it sends immune cells to kill them. If the infection doesn’t go away, more immune cells show up to try to kill the bacteria or fungi. In time, this buildup forms a hard lump called a granuloma (gran-yoo-low-muh). A genetic condition is caused by a change, or mutation, in a gene. The gene may be passed down to a child from one or both parents. CGD is a genetic disorder, usually diagnosed in childhood, that affects some cells of the immune system and the body’s ability to fight infections effectively. In addition to making informed health and lifestyle choices, people with CGD can take medicines that help manage symptoms and reduce the risk of serious infections. This may include antibiotics, antifungals, and interferon gamma such as ACTIMMUNE (Interferon gamma-1b).
  • #1 Chronic Granulomatous Disease (CGD) | Dana-Farber Cancer Institute
    https://www.dana-farber.org/cancer-care/types/childhood-chronic-granulomatous-disease
    Chronic granulomatous disease (CGD) is an inherited immune system disorder that occurs when a type of white blood cell that usually helps the body fight infection, called a phagocyte, does not work properly. […] In CGD, the phagocytes can’t kill germs that are ingested, and cannot protect the body from bacterial and fungal infections. […] Children with CGD may also develop masses of inflammatory tissue called granulomas in response to chronic infections. These granulomas usually develop in the skin, gastrointestinal tract, and genitourinary tract.
  • #1 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    In CGD patients and some animal model mimicking CGD with specific pathogen challenging, the proliferation and mobilization of myeloid immune cells, especially neutrophils, coupled with the significant expression of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-1β, are considered major contributors to the induction of inflammatory states. […] However, these treatments are constrained by substantial side effects or low remission rates in severely ill patients. […] Therefore, constructing a comprehensive immune cell atlas of CGD to understand the key endogenous signals driving persistent inflammation in the special disease is critical for developing new targeted therapies. […] Macrophage migration inhibitory factor (MIF) is a significant regulator in inflammatory and autoimmune diseases, known to intensify inflammation by activating signaling pathways such as MAPK, PI3K/AKT, and NF-κB.
  • #1
    https://igj.tums.ac.ir/index.php/igj/article/view/53
    Chronic granulomatous disease (CGD) is a relatively rare inborn error of immune system caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex which leads to impaired production of reactive oxygen species (ROS) and ineffective phagocyte function. […] Genetic defects of any of proteinaceous components of NADPH oxidase complex results in CGD. […] The most common type of CGD (65-70%) is caused by X-linked mutations in the CYBB gene encoding gp91phox, followed by autosomal recessive mutations in the NCF1, NCF2, CYBA and NCF4 genes encoding p47phox, p67phox, p22phox, and p40phox, respectively. […] Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease. […] Gene expression profiling provides insight into the pathophysiology of chronic granulomatous disease.
  • #1 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. […] Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2high-neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. […] This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions. […] Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by loss-of-function mutations in the genes encoding the NADPH Oxidase 2 (NOX2) subunits (CYBB, CYBA, NCF1, NCF2, NCF4) and the subunit assembly-related gene (CYBC1).
  • #1
    https://link.springer.com/article/10.1007/s00018-011-0834-z
    The key features in the pathophysiology of CGD are the exaggerated inflammatory responses and the formation of granuloma. The exaggerated inflammatory responses in CGD may in part be explained by insufficient clearance of the causative microorganisms. Frequently though, inflamed sites are sterile, indicating that this microbial persistence may not be the only explanation. […] The hyperinflammatory reactivity of the host immune system was extended in in vitro studies showing that CGD phagocytes display exaggerated inflammatory mediator responses to various stimuli. The absence of ROS in CGD phagocytes resulted in exaggerated TNF- production and inflammasome activity which under certain conditions may be held responsible for the IL-1 production in CGD. […] The formation of granulomas is the other key feature in CGD, hence its name chronic granulomatous disease. Granulomas are highly dynamic structures that, at least initially, center on the micro-organism or cells containing the intracellular micro-organism and at its border consist of a cellular barrier. The formation of granuloma is particularly manifest in conditions with an inadequate anti-microbial defense, which may relate to the causative pathogen and/or to the condition of the host. In that respect, granuloma may be viewed as a means to contain persisting microorganisms and to seclude these from the hosts immune response. In CGD, the granulomas found are often sterile, indicating that the presence of granuloma does not appear to require the continued presence of microorganisms. […] The molecular defects in CGD are known, but how this leads to the resulting pathophysiology is not well understood.
  • #1 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    Here we hypothesize that Morrbid plays a role in driving excessive inflammatory state in CGD. […] In our most recent study, we demonstrated that NCF2 is associated with acute myeloid leukemia and anti-leukemia drug resistance. […] However, its physiological roles remain largely unknown. […] Neutrophil Cytosolic Factor 2 (NCF2) encodes the cytosolic subunit p67phox of the NOX2 holoenzyme, which is critical for the NADPH oxidase activity. […] Germline mutations in NCF2, as with other NOX2 subunit genes, have been reported to be associated with CGD. […] Notably, certain genetic variants of NCF2 are also linked to increased susceptibility to autoinflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis, underscoring its pivotal role in regulating intrinsic inflammation.
  • #1 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    In this study, we changed the husbandry condition from specific pathogen free facility (SPF) to a clean-grade (CL) condition and observed a natural occurrence of CGD in Ncf2-/- mice. […] We thoroughly decoded the pathogenies of the nature CGD by combining regular single-cell transcriptomics and spatial transcriptomics and developed three different but correlated perturbations for the rare hypo-inflammation condition.
  • #2 Chronic Granulomatous Disease: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/1116022-overview
    Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. […] Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from the inability of phagocytes to kill microbes they have ingested. This impairment in killing is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which generates the microbicidal respiratory burst. In CGD, phagocytes ingest bacteria normally, but they cannot kill them. […] The main defect in chronic granulomatous disease (CGD) is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. The intracellular survival of ingested bacteria leads to the development of granulomata in the lymph nodes, skin, lungs, liver, gastrointestinal tract, and/or bones.
  • #2 Chronic granulomatous disease: a review of the infectious and inflammatory complications | Clinical and Molecular Allergy | Full Text
    https://clinicalmolecularallergy.biomedcentral.com/articles/10.1186/1476-7961-9-10
    Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. […] The disease is the result of a disorder of the NADPH oxidase system, culminating in an inability of the phagocyte to generate superoxide, leading to the defective killing of pathogenic organisms. […] CGD represents a heterogeneous group of disorders characterized by defective generation of a respiratory burst in human phagocytes (neutrophils, mononuclear cells, macrophages, and eosinophils). The resultant defect is an inability to generate superoxide and hence an inability to contain certain infectious pathogens. […] The presumed mechanism of CGD and the associated defects in NADPH oxidase system are shown in Figure 4. The assembly of the various subunits of NADPH oxidase is shown in the figure, while the molecular genetics, rough prevalence, inheritance pattern, and chromosomal localization are shown in the bottom of the figure.
  • #2 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Chronic-Granulomatous-Disease.aspx
    Chronic granulomatous disease (CGD) is a rare genetic immunodeficiency associated with phagocyte function. It is caused due to functional impairment in the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex. […] CGD occurs due to NADPH oxidase complex dysfunction in neutrophilic granulocytes and monocytes. It is due to mutations that inactivate NOX2 and its auxiliary proteins. These proteins work together to construct the phagocyte NADPH oxidase enzyme, which produces superoxide. […] As a result, CGD patients with a dysfunctional phagocyte NADPH oxidase suffer from recurring, life-threatening infections with specific bacteria, fungi, and yeasts. […] CGD pathogenesis is mediated by six genes with two distinct inheritance patterns. These are – CYBB, CYBA, CYBC1, NCF1, NCF2, and NCF4. The most common form of CGD is the X-linked form, caused by mutations in the CYBB gene – found on the X chromosome and codes for NOX2.
  • #2 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Chronic-Granulomatous-Disease.aspx
    CYBB mutations range from single nucleotide changes to megabase deletions. Missense, nonsense mutations (direct or by frameshift) produce a stop codon farther downstream, causing protein synthesis to be terminated prematurely. […] The active NADPH oxidase complex is a six-protein complex. It has two components in its basic state: a membrane-bound complex embedded in the walls of secondary granules and separate cytosolic components. […] The NADH oxidase enzyme is a multicomponent enzyme that consists of a membrane-bound, heterodimeric b-type cytochrome that includes the subunits gp91phox (also known as Nox2) and p22phox. All of these elements are essential for the normal production of superoxide.
  • #2 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    As a result of the failure to mount a respiratory burst in their phagocytes, the majority of CGD patients suffers from severe recurrent infections and also from dysregulated Th-17-lymphocyte-controled inflammation. […] The enzyme that catalyzes the respiratory burst, the leukocyte NADPH oxidase, consists of subunits, four of which are important for CGD (designated phox for phagocyte oxidase): gp91phox (or Nox2) and p22phox, located in membranes, as well as two cytosolic oxidase components, p47phox and p67phox. CGD is caused by a defect in any of these four components. […] Mutations in the gp91phox gene (CYBB on chromosome Xp21.1) cause the X-linked recessive form of the disease that affects the majority of CGD patients (70%). […] The remaining 30% of cases has inherited the disease in an autosomal recessive manner, in which males and females are equally affected. These patients have mutations in the genes encoding p47phox (NCF1 on chromosome 7q11.23), p67phox (NCF2 on chromosome 1q25), or p22phox (CYBA on chromosome 16q24).
  • #2 Pediatric Chronic Granulomatous Disease: Practice Essentials, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/956936-overview
    Chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-). […] This consequently interferes with the production of hydroxyl radical (OH-), hydrogen peroxide (H2O2), peroxynitrite anion (ONOO-), and oxyhalides, products that play a critical role in killing certain pathogenic bacterial and fungal agents. […] CGD is known to be caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH), reduced form, oxidase enzyme complex of phagocytes. […] The cause of chronic granulomatous disease is an inherited defect in one of the six components of phagocyte NADPH oxidase enzyme complex. […] The most common molecular defect in chronic granulomatous disease is a mutation in the CYBB (cytochrome B, b subunit) gene, which is located on the X chromosome and that encodes for gp91phox (the b subunit of flavocytochrome b558).
  • #2 Pediatric Chronic Granulomatous Disease: Practice Essentials, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/956936-overview
    The CGD phagocyte can kill numerous microorganisms despite its defects because most microorganisms endogenously produce hydrogen peroxide, which the CGD-affected phagocyte can modify and use against the organism in the phagosome. […] Bacteria and fungi that cause most infections in CGD are catalase-positive organisms. […] The diagnosis of chronic granulomatous disease should be considered in any patient with recurrent infections with catalase-positive organisms; infections with unusual organisms such as Serratia marcescens, A nidulans, or B cepacia; or infections in sites normally considered to be rare in children, such as a Staphylococcus aureus infection in a liver abscess.
  • #2 Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis/print
    Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase (phox). […] These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. […] Infections in patients with CGD are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase positive), but catalase is neither necessary nor sufficient for pathogenicity in CGD. […] Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts.
  • #2 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the phagocytic NADPH oxidase system. […] In this article, we systematically review the possible mechanisms of hyperinflammation in this rare primary immunodeficiency condition and their correlations with clinical aspects. […] Chronic granulomatous disease (CGD) is a fatal primary immunodeficiency caused by mutations in the genes encoding subunits of the NADPH oxidase system, which consists of five subunits. […] These defects lead to a failure of phagocytes to catalytically convert oxygen to superoxide and other reactive oxygen species (ROS) that play a key role in killing intracellular pathogens. […] Inflammation is frequent in patients with CGD, and in some instances it can be the first clinical manifestation. […] Current data indicate that either increased or decreased NOX2 activity may lead to inflammatory complications.
  • #2 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    NADPH oxidase deficiency has been seen predominantly as an immunodeficiency, characterized by an inability to mount an inflammatory response. However, there is current evidence for hyperinflammatory complications of CGD. […] The main manifestations are represented prominently by granulomas, as well as colitis, which is frequent and leads to substantial morbidity. […] Defects of microbicidal activity can facilitate the persistence of pathogens and increase the inflammatory response in some patients. […] Granulomas can occur in most instances without an infectious pathogen. […] Nevertheless, the primary mechanism of the increased inflammatory response remains poorly understood. […] A high production of ROS is usually associated with hyperinflammation. […] It is possible that ROS can modulate the inflammatory response, and the NADPH oxidase system is likely to play an important role in this resolution.
  • #2 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    The absence of ROS in CGD leukocytes creates signaling alterations that favor proinflammatory responses. […] CGD phagocytes produce high levels of tumor necrosis factor-alpha and interleukin (IL)-8, probably through hyperactivation of NF-kappa B, contributing to the inflammatory response. […] There is evidence suggesting that ROS can induce neutrophil apoptosis. […] The failure to ingest apoptotic cells is hypothesized to cause immunization to self-antigens, leading, for example, to a higher prevalence of lupus in CGD patients. […] The expression of some TLRs, like TLR-5 and TLR-9, can be low in CGD patient neutrophils. […] This can contribute to impaired pathogen recognition, phagocytosis, and chemotaxis, leading to increased disease severity. […] A deficiency in the NADPH oxidase system in CGD patient phagocytes leads to reduced degradation of phagocytosed material or apoptotic cells, which implicates either the remaining phagocytosed pathogen or apoptotic neutrophils phagocytosed by macrophages, such as pathognomonic eosinophilic crystals. […] The main consequence is a persistent activation and hyperinflammation at the cellular level.
  • #2 Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era
    https://www.mdpi.com/2077-0383/13/15/4435
    Mutation of RAC2, therefore, disrupts signalling to the NADPH oxidase complex, resulting in defects in ROS production and other neutrophil and lymphocyte functions, which manifest as an autosomal dominant CGD-like syndrome. […] Overall, neutrophils deficient in the respiratory burst show defective killing of microorganisms by phagocytosis, neutrophil extracellular traps, and other forms of regulated cell death. […] However, defects of ROS-related inflammatory regulation and other innate immune pathways are thought to be responsible for the hyperinflammatory manifestations of CGD. […] Granulomas are believed to arise where microbes fail to be eliminated, or there is persistent dysregulated local cytokine production following microbial sterilisation.
  • #2 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    The data presented in this paper have confirmed earlier reports and show a clear statistically significant difference in life span between the two main types of CGD, although it is important to keep in mind that there have been individual AR-CGD patients with early and extremely severe expression of the disease. […] It is not clear why AR CGD in general follows a milder course, although residual NADPH-oxidase activity has been shown in p47phox deficiency.
  • #2
    https://link.springer.com/article/10.1007/s12325-017-0636-2
    Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. […] Mutations in any of the five structural subunits of the NADPH oxidase complex result in defective ROS production and the syndrome of CGD. […] Mechanistically, the survival of patients with CGD is strongly associated with residual superoxide production independent of the specific gene affected. […] CGD was initially described as a fatal granulomatous disease of childhood, and historically, most patients with CGD died by 10 years of age. […] However, improved awareness of the disease and advances in management have led to a marked improvement in life expectancy. […] Nevertheless, the median age of death remains around 30-40 years, and patients tend to become increasingly debilitated with poor quality of life with advancing age.
  • #2 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    The trend to develop granulomatous complications in CGD patients appears to be influenced by genetic modifiers. […] Thus, subtle genetic differences in molecules of innate immunity seem to contribute to specific inflammatory responses in CGD patients. […] CGD patients usually exhibit a ROSlow inflammatory response, characterized by a strong activation of oxygen-independent killing mechanisms and an increase in neutrophil influx. […] In addition, this kind of response can be associated with autoimmune disease, as is often observed in CGD patients.
  • #2 Chronic Granulomatous Disease (CGD) – Immunology; Allergic Disorders – Merck Manual Professional Edition
    https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/chronic-granulomatous-disease-cgd
    Chronic granulomatous disease is characterized by white blood cells that cannot produce activated oxygen compounds and by defects in phagocytic cell microbicidal function. […] In CGD, white blood cells (WBCs) do not produce hydrogen peroxide, superoxide, and other activated oxygen compounds because nicotinamide adenine dinucleotide phosphate oxidase activity is deficient. Phagocytic cell microbicidal function is defective; thus, bacteria and fungi are not killed despite normal phagocytosis. […] Diagnosis of chronic granulomatous disease is by a flow cytometric oxidative (respiratory) burst assay to detect oxygen radical production using dihydrorhodamine 123 (DHR) or nitroblue tetrazolium (NBT). This test can also identify female carriers of the X-linked form and recessive forms. In these forms, the assay using DHR demonstrates 2 populations of phagocytes, normal and affected.
  • #2 Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis
    Chronic granulomatous disease (CGD) is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase (phox). […] These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. […] Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts. […] The diagnosis is made by neutrophil function testing for superoxide production (nitroblue tetrazolium reduction or dihydrorhodamine [DHR] 123 flow cytometry assay). […] The exact molecular defect is determined by genotyping.
  • #2
    https://sciety.org/articles/activity/10.1101/2025.01.23.634507
    Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. […] Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2 high -neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. […] Spatial transcriptomics demonstrated that NOS2 high -neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. […] This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions.
  • #2 CGD – The Basics – CGDSociety
    https://cgdsociety.org/about-cgd/cgd-the-basics/
    CGD is a disorder that prevents the immune system fighting off certain infections. People with CGD carry a faulty immune system gene, which means that white blood cells, called phagocytes, don’t work properly. […] People with CGD can’t produce these attacking chemicals, because genetic mutations mean they are missing a vital protein in an enzyme called NADPH oxidase. This makes them more susceptible to fungal and bacterial infections. […] Inflammatory problems can be severe and include inflammation of the bowel (colitis), lung, bladder (cystitis) and gums (gingivitis). Sometimes problems are caused by granulomas. These are nodules of immune cells that form tight ball-like structures that can cause obstruction in body tissues.
  • #2 Chronic Granulomatous Disease Facts, Symptoms, and Treatment
    https://www.cgdconnections.com/about-cgd
    Chronic granulomatous disease, or C-G-D, is a rare disease that about 20 children are born with every year in the United States. CGD is a rare, inherited disease. It affects the immune system and makes it harder to fight off certain types of infections caused by bacteria and fungi. With CGD, infections that could typically be prevented by a healthy immune system may grow to become serious*, or even life-threatening. CGD is a chronic condition, meaning it is a persistent disease, and for CGD patients means that it is lifelong. People with CGD have an immune system that doesn’t work properly, so they are at more of a risk of getting serious, life-threatening infections that lead to hospitalization. As the immune cells try and fail to kill the fungi or bacteria, they build up and form hard lumps called granulomas. When the immune system finds harmful things in the body, like bacteria and fungi, it sends immune cells to kill them. If the infection doesn’t go away, more immune cells show up to try to kill the bacteria or fungi. In time, this buildup forms a hard lump called a granuloma (gran-yoo-low-muh). A genetic condition is caused by a change, or mutation, in a gene. The gene may be passed down to a child from one or both parents. CGD is a genetic disorder, usually diagnosed in childhood, that affects some cells of the immune system and the body’s ability to fight infections effectively. In addition to making informed health and lifestyle choices, people with CGD can take medicines that help manage symptoms and reduce the risk of serious infections. This may include antibiotics, antifungals, and interferon gamma such as ACTIMMUNE (Interferon gamma-1b).
  • #2 Chronic Granulomatous Disease (CGD) | Boston Children’s Hospital
    https://www.childrenshospital.org/conditions/chronic-granulomatous-disease-cgd
    Chronic granulomatous disease (CGD) is an inherited immune system disorder that occurs when a type of white blood cell (phagocyte), which usually helps the body fight infection, does not work properly. […] In CGD, the phagocytes cant kill germs that are ingested and therefore cannot protect the body from bacterial and fungal infections. […] Because they are unable to fight off infections, children with CGD often get very sick from bacteria that could be mild or cause no disease at all in a healthy child. […] These infections may affect the lungs, skin, liver, lymph nodes and intestines. […] Children may also develop masses of inflammatory tissue called granulomas in response to chronic infections. […] CGD was named for these masses of inflammation before the genetic causes were discovered.
  • #2 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    In CGD patients and some animal model mimicking CGD with specific pathogen challenging, the proliferation and mobilization of myeloid immune cells, especially neutrophils, coupled with the significant expression of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-1β, are considered major contributors to the induction of inflammatory states. […] However, these treatments are constrained by substantial side effects or low remission rates in severely ill patients. […] Therefore, constructing a comprehensive immune cell atlas of CGD to understand the key endogenous signals driving persistent inflammation in the special disease is critical for developing new targeted therapies. […] Macrophage migration inhibitory factor (MIF) is a significant regulator in inflammatory and autoimmune diseases, known to intensify inflammation by activating signaling pathways such as MAPK, PI3K/AKT, and NF-κB.
  • #2 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. […] Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2high-neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. […] This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions. […] Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by loss-of-function mutations in the genes encoding the NADPH Oxidase 2 (NOX2) subunits (CYBB, CYBA, NCF1, NCF2, NCF4) and the subunit assembly-related gene (CYBC1).
  • #2
    https://igj.tums.ac.ir/index.php/igj/article/view/53
    Chronic granulomatous disease (CGD) is a relatively rare inborn error of immune system caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex which leads to impaired production of reactive oxygen species (ROS) and ineffective phagocyte function. […] Genetic defects of any of proteinaceous components of NADPH oxidase complex results in CGD. […] The most common type of CGD (65-70%) is caused by X-linked mutations in the CYBB gene encoding gp91phox, followed by autosomal recessive mutations in the NCF1, NCF2, CYBA and NCF4 genes encoding p47phox, p67phox, p22phox, and p40phox, respectively. […] Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease. […] Gene expression profiling provides insight into the pathophysiology of chronic granulomatous disease.
  • #2
    https://link.springer.com/article/10.1007/s00018-011-0834-z
    The key features in the pathophysiology of CGD are the exaggerated inflammatory responses and the formation of granuloma. The exaggerated inflammatory responses in CGD may in part be explained by insufficient clearance of the causative microorganisms. Frequently though, inflamed sites are sterile, indicating that this microbial persistence may not be the only explanation. […] The hyperinflammatory reactivity of the host immune system was extended in in vitro studies showing that CGD phagocytes display exaggerated inflammatory mediator responses to various stimuli. The absence of ROS in CGD phagocytes resulted in exaggerated TNF- production and inflammasome activity which under certain conditions may be held responsible for the IL-1 production in CGD. […] The formation of granulomas is the other key feature in CGD, hence its name chronic granulomatous disease. Granulomas are highly dynamic structures that, at least initially, center on the micro-organism or cells containing the intracellular micro-organism and at its border consist of a cellular barrier. The formation of granuloma is particularly manifest in conditions with an inadequate anti-microbial defense, which may relate to the causative pathogen and/or to the condition of the host. In that respect, granuloma may be viewed as a means to contain persisting microorganisms and to seclude these from the hosts immune response. In CGD, the granulomas found are often sterile, indicating that the presence of granuloma does not appear to require the continued presence of microorganisms. […] The molecular defects in CGD are known, but how this leads to the resulting pathophysiology is not well understood.
  • #2 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    Here we hypothesize that Morrbid plays a role in driving excessive inflammatory state in CGD. […] In our most recent study, we demonstrated that NCF2 is associated with acute myeloid leukemia and anti-leukemia drug resistance. […] However, its physiological roles remain largely unknown. […] Neutrophil Cytosolic Factor 2 (NCF2) encodes the cytosolic subunit p67phox of the NOX2 holoenzyme, which is critical for the NADPH oxidase activity. […] Germline mutations in NCF2, as with other NOX2 subunit genes, have been reported to be associated with CGD. […] Notably, certain genetic variants of NCF2 are also linked to increased susceptibility to autoinflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis, underscoring its pivotal role in regulating intrinsic inflammation.
  • #3 Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis/print
    Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterized by recurrent, life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which constitutes the phagocyte oxidase (phox). […] These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes. […] Infections in patients with CGD are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase positive), but catalase is neither necessary nor sufficient for pathogenicity in CGD. […] Inflammatory complications such as the formation of granulomata are especially problematic in the lungs and the gastrointestinal and genitourinary tracts.
  • #3 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. […] Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a respiratory burst, essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. […] CGD is caused by a defect in the burst of oxygen consumption that normally accompanies phagocytosis in myeloid cells (i.e. neutrophils, eosinophils, monocytes, and macrophages). The respiratory burst involves the catalytic conversion of molecular oxygen to the oxygen free-radical superoxide (O2), which in turn gives rise to hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and hydroxyl radical (.OH). These oxygen derivatives play a critical role in the killing of certain pathogenic bacteria and fungi.
  • #3 Azthena logo with the word Azthena
    https://www.news-medical.net/health/What-is-Chronic-Granulomatous-Disease.aspx
    Chronic granulomatous disease (CGD) is a rare genetic immunodeficiency associated with phagocyte function. It is caused due to functional impairment in the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex. […] CGD occurs due to NADPH oxidase complex dysfunction in neutrophilic granulocytes and monocytes. It is due to mutations that inactivate NOX2 and its auxiliary proteins. These proteins work together to construct the phagocyte NADPH oxidase enzyme, which produces superoxide. […] As a result, CGD patients with a dysfunctional phagocyte NADPH oxidase suffer from recurring, life-threatening infections with specific bacteria, fungi, and yeasts. […] CGD pathogenesis is mediated by six genes with two distinct inheritance patterns. These are – CYBB, CYBA, CYBC1, NCF1, NCF2, and NCF4. The most common form of CGD is the X-linked form, caused by mutations in the CYBB gene – found on the X chromosome and codes for NOX2.
  • #3 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    NADPH oxidase deficiency has been seen predominantly as an immunodeficiency, characterized by an inability to mount an inflammatory response. However, there is current evidence for hyperinflammatory complications of CGD. […] The main manifestations are represented prominently by granulomas, as well as colitis, which is frequent and leads to substantial morbidity. […] Defects of microbicidal activity can facilitate the persistence of pathogens and increase the inflammatory response in some patients. […] Granulomas can occur in most instances without an infectious pathogen. […] Nevertheless, the primary mechanism of the increased inflammatory response remains poorly understood. […] A high production of ROS is usually associated with hyperinflammation. […] It is possible that ROS can modulate the inflammatory response, and the NADPH oxidase system is likely to play an important role in this resolution.
  • #3 SciELO Brazil – Chronic granulomatous disease: why an inflammatory disease? Chronic granulomatous disease: why an inflammatory disease?
    https://www.scielo.br/j/bjmbr/a/GFn4cFkyc8VvDggkfD3nW4S/?lang=en
    The absence of ROS in CGD leukocytes creates signaling alterations that favor proinflammatory responses. […] CGD phagocytes produce high levels of tumor necrosis factor-alpha and interleukin (IL)-8, probably through hyperactivation of NF-kappa B, contributing to the inflammatory response. […] There is evidence suggesting that ROS can induce neutrophil apoptosis. […] The failure to ingest apoptotic cells is hypothesized to cause immunization to self-antigens, leading, for example, to a higher prevalence of lupus in CGD patients. […] The expression of some TLRs, like TLR-5 and TLR-9, can be low in CGD patient neutrophils. […] This can contribute to impaired pathogen recognition, phagocytosis, and chemotaxis, leading to increased disease severity. […] A deficiency in the NADPH oxidase system in CGD patient phagocytes leads to reduced degradation of phagocytosed material or apoptotic cells, which implicates either the remaining phagocytosed pathogen or apoptotic neutrophils phagocytosed by macrophages, such as pathognomonic eosinophilic crystals. […] The main consequence is a persistent activation and hyperinflammation at the cellular level.
  • #3 Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model | bioRxiv
    https://www.biorxiv.org/content/10.1101/2025.01.23.634507v1.full-text
    In CGD patients and some animal model mimicking CGD with specific pathogen challenging, the proliferation and mobilization of myeloid immune cells, especially neutrophils, coupled with the significant expression of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-1β, are considered major contributors to the induction of inflammatory states. […] However, these treatments are constrained by substantial side effects or low remission rates in severely ill patients. […] Therefore, constructing a comprehensive immune cell atlas of CGD to understand the key endogenous signals driving persistent inflammation in the special disease is critical for developing new targeted therapies. […] Macrophage migration inhibitory factor (MIF) is a significant regulator in inflammatory and autoimmune diseases, known to intensify inflammation by activating signaling pathways such as MAPK, PI3K/AKT, and NF-κB.
  • #3
    https://sciety.org/articles/activity/10.1101/2025.01.23.634507
    Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. […] Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2 high -neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. […] Spatial transcriptomics demonstrated that NOS2 high -neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. […] This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions.
  • #4 Chronic Granulomatous Disease: The European Experience | PLOS One
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005234
    As a result of the failure to mount a respiratory burst in their phagocytes, the majority of CGD patients suffers from severe recurrent infections and also from dysregulated Th-17-lymphocyte-controled inflammation. […] The enzyme that catalyzes the respiratory burst, the leukocyte NADPH oxidase, consists of subunits, four of which are important for CGD (designated phox for phagocyte oxidase): gp91phox (or Nox2) and p22phox, located in membranes, as well as two cytosolic oxidase components, p47phox and p67phox. CGD is caused by a defect in any of these four components. […] Mutations in the gp91phox gene (CYBB on chromosome Xp21.1) cause the X-linked recessive form of the disease that affects the majority of CGD patients (70%). […] The remaining 30% of cases has inherited the disease in an autosomal recessive manner, in which males and females are equally affected. These patients have mutations in the genes encoding p47phox (NCF1 on chromosome 7q11.23), p67phox (NCF2 on chromosome 1q25), or p22phox (CYBA on chromosome 16q24).

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pierwotny niedobór odporności TNF-alfa wybuch tlenowy nadtlenek wodoru CGD sprzężone z chromosomem X choroba autoimmunologiczna NETs gen CYBB reaktywne formy tlenu nieswoiste zapalenie jelit cytometria przepływowa mieloperoksydaza inflamasom oksydaza NADPH zespół kliniczny dysmutaza ponadtlenkowa przewlekła choroba ziarniakowa fagocytoza rodnik hydroksylowy ziarniniaki