Pęcherzyca pęcherzowa – Patofizjologia i mechanizm

Pęcherzyca pęcherzowa
Patofizjologia i mechanizm

Pęcherzyca pęcherzowa (Bullous pemphigoid) to najczęstsza autoimmunologiczna choroba pęcherzowa skóry, charakteryzująca się obecnością autoprzeciwciał IgG i IgE skierowanych przeciwko białkom hemidesmosomów BP180 (kolagen XVII) i BP230. Patogeneza obejmuje mechanizmy zależne od układu dopełniacza, gdzie wiązanie autoprzeciwciał aktywuje kaskadę zapalną z udziałem anafilatoksyn C3a i C5a, prowadząc do rekrutacji neutrofili, eozynofilów i komórek tucznych, które uwalniają proteazy (m.in. MMP9, elastazę neutrofilową) i reaktywne formy tlenu, powodując uszkodzenie połączenia skórno-naskórkowego i tworzenie pęcherzy podnaskórkowych. W patogenezie kluczową rolę odgrywa odpowiedź immunologiczna typu Th2 z podwyższonymi poziomami cytokin IL-4, IL-5, IL-13 oraz chemokin (CCL11, CCL26, CCL13, CCL17), co koreluje z eozynofilią i podwyższonym poziomem IgE, zwłaszcza swoistych przeciwciał IgE anty-NC16A BP180, które korelują z ciężkością choroby. Komórki T pomocnicze pęcherzykowe (Tfh) oraz IL-21 również uczestniczą w stymulacji produkcji autoprzeciwciał.

Patogeneza pęcherzycy pęcherzowej – wprowadzenie
Odpowiedź autoimmunologiczna w pęcherzycy pęcherzowej

Rola komórek Tfh i IL-21

Mechanizmy zależne od układu dopełniacza
Mechanizmy niezależne od układu dopełniacza

Makropinocytoza BP180
Rola keratynocytów

Rola eozynofilów w patogenezie
Rola komórek tucznych
Rola zapalenia typu 2

Oś IL-13-IL13RA1

Czynniki wyzwalające i predysponujące

Pęcherzyca pęcherzowa wywołana lekami

Podsumowanie patogenezy

Kolejne rozdziały

Patogeneza pęcherzycy pęcherzowej – wprowadzenie

Pęcherzyca pęcherzowa (Bullous pemphigoid) jest najczęstszą autoimmunologiczną chorobą pęcherzową skóry, charakteryzującą się tworzeniem pęcherzy podnaskórkowych. Choroba wywołana jest przez autoprzeciwciała skierowane przeciwko białkom hemidesmosomów – BP180 (kolagen XVII, BPAg2) oraz BP230 (BPAg1), które są kluczowymi elementami połączenia skórno-naskórkowego. Proces patogenetyczny jest złożony i obejmuje zarówno mechanizmy zależne od układu dopełniacza, jak i niezależne od niego, prowadzące do utraty adhezji komórek podstawnych naskórka do błony podstawnej i tworzenia pęcherzy podskórnych.¹²³

Białko BP180 jest transbłonowym białkiem z dużą zewnątrzkomórkową domeną kolagenową pełniącą funkcję molekuły adhezyjnej. Jego ektodomena wiąże się z lamininą 332 i kolagenem typu IV, łącząc keratinocyty podstawne z macierzą pozakomórkową błony podstawnej naskórka. Natomiast BP230, czyli naskórkowa izoforma BPAG1, jest białkiem cytoplazmatycznym z rodziny plakin, które głównie łączy układ filamentów pośrednich keratyny z hemidesmosomami w błonie komórkowej keratinocytów podstawnych.¹²

Surowica pacjentów rozpoznaje wiele regionów antygenowych na obu antygenach docelowych, przy czym domena NC16A na zewnątrzkomórkowej części błonowej BP180 zawiera immunodominujące determinanty antygenowe. Autoreaktywna odpowiedź limfocytów B i T w pęcherzycy pęcherzowej jest skierowana głównie na ten region BP180.¹²

Odpowiedź autoimmunologiczna w pęcherzycy pęcherzowej

W pęcherzycy pęcherzowej antygeny BP180 i BP230 są wychwytywane przez komórki prezentujące antygen, przetwarzane, wiązane do kompleksu głównego układu zgodności tkankowej klasy II (MHC II) i następnie eksponowane na powierzchni komórki. Rozpoznanie tych epitopów przez limfocyty T indukuje produkcję cytokin, a następnie stymuluje limfocyty B do produkcji autoprzeciwciał. Izotypami autoprzeciwciał przeciwko BP180 i BP230 są zwykle immunoglobuliny klasy G (IgG), ale w patogenezę zaangażowane są również przeciwciała IgE.¹²

Badania wykazały, że w pęcherzycy pęcherzowej kluczową rolę odgrywają komórki pomocnicze T typu 2 (Th2). Dominująca rola odpowiedzi immunologicznej typu Th2 wiąże się z uwalnianiem cytokin takich jak IL-4, IL-5 i IL-13, które są podwyższone w zmianach skórnych. Dodatkowo, u pacjentów z pęcherzycą pęcherzową stwierdza się podwyższony poziom IgE oraz eozynofilów zarówno we krwi obwodowej, jak i w zmianach skórnych.¹²³

Zwiększone poziomy przeciwciał IgE swoistych dla domeny NC16A białka BP180 korelują z ciężkością choroby. Ponadto, badania wykazały, że eozynofile są niezbędne do pośredniczonego przez przeciwciała IgE anty-BP180 tworzenia pęcherzy skórnych i uczestniczą w separacji połączenia skórno-naskórkowego poprzez generowanie reaktywnych form tlenu, uwalnianie ziarnistości eozynofilowych i tworzenie zewnątrzkomórkowych pułapek eozynofilowych.¹²

Rola komórek Tfh i IL-21

Warto podkreślić, że w patogenezie pęcherzycy pęcherzowej uczestniczą również limfocyty T pomocnicze pęcherzykowe (Tfh). Komórki te odgrywają ważną rolę w produkcji autoprzeciwciał patogennych. Badania wykazały, że odsetek komórek Tfh i poziomy IL-21 dodatnio korelują z mianami autoprzeciwciał anty-BP180-NC16A u pacjentów z pęcherzycą pęcherzową. Co więcej, deplecja komórek T CD4+CXCR5+ może zmniejszyć wydzielanie autoprzeciwciał BP w układzie ko-hodowli ludzkich komórek T CD4+ aktywowanych anty-CD3 z komórkami B, podobnie jak blokada IL-21 przez przeciwciała neutralizujące.¹²

Mechanizmy zależne od układu dopełniacza

Klasyczny model patogenezy pęcherzycy pęcherzowej opiera się na mechanizmach zależnych od układu dopełniacza. Wiązanie autoprzeciwciał IgG do antygenów BP180 i BP230 w strefie błony podstawnej aktywuje układ dopełniacza, co prowadzi do tworzenia się kompleksu ataku błony i uwalniania anafilatoksyn C3a i C5a. Te z kolei przyciągają komórki zapalne, w tym neutrofile i eozynofile, które migrują do skóry właściwej i degranulują, uwalniając enzymy proteolityczne, w tym metaloproteinazę macierzy 9 (MMP9) i elastazę neutrofilową, a także reaktywne formy tlenu.¹²

W badaniu immunofluorescencji bezpośredniej (DIF) czynnik dopełniacza C3 jest wykrywany u praktycznie wszystkich pacjentów wzdłuż strefy błony podstawnej naskórka, co sugeruje, że szlaki zależne od dopełniacza mogą prowadzić do stanu zapalnego i klinicznych objawów choroby. Aktywacja układu dopełniacza jest uważana za kluczową w przyciąganiu komórek zapalnych do błony podstawnej.¹²³

Komórki zapalne uwalniają proteazy, które degradują białka hemidesmosomalne i prowadzą do tworzenia pęcherzy. Ta kaskada zapalna ostatecznie prowadzi do uszkodzenia tkanek i tworzenia pęcherzy podnaskórkowych. Aktywacja układu dopełniacza z wytwarzaniem anafilatoksyn oraz aktywacja odpowiedzi immunologicznej wrodzonej z późniejszą rekrutacją i aktywacją bazofili, eozynofilów, neutrofilów, monocytów/makrofagów i komórek tucznych odgrywają kluczową rolę w pęcherzycy pęcherzowej.¹²

Mechanizmy niezależne od układu dopełniacza

W ostatniej dekadzie pojawiły się przekonujące dowody na istnienie procesów niezależnych od dopełniacza, które są zaangażowane w patogenezę pęcherzycy pęcherzowej, bezpośrednio przyczyniając się do stanu zapalnego, uszkodzenia tkanek i oddzielenia skórno-naskórkowego. Wśród kluczowych obserwacji potwierdzających rolę mechanizmów niezależnych od dopełniacza można wymienić:¹²

Przeciwciała IgG anty-NC16A pochodzące z surowicy i rekombinowane przeciwciała IgG anty-ludzkiego NC16a upośledzają adhezję keratynocytów i usuwają BP180 poprzez indukcję makropinocytozy¹
Bierne przeniesienie fragmentów F(ab)2 ludzkich przeciwciał BP lub przeciwciał IgG przeciwko BP180, które nie mogą aktywować dopełniacza, może powodować kruchość skóry u noworodków myszy z humanizowanym BP180¹
Myszy C5-/- oraz myszy C5ar1-/- wstrzyknięte przeciwciałami anty-NC15A, mysim analogiem NC16A u ludzi, rozwijają fenotyp podobny do BP, chociaż jego nasilenie jest łagodniejsze w porównaniu z myszami typu dzikiego¹
Przeciwciała IgG BP mogą indukować ekspresję IL-6, IL-8 i Hsp90 z hodowanych keratynocytów niezależnie od dopełniacza¹
Autoprzeciwciała IgG4, które są dominującym izotypem IgG u ponad 50% pacjentów z BP, mogą indukować tworzenie pęcherzy w badaniach kriosekcji¹

Makropinocytoza BP180

Bezpośredni nieimmunologiczny, ale złożony biologicznie wpływ przeciwciał anty-BP180 na bazalne keratynocyty stanowi ważny sposób, w jaki mechanizmy niezależne od dopełniacza przyczyniają się do utraty adhezji w błonie podstawnej i tworzenia pęcherzy skórno-naskórkowych. Przeciwciała IgG BP (a także IgE BP) mogą powodować internalizację BP180, prawdopodobnie poprzez makropinocytozę, z błon komórkowych komórek podstawnych w hodowanych ludzkich keratynocytach i hodowlach ludzkich skóry, zmniejszając siłę adhezji tych komórek do błony podstawnej.¹²

Internalizacja BP180 indukowana przez przeciwciała BP-IgG następuje poprzez szlak makropinocytozy. W procesie tym uczestniczy zarówno degradacja BP180 zależna od ubikwityny i proteasomu, jak i internalizacja makropinocytarna BP180. Spekuluje się, że tworzenie pęcherzy w pęcherzycy pęcherzowej wymaga najpierw osłabienia siły adhezyjnej keratynocytów, któremu towarzyszy następnie odpowiedź zapalna, która ostatecznie powoduje oddzielenie skórno-naskórkowe.¹²³

Rola keratynocytów

Oprócz bezpośrednich, niezapalnych efektów autoprzeciwciał anty-BP180, istnieją również dowody na niezależne od dopełniacza mechanizmy zapalne, za pomocą których przeciwciała BP mogą wywoływać chorobę. W szczególności keratynocyty są w stanie wydzielać różne cytokiny prozapalne, które wydają się istotne patogenetycznie. Po interakcji między przeciwciałami anty-BP180 a ektodomeny BP180, keratynocyty uwalniają prozapalne cytokiny, takie jak IL-6 i IL-8, prawdopodobnie za pośrednictwem regulacji w górę NF-kappa beta i STAT3.¹²

Obserwacje te wskazują, że keratynocyty, poprzez uwalnianie cytokin prozapalnych, odgrywają również wcześniej nierozpoznaną rolę w patogenezie chorób pęcherzowych. Uważa się, że zarówno mechanizmy zależne od dopełniacza, jak i niezależne od dopełniacza odgrywają wspólną rolę w wywoływaniu i utrwalaniu pęcherzycy pęcherzowej.¹²

Rola eozynofilów w patogenezie

Eozynofile, które są zazwyczaj obficie obecne w zmienionej skórze pacjentów z pęcherzycą pęcherzową, odgrywają ważną rolę w uszkodzeniu tkanek poprzez różne mechanizmy. Mogą one bezpośrednio pośredniczyć w oddzieleniu skórno-naskórkowym w obecności zarówno IgG, jak i IgE.¹²

Eozynofile mogą również wytwarzać zewnątrzkomórkowe pułapki (EET), które składają się z białek ziarnistych, DNA i składników jądrowych w strukturze sieciowej, która może rozszerzać się do 15 razy większej niż sama komórka. Te pułapki przyczyniają się do uszkodzenia tkanek i tworzenia pęcherzy. Ponadto eozynofile bezpośrednio przyczyniają się do objawów pęcherzycy pęcherzowej poprzez produkcję IL-31, znanego pruritogenu.¹²

Eozynofile mogą wzmacniać lokalny stan zapalny typu 2 w zmianach skórnych poprzez uwalnianie cytokin i chemokin (eotaksyna i MCP-4), które działają w pętli dodatniego sprzężenia zwrotnego, rekrutując więcej eozynofilów. Badania wykazują, że eozynofile są niezbędne do tworzenia pęcherzy skórnych za pośrednictwem przeciwciał IgE anty-BP180 i że eozynofile uczestniczą w separacji połączenia skórno-naskórkowego poprzez wytwarzanie reaktywnych form tlenu, uwalnianie ziarnistości eozynofilowych i tworzenie pułapek zewnątrzkomórkowych eozynofilów.¹²

Najsilniejsze dowody na rolę eozynofilów w pośredniczeniu w uszkodzeniu tkanek w pęcherzycy pęcherzowej pochodzą od Lin i współpracowników, którzy wygenerowali transgeniczną mysz, która ekspresjonowała ludzki hNC16A, a także ludzki FCRI. Ogólnie rzecz biorąc, te odkrycia dostarczają silnych dowodów na dodatkowy, niezależny od dopełniacza, zależny od Th2, pośredniczony przez eozynofile szlak, który przyczynia się do uszkodzenia tkanek i objawów klinicznych w pęcherzycy pęcherzowej.¹

Rola komórek tucznych

Udział komórek tucznych w patofizjologii pęcherzycy pęcherzowej jest dobrze udokumentowany, chociaż ich dokładna rola jest prawdopodobnie wysoce złożona. Komórki tuczne mogą być zaangażowane w rekrutację innych komórek zapalnych do zmienionej skóry; badania pokazują, że aktywacja komórek tucznych poprzedza infiltrację neutrofilów i eozynofilów, a hamowanie degranulacji komórek tucznych u myszy zapobiega infiltracji neutrofilów i późniejszemu tworzeniu pęcherzy.¹

Przeciwciała IgE mogą oddziaływać z receptorami FcRI na komórkach tucznych i promować ich wiązanie krzyżowe poprzez wiązanie domeny NC16A białka BP180, po którym następuje degranulacja histaminy i cytokin oraz chemotaksja eozynofilów i neutrofilów. Dodatkowo, IgE może również wiązać się bezpośrednio z domeną NC16A białka BP180 ekspresjonowanego na keratynocytach; internalizacja tego kompleksu immunologicznego prowadzi do uwolnienia IL-6 i IL-8, które rekrutują dodatkowe komórki odpornościowe.¹²

Rola zapalenia typu 2

Szereg dowodów wskazuje na ważną rolę cytokin i chemokin zapalnych typu 2 w patofizjologii pęcherzycy pęcherzowej. W zmianach typowych dla BP podwyższone są poziomy cytokin zapalnych typu 2 IL-4, IL-5 i IL-13, a także poziomy chemokin CCL11 (zwana również eotaksyną 1), CCL26 (eotaksyna 3), CCL13 (białko chemotaktyczne monocytów 4, lub MCP-4) i CCL17 (chemokina regulowana przez grasicę i aktywację, lub TARC).¹

IL-4 i IL-13 są kluczowymi i centralnymi czynnikami napędzającymi zapalenie typu 2 w wielu chorobach i mogą być również zaangażowane w pęcherzycę pęcherzową. Biorąc pod uwagę, że eotaksyny silnie przyciągają eozynofile, a IL-5 odgrywa ważną rolę w różnicowaniu, dojrzewaniu i proliferacji eozynofilów, uważa się, że te mediatory mogą odgrywać ważną rolę w eozynofilii krwi i tkanek u pacjentów z pęcherzycą pęcherzową.¹

Dane z zastosowania inhibitorów JAK i IVIG podkreślają znaczenie autoprzeciwciał i eozynofilów, a podwójna inhibicja IL-4 i IL-13 za pomocą dupilumabu potwierdza rolę tych cytokin w patofizjologii pęcherzycy pęcherzowej. Badania kliniczne wykazały, że pacjenci leczeni dupilumabem doświadczyli trwałej remisji choroby w porównaniu z tymi, którzy otrzymywali placebo. Dupilumab może pomagać w utrzymaniu lub przywróceniu tolerancji immunologicznej, zapobiegając nadmiernej subwersji limfocytów T pośredniczonej przez receptor IL-4R.¹²³

Oś IL-13-IL13RA1

Najnowsze badania wskazują, że para ligand-receptor IL13-IL13RA1 jest najważniejszym mediatorem interakcji immunologiczno-podścieliskowej w pęcherzycy pęcherzowej. Fibroblasty i komórki dendrytyczne (DC) ekspresjonujące IL13RA1 reagują na komórki Th2 wydzielające IL-13, wzmacniając w ten sposób kaskadowe odpowiedzi pośredniczone przez komórki Th2. Proces ten zachodzi poprzez specyficzną regulację w górę PLA2G2A w fibroblastach i CCL17 w komórkach mieloidalnych, tworząc pętlę pozytywnego sprzężenia zwrotnego integralną dla interakcji immunologiczno-podścieliskowej.¹²

Interesujące jest, że PLA2G2A, kodujące wydzielniczą fosfolipazę A2 zależną od wapnia, która, jak donoszono, rekrutuje komórki odpornościowe w raku piersi, było wysoko ekspresjonowane zarówno w fibroblastach CCL19+, jak i fibroblastach APCDD1+ od pacjentów z pęcherzycą pęcherzową. Wyniki te sugerują, że surowicze PLA2G2A może służyć jako obiecujący marker do oceny ciężkości choroby.¹

CCL17, ekspresjonowane przez komórki mieloidalne, odgrywa kluczową rolę w przyciąganiu komórek Th2 do skóry, przyczyniając się do rozwoju różnych chorób skórnych typu zapalnego Th2, a także chłoniaka skórnego. W badaniach odkryto, że PLA2G2A pochodzące z fibroblastów wyzwala wydzielanie CCL17, ponieważ stymulacja rekombinowanym białkiem PLA2G2A podnosiła poziomy CCL17. Odkrycia te wyjaśniają mechanizm zaangażowany w regulację w górę CCL17 w chorobach zapalnych typu 2 i wykazują amplifikację patogennych autoprzeciwciał przez CCL17 w mechanizmie pęcherzycy pęcherzowej.¹

Czynniki wyzwalające i predysponujące

Patogeneza pęcherzycy pęcherzowej zależy od interakcji między czynnikami predysponującymi, takimi jak geny ludzkich antygenów leukocytarnych (HLA), choroby współistniejące, starzenie się i czynniki wyzwalające. Kilka czynników wyzwalających, takich jak leki, oparzenia termiczne lub elektryczne, zabiegi chirurgiczne, urazy, promieniowanie ultrafioletowe, radioterapia, preparaty chemiczne, przeszczepy i infekcje, może wywoływać lub zaostrzać chorobę.¹

Allel HLA klasy II DQB1*03:01 jest bardziej rozpowszechniony u pacjentów rasy kaukaskiej z pęcherzycą pęcherzową niż w populacji ogólnej i został również powiązany z chorobami neurologicznymi. Hipotetycznym mechanizmem powiązania pęcherzycy pęcherzowej z chorobami neurologicznymi jest możliwy udział antygenów BP (BPA1 i BPA2) jako autoprzeciwciał autoreaktywnych w ośrodkowym układzie nerwowym i w skórze.¹²

Pęcherzyca pęcherzowa wywołana lekami

Patogeneza pęcherzycy pęcherzowej wywołanej lekami (DIBP) jest kontrowersyjna i często trudna do zrozumienia i wykazania. Zakłada się, że patogeneza DIBP jest związana z kombinacją i interakcją różnych mechanizmów, a nie z jednym. Kolejnym możliwym wyzwalaczem dla układu odpornościowego jest interakcja między grupami sulfhydrylowymi w desmosomach i strefie błony podstawnej (BMZ) a lekami zawierającymi siarkę, które poprzez przerwanie integralności połączenia naskórkowo-skórnego mogą prowadzić do ekspozycji ukrytych miejsc antygenowych.¹

Leki mogą działać jako wyzwalacze u osób z podstawową predyspozycją genetyczną, prowadząc do zwiększenia odpowiedzi immunologicznej lub zmiany właściwości antygenowych strefy błony podstawnej naskórka. Leki mogą zmieniać te właściwości antygenowe, wiążąc się z cząsteczkami w blaszce jasnej BMZ, działając w ten sposób jako neoantyigeny i indukując tworzenie przeciwciał anty-BMZ. Alternatywnie mogą strukturalnie modyfikować cząsteczki i odkrywać wcześniej ukryte epitopy, stymulując w ten sposób odpowiedź immunologiczną.¹

Kilka czynników może indukować pęcherzycę pęcherzową, w tym leki, czynniki fizyczne, szczepionki, infekcje, przeszczepy i inne. Wśród leków, które mogą wywołać BP, wymienia się diuretyki (furosemid, spironolakton), inhibitory konwertazy angiotensyny (kaptopryl, enalapryl, lizinopryl), inhibitory dipeptydylopeptydazy-4 (np. linagliptyna, sitagliptyna) oraz inhibitory punktów kontrolnych programowanej śmierci 1 (PD-1) i ligandu 1 programowanej śmierci (PD-L1) (np. niwolumab).¹²

Podsumowanie patogenezy

Patogeneza pęcherzycy pęcherzowej jest złożonym procesem obejmującym zarówno mechanizmy zależne od dopełniacza, jak i niezależne od niego. Autoprzeciwciała skierowane przeciwko białkom hemidesmosomów (BP180 i BP230) wiążą się z błoną podstawną, aktywując kaskadę zapalną obejmującą dopełniacz, komórki tuczne, eozynofile i neutrofile. Kluczową rolę odgrywa również zapalenie typu 2, z udziałem cytokin IL-4, IL-5 i IL-13, które wraz z autoprzeciwciałami IgE przyczyniają się do rozwoju choroby. Mechanizmy niezależne od dopełniacza, takie jak makropinocytoza BP180, bezpośrednie działanie na keratynocyty i aktywacja eozynofilów, również odgrywają istotną rolę w patologii pęcherzycy pęcherzowej.¹²²³

Lepsze zrozumienie złożonych mechanizmów patogenetycznych pęcherzycy pęcherzowej doprowadziło do rozwoju nowych, ukierunkowanych strategii terapeutycznych, takich jak zastosowanie dupilumabu, który hamuje sygnalizację IL-4 i IL-13, wykazując obiecujące wyniki w leczeniu tej choroby. Przyszłe badania nad interakcjami immunologiczno-podścieliskowymi i rolą różnych mediatorów zapalnych mogą prowadzić do dalszych postępów w leczeniu pęcherzycy pęcherzowej.¹²³

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

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

Materiały źródłowe

#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement-mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. […] There is ample evidence indicating that BP occurs due to a loss of immune tolerance leading to autoantibody formation against BP180 and BP230. BP180 is transmembrane protein with a large collagenous extra-cellular domain serving as an adhesion molecule. Its ectodomain binds to laminin 332 and type IV collagen, connecting the basal keratinocytes to the extracellular matrix of the epidermal basement membrane. BP230, the epithelial isoform of BPAG1, is a cytoplasmic protein of the plakin family of cytolinkers. It primarily connects the keratin intermediate filament system to hemidesmosomes at the basal keratinocyte cell membrane.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Patients sera recognize multiple antigenic regions on both target antigens, although the NC16A domain, on the extracellular membrane of BP180, contains the immunodominant antigenic determinants. The autoreactive B and T cell response in BP is primarily directed at this region of BP180. BP autoantibodies lead to an inflammatory response with a large number of eosinophils and, to a lesser degree, neutrophils, migrating to the dermis and degranulating. These cells contain and release upon activation dozens of cytokines, chemokines, hydrolytic degrading enzymes, including matrix metalloprotease 9 (MMP9) and neutrophil elastase, as well reactive oxygen species. This inflammatory cascade ultimately leads to tissue damage and subepidermal blister formation. […] In vitro and in vivo studies have allowed the characterization of several pathways critically involved in BP pathogenesis that directly contribute to tissue damage. Among these, activation of the complement system with production of anaphylatoxins, and activation of the innate immune response with subsequent recruitment and activation of basophils, eosinophils, neutrophils, monocytes/macrophages, and mast cells, play a key role in BP.
#1 Bullous Pemphigoid: Trigger and Predisposing Factors
https://www.mdpi.com/2218-273X/10/10/1432
In BP patients, BP180 and BP230 antigens are taken up by antigen-presenting cells, processed, bound to major histocompatibility complex class (MHC) II, and subsequently exposed on the cell surface. The recognition of these epitopes by T-cells induces the production of some cytokines and, subsequently, B cells are stimulated to produce autoantibodies (autoAbs). AutoAb isotypes against BP180 and BP230 are usually class G immunoglobulin (IgG), but IgE have been also implicated. […] The binding of autoAbs leads to complement activation, recruitment of inflammatory cells, and release of proteolytic enzymes, activating an inflammatory cascade that could be even triggered by the activation of Th17 cells. […] The etiopathogenesis of BP is largely unknown, but in several cases the occurrence or exacerbation of the disease has been reported in association with a specific âtrigger factorâ, such as drugs, physical factors, vaccines, infections, transplantations, and others.
#1
https://link.springer.com/article/10.1007/s12325-024-02992-w
Bullous pemphigoid (BP) is an autoimmune blistering disease that most often affects elderly individuals and has a significant negative impact on quality of life. The disease is characterized primarily by autoantibodies to hemidesmosomal proteins BP180 and/or BP230, and an inflammatory reaction with notable features of type 2 inflammation, including elevated serum IgE, increased numbers of eosinophils in lesions and peripheral blood, and elevated expression of type 2 cytokines and chemokines in skin lesions. […] BP pathophysiology is not completely understood but is characterized primarily by the production of immunoglobin G (IgG) autoantibodies directed against hemidesmosomal anchoring proteins BP antigen 180 (BP180) and/or BP antigen 230 (BP230). Several lines of evidence also suggest a prominent type 2 inflammatory response in BP. Type 2 inflammation predominantly involves the activation of group 2 innate lymphoid cells, T helper type 2 cells, eosinophils, and inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13.
#1 Targeting Type 2 Inflammation for Treatment of Bullous Pemphigoid
https://www.dermatoljournal.com/articles/targeting-type-2-inflammation-for-treatment-of-bullous-pemphigoid.html
While anti-BP180 and anti-BP230 IgG autoantibodies are well-established drivers of BP pathogenesis, IgE antibodies against these epitopes have also been shown to play an important role. […] Elevated serum IgE is a hallmark of type 2 inflammation and is present in patients with BP, and increased IgE auto-antibodies targeting the NC16a domain of BP180 correlate with disease severity. […] Further studies have shown that eosinophils are necessary for anti-BP180 IgE-mediated skin blistering and participate in dermal epidermal junction (DEJ) separation through reactive oxygen species generation, release of eosinophilic granules, and eosinophil extracellular trap formation. […] Dupilumab may help maintain or re-establish immune tolerance by preventing excessive IL-4R mediated T cell subversion.
#1 Follicular Helper T Cells (Tfh) and IL-21 Involvement in the Pathogenesis of Bullous Pemphigoid | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068145
The pathogenesis of bullous pemphigoid (BP) is characterized by the T cell-dependent production of autoantibodies. […] Tfh cells play an important role in autoantibody production and are involved in the pathogenesis of BP. […] The present study aimed to determine whether Tfh cells play an important role in pathogenic autoantibody production in BP and to clarify their involvement in the pathogenesis of BP. […] These results have indicated the possible involvement of Tfh cells and IL-21 in the pathogenesis of BP. […] The percentages of Tfh cells and the IL-21 levels were positively correlated with the anti-BP180-NC16A autoantibody titers in BP patients. […] More importantly, depletion of CD4+CXCR5+ T cells can decrease the secretion of BP autoantibody in anti-CD3-activated human CD4+ T cells/B cells co-culture system, and so as to the blockade of IL-21 by neutralizing Ab.
#1 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid
https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/
Immunoelectron microscopy localized the antigens targeted in BP to the epidermal hemidesmosome, distributed in both intra- and extracellular sites. […] BP180, being accessible to autoantibodies as opposed to the intracellular BP230, is critical for disease induction by autoantibodies, as demonstrated in animal and cell culture models of disease. […] By DIF, complement factor C3 has been found in virtually all patients at the epidermal BMZ, implying that complement-dependent pathways may lead to inflammation and clinical disease. […] BP-IgG (as well as BP-IgE) can cause internalization of BP180, probably via macropinocytosis, from the basal cell membranes of basal cells in cultured human keratinocytes and human skin organ cultures, reducing the adhesive strength of these cells to the basement membrane.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Increasing evidence has emerged pointing to the presence of complement-independent pathways in mediating tissue damage and subepidermal formation in BP. […] In the last decade, a number of laboratories have provided convincing evidence that complement-independent processes are implicated in the pathogenesis of BP, directly contributing to inflammation, tissue damage and dermo-epidermal separation. […] Serum derived anti-NC16A IgG antibodies and recombinant anti human NC16a IgG antibodies impair keratinocyte adhesion and deplete BP180 by induction of macropinocytosis; Passive transfer of F(ab)2 fragments of the human BP or IgG antibodies, against BP180, that cannot activate complement, are able to cause skin fragility in neonatal BP180-humanized mice; C5-/- mice as well as C5ar1-/- mice injected with anti-NC15A antibodies, the murine analog to NC16A in humans, develop a BP-like phenotype, although its severity is milder when compared to that of wild type (WT) mice.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Notably, this study demonstrates that inhibition of complement has therapeutic benefit, once again reaffirming the importance of complement in BP. However, C5ar-/- mice demonstrated a relatively increased extent of skin lesions following BP-IgG injection, raising the possibility of complement-independent induced blistering as well. […] Production of neutrophil reactive oxygen species (ROS), which contribute to tissue damage, does not differ between WT, C5ar1-/-, and C5ar2-/- mice; Passive transfer of human BP-IgG into C3-/- BP180 humanized mice develop blisters; Non-complement binding autoantibodies are able to cause blister formation in vivo; BP-IgG antibodies are able to induce IL-6, IL-8, and Hsp90 expression from cultured keratinocytes independent of complement; IgG4 autoantibodies, which are the dominant IgG isotype in over 50% of BP patients, are able to induce blistering in cryosection assays; IgE autoantibodies and eosinophils contribute to blister formation by means of various mechanisms including secretion of proteases, eosinophil degranulation, and extracellular traps, as well as cytokine and chemokine release in a complement independent manner.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
The recent Phase 2a trial results of the complement inhibiting drug nomacopan offer an important caveat to the prospect of physiologically significant complement-independent effects. […] The direct non-immunologic, but complex biologic impact of anti-BP180 antibodies on basal keratinocytes represents an important means by which complement-independent mechanisms contribute to basement membrane disadhesion and dermo-epidermal blistering. […] Both ubiquitin- and proteasome-mediated degradation of BP180, as well as macropinocytic internalization of BP180 appear to be involved. […] It has been speculated that blistering in BP first requires a weakening of the adhesive strength of keratinocytes, which is then accompanied by an inflammatory response that ultimately causes dermo-epidermal separation.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
BP-IgG induced internalization of BP180 occurs through the macropinocytosis pathway. […] In addition to the direct non-inflammatory effects of anti-BP180 autoantibodies, there is growing evidence for complement-independent inflammatory mechanisms by which BP antibodies can induce disease. […] Specifically, keratinocytes are able to secrete a variety of proinflammatory cytokines which appear to be pathogenetically relevant. […] Overall these observations indicate that keratinocytes, by releasing pro-inflammatory cytokines, also play a previously unrecognized role in the pathogenesis of pemphigoid diseases. […] Eosinophils can directly mediate dermo-epidermal separation in the presence of either IgG or IgE. […] Eosinophils, which are typically abundantly present in lesional skin of BP patients, play an important role in tissue damage by means of different mechanisms.
#1 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Eosinophils can also produce extracellular traps (EETs) which are made up of granule proteins, DNA, and nuclear components in a network-like structure which can expand to be 15 times larger than the cell itself. […] Eosinophils also directly contribute to BP symptomatology by producing IL-31, a known pruritogen. […] The most compelling evidence for the role of eosinophils in mediating tissue injury in BP comes from Lin et al. who generated a transgenic mouse which expressed human hNC16A as well as the human FCRI. […] Overall, these findings provide strong evidence for an additional complement-independent, Th2-dependent, eosinophil-mediated pathway that contributes to tissue damage and clinical features in BP.
#1
https://link.springer.com/article/10.1007/s12325-024-02992-w
The involvement of mast cells in BP pathophysiology is well documented, although their precise role is likely highly complex. […] Additionally, mast cells may be involved in recruiting other inflammatory cells into lesional skin; studies show that mast cell activation precedes neutrophil and eosinophil infiltration, and inhibition of mast cell degranulation in mice prevents neutrophil infiltration and subsequent blister formation. […] Eosinophils may amplify local type 2 inflammation in BP skin lesions by releasing cytokines and chemokines (eotaxin and MCP-4) that act in a positive feedback loop by recruiting more eosinophils. […] Studies show that eosinophils are necessary for anti-BP180 IgE-mediated skin blistering, and that eosinophils participate in dermal-epidermal junction separation through the generation of reactive oxygen species, eosinophilic granule release, and eosinophil extracellular trap formation.
#1 SciELO Brazil – Bullous pemphigoid Bullous pemphigoid
https://www.scielo.br/j/abd/a/BsschZpGNWjSKJ3rFKBCXjm/
Messingham et al. proposed two IgE-mediated mechanisms of blister formation: IgE may interact with the FcRI receptors on mast cells and promote their cross-linking through binding of the NC16A domain of BP180, followed by the degranulation of histamine and cytokines and chemotaxis of eosinophils and neutrophils; in addition, IgE may also bind directly to the NC16A domain of BP180 expressed on keratinocytes; the internalization of this immune complex leads to the release of IL-6 and IL-8, which recruit additional immune cells.
#1
https://link.springer.com/article/10.1007/s12325-024-02992-w
Several lines of evidence point to an important role of type 2 inflammatory cytokines and chemokines in BP pathophysiology. […] In BP lesions, levels of type 2 inflammatory cytokines IL-4, IL-5, and IL-13 are elevated, as are levels of chemokines CCL11 (also called eotaxin 1), CCL26 (eotaxin 3), CCL13 (monocyte chemoattractant protein 4, or MCP-4), and CCL17 (thymus- and activation-regulated chemokine, or TARC). […] IL-4 and IL-13 are key and central drivers of type 2 inflammation in multiple diseases, and they might be involved in BP as well. […] Given that eotaxins strongly attract eosinophils and that IL-5 plays an important role in eosinophil differentiation, maturation, and proliferation, it is thought that these mediators may play an important role in blood and tissue eosinophilia in patients with BP.
#1
https://link.springer.com/article/10.1007/s12325-024-02992-w
Data from the use of JAK inhibitors and IVIG highlight the importance of autoantibodies and eosinophils, and dual inhibition of IL-4 and IL-13 with dupilumab supports the role of these cytokines in BP pathophysiology. […] The development of biologics for the treatment of BP is ongoing, but results from studies thus far have helped elucidate the pathophysiology of BP and support the role of the involvement of type 2 inflammation.
#1 Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease | Nature Communications
https://www.nature.com/articles/s41467-024-50283-3
Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. […] The IL13-IL13RA1 ligandreceptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. […] Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.
#1 Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease | Nature Communications
https://www.nature.com/articles/s41467-024-50283-3
Intriguingly, PLA2G2A, encoding secretory calcium-dependent phospholipase A2, which was reported to recruit immune cells in breast cancer, was highly expressed in both CCL19+ FB and APCDD1+ FB from BP patients. […] These results suggest that serum PLA2G2A could serve as a promising marker for assessing the disease severity. […] Collectively, these results implied that the overexpression of PLA2G2A from fibroblasts promoted immune infiltration through CXCL12/CXCR4 axis. […] CCL17, expressed by myeloid cells, plays a pivotal role in attracting Th2 cells into the skin, contributing to the development of various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. […] In our study, we discovered that fibroblast-derived PLA2G2A triggered the secretion of CCL17, as the stimulation of PLA2G2A recombinant protein elevated the levels of CCL17. […] These findings elucidate the mechanism involved in the upregulation of CCL17 in type 2 inflammatory diseases and demonstrate the amplification of pathogenic autoantibodies by CCL17 in the mechanism of BP.
#1 Bullous Pemphigoid: Trigger and Predisposing Factors
https://www.mdpi.com/2218-273X/10/10/1432
Bullous pemphigoid (BP) is the most frequent autoimmune subepidermal blistering disease provoked by autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. Its pathogenesis depends on the interaction between predisposing factors, such as human leukocyte antigen (HLA) genes, comorbidities, aging, and trigger factors. […] Several trigger factors, such as drugs, thermal or electrical burns, surgical procedures, trauma, ultraviolet irradiation, radiotherapy, chemical preparations, transplants, and infections may induce or exacerbate BP disease. Identification of predisposing and trigger factors can increase the understanding of BP pathogenesis. Furthermore, an accurate anamnesis focused on the recognition of a possible trigger factor can improve prognosis by promptly removing it.
#1 Bullous Pemphigoid – Dermatologic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/bullous-pemphigoid
Bullous pemphigoid occurs more often in patients age 60 but can occur in children. IgG autoantibodies bind to certain hemidesmosomal antigens (BPAg1 [BP230], BPAg2 [BP180]), resulting in the activation of complement to form a subepidermal blister. […] Triggers may induce an autoimmune reaction by mimicking molecular sequences in the epidermal basement membrane (molecular mimicry, as with drugs and possibly infections), by exposing or altering normally tolerated host antigens (as with physical triggers and certain disorders), or by other mechanisms. Epitope spreading refers to the recruitment of autoreactive lymphocytes against normally tolerated host antigens, which contributes to disease chronicity and course. […] Hypothesized shared causes include a cross-reactive immune response between neural and cutaneous antigens (BPAg1 is expressed in the CNS), as well as triggering by certain drugs used to treat the CNS disorders (eg, phenothiazine antipsychotics, spironolactone); however, a mechanism of triggering by drugs is not understood.
#1 Bullous Pemphigoid: Trigger and Predisposing Factors
https://www.mdpi.com/2218-273X/10/10/1432
The pathogenesis of drug induced BP (DIBP) is controversial and often difficult to understand and to demonstrate. […] It has been hypothesized that the pathogenesis of DIBP is linked to the combination and interaction of various mechanisms, and not to a single one. […] A further possible trigger for the immune system is the interaction between the sulfhydryl groups in desmosomes and basement membrane zone (BMZ) and the sulfur-containing drugs that, by interrupting the DEJ integrity, could lead to the exposure of hidden antigenic sites. […] The pathogenesis underlying the association between DPP-4i and BP is not clear. […] The inhibition of plasmin by DPP-4i could provoke alterations in the correct cleavage of BP180, modifying its antigenicity and function. […] The association between BP and radiotherapy has been widely described.
#1 A Systematic Review of Drug-Induced Pemphigoid | HTML | Acta Dermato-Venereologica
https://www.medicaljournals.se/acta/content/html/10.2340/00015555-3457
In general terms, the pathogenesis of the drug-reaction in DABP is beginning to be unravelled, however, the specific causal relationships remain to be elucidated. Drugs are considered to act as triggers in those with an underlying genetic predisposition, leading to either augmentation of the immune response or an alteration of the antigenic properties of the epidermal BMZ. Drugs may alter these antigenic properties by binding to molecules in the lamina lucida of the BMZ, thereby acting as neoantigens, and inducing the formation anti-BMZ antibodies. Alternatively, they may structurally modify molecules and uncover previously hidden epitopes, hence stimulating the immune response. […] A two-step theory has been hypothesised proposing that two separate drugs may induce the disease with evidence observed in BP, and other related bullous dermatoses.
#2 Bullous Pemphigoid: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1062391-overview
In patients with bullous pemphigoid, immunoglobulin G (IgG) autoantibodies bind to the skin basement membrane. This binding activates complement and inflammatory mediators. Activation of the complement system is thought to play a critical role in attracting inflammatory cells to the basement membrane. These inflammatory cells are postulated to release proteases, which degrade hemidesmosomal proteins and lead to blister formation. […] The precise role of bullous pemphigoid antigens (BPAgs) in the pathogenesis of bullous pemphigoid is not completely clear. BPAg1 (BP230) is an intracellular component of the hemidesmosome; BPAg2 (BP180, type XVII collagen) is a transmembranous protein with a collagenous extracellular domain. […] Passive transfer experiments in newborn mice demonstrated that rabbit antibodies against mouse BPAg2 can induce subepidermal blisters similar to those observed in patients with bullous pemphigoid. However, the eosinophil infiltration that is frequently observed in human bullous pemphigoid lesional skin was not detected in the passive transfer experimental model.
#2 Bullous pemphigoid – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/bullous-pemphigoid/
The pathogenesis of BP is characterized by tissue-bound and circulating IgG autoantibodies against two components of the hemidesmosome of stratified epithelia, BP 230 kD (BPAg1) and BP 180 kD (BPAg2, COL17). […] Antibodies to BPAg2 appear to be important in subepidermal blister formation. BPAg1 may have a secondary role, and its exact function in the pathogenesis is not fully defined. […] IgG autoantibodies bind to the basement membrane which activates complement and inflammatory mediators. Activation of the complement system is thought to play a critical role in attracting inflammatory cells to the basement membrane. […] These inflammatory cells release proteases, which degrade hemidesmosomal proteins leading to blister formation. […] The early urticarial phase in BP seems to be associated with IgE, and IgE autoantibodies against COL17 (BP180Kd Ag) are detected in 86% of untreated BP patients. […] Iwata et al. reported that the presence of IgE autoantibodies against COL17 was associated with a severe form of BP, and these patients required more intensive and longer treatment period for remission and higher dose of prednisolone.
#2 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid
https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/
Immunoelectron microscopy localized the antigens targeted in BP to the epidermal hemidesmosome, distributed in both intra- and extracellular sites. […] BP180, being accessible to autoantibodies as opposed to the intracellular BP230, is critical for disease induction by autoantibodies, as demonstrated in animal and cell culture models of disease. […] By DIF, complement factor C3 has been found in virtually all patients at the epidermal BMZ, implying that complement-dependent pathways may lead to inflammation and clinical disease. […] BP-IgG (as well as BP-IgE) can cause internalization of BP180, probably via macropinocytosis, from the basal cell membranes of basal cells in cultured human keratinocytes and human skin organ cultures, reducing the adhesive strength of these cells to the basement membrane.
#2
https://link.springer.com/article/10.1007/s12325-024-02992-w
Bullous pemphigoid (BP) is an autoimmune blistering disease that most often affects elderly individuals and has a significant negative impact on quality of life. The disease is characterized primarily by autoantibodies to hemidesmosomal proteins BP180 and/or BP230, and an inflammatory reaction with notable features of type 2 inflammation, including elevated serum IgE, increased numbers of eosinophils in lesions and peripheral blood, and elevated expression of type 2 cytokines and chemokines in skin lesions. […] BP pathophysiology is not completely understood but is characterized primarily by the production of immunoglobin G (IgG) autoantibodies directed against hemidesmosomal anchoring proteins BP antigen 180 (BP180) and/or BP antigen 230 (BP230). Several lines of evidence also suggest a prominent type 2 inflammatory response in BP. Type 2 inflammation predominantly involves the activation of group 2 innate lymphoid cells, T helper type 2 cells, eosinophils, and inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13.
#2
https://link.springer.com/article/10.1007/s12325-024-02992-w
In patients with BP, immunoglobin E (IgE) and eosinophils were elevated in both peripheral blood and skin lesions, and levels of inflammatory cytokines IL-4, IL-5, and IL-13 were also increased in skin lesions. […] The pathogenic mechanisms involved in blister formation following BP autoantibody binding are complex and can be subdivided into complement-dependent and complement-independent mechanisms. […] Elevated serum levels of IgE are also seen in patients with BP, with anti-BP180 and anti-BP230 IgE autoantibodies playing an important role. […] Recent research also suggests that IgE and BP180 form immune complexes in BP skin, which may activate mast cells and eosinophils through the high-affinity IgE receptor FcRI. […] Inflammatory cell infiltration (including mast cells, neutrophils, and eosinophils) is a consistent feature of skin lesions in BP, and studies suggest that these cells play an important role in BP blister formation.
#2 SciELO Brazil – Bullous pemphigoid Bullous pemphigoid
https://www.scielo.br/j/abd/a/BsschZpGNWjSKJ3rFKBCXjm/
Bullous pemphigoid is characterized by autoantibodies that recognize self-antigens at the basement membrane zone (BMZ), known as BP180 (180kDa) or BPAG2, and BP230 (230kDa) or BPAG1. Both antigens are key components of the hemidesmosome, which is responsible for the adhesion between the epidermis and dermis. […] Once anti-NC16A autoantibodies bind to BP180, several pathways are activated, including complement activation and deposition, neutrophilic chemotaxis with release of proteases and elastases that promote the disruption of the BMZ leading to blister formation. […] Disease activity correlates with circulating levels of anti-BP180 IgG and potentially to serum levels of anti-BP180 IgE. […] Eosinophils are necessary for IgE-mediated blister formation in BP, providing the cellular link between IgE autoantibodies and skin lesions in the murine model.
#2 Follicular Helper T Cells (Tfh) and IL-21 Involvement in the Pathogenesis of Bullous Pemphigoid | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068145
From the present results, we considered that Tfh cells and IL-21 play an important role in the production of pathogenic autoantibody are involved in the pathogenesis of BP. […] Our findings may provide important clues for a further evaluation of the source of the autoantibody involved and the pathogenesis as well as more effective therapy of BP. […] Our results suggest that Tfh cells participate in the pathogenesis of BP.
#2 From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid
https://www.mdpi.com/1422-0067/24/23/16786
It is well accepted that bullous pemphigoid arises from a loss of immune tolerance, resulting in the production of autoantibodies against BP180 and BP230. These antibodies trigger an inflammatory reaction, attracting numerous neutrophils, eosinophils and mast cells, which migrate to the dermis and release a wide range of cytokines and proteases, responsible for dermoepidermal cleavage and blister formation. […] Until the last decade, a complement was believed to be a prerequisite for blister formation by autoantibodies. […] Nonetheless, more recent studies have questioned its major pathogenic role in bullous pemphigoid, proposing the existence of complement-independent mechanisms mediating blister formation. […] The binding of autoantibodies to BP180 in hemidesmosomes results in the internalization of BP180 into basal keratinocytes, so the adhesive strength of the dermoepidermal junction decreases. This appears to be an early event in disease pathogenesis, followed by an inflammatory response that finally causes dermoepidermal separation.
#2 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Notably, this study demonstrates that inhibition of complement has therapeutic benefit, once again reaffirming the importance of complement in BP. However, C5ar-/- mice demonstrated a relatively increased extent of skin lesions following BP-IgG injection, raising the possibility of complement-independent induced blistering as well. […] Production of neutrophil reactive oxygen species (ROS), which contribute to tissue damage, does not differ between WT, C5ar1-/-, and C5ar2-/- mice; Passive transfer of human BP-IgG into C3-/- BP180 humanized mice develop blisters; Non-complement binding autoantibodies are able to cause blister formation in vivo; BP-IgG antibodies are able to induce IL-6, IL-8, and Hsp90 expression from cultured keratinocytes independent of complement; IgG4 autoantibodies, which are the dominant IgG isotype in over 50% of BP patients, are able to induce blistering in cryosection assays; IgE autoantibodies and eosinophils contribute to blister formation by means of various mechanisms including secretion of proteases, eosinophil degranulation, and extracellular traps, as well as cytokine and chemokine release in a complement independent manner.
#2 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
BP-IgG induced internalization of BP180 occurs through the macropinocytosis pathway. […] In addition to the direct non-inflammatory effects of anti-BP180 autoantibodies, there is growing evidence for complement-independent inflammatory mechanisms by which BP antibodies can induce disease. […] Specifically, keratinocytes are able to secrete a variety of proinflammatory cytokines which appear to be pathogenetically relevant. […] Overall these observations indicate that keratinocytes, by releasing pro-inflammatory cytokines, also play a previously unrecognized role in the pathogenesis of pemphigoid diseases. […] Eosinophils can directly mediate dermo-epidermal separation in the presence of either IgG or IgE. […] Eosinophils, which are typically abundantly present in lesional skin of BP patients, play an important role in tissue damage by means of different mechanisms.
#2 From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid
https://www.mdpi.com/1422-0067/24/23/16786
Following the interaction between anti-BP180 antibodies and BP180 ectodomain, keratinocytes release proinflammatory cytokines such as IL-6 and IL-8, possibly mediated by the upregulation of NF-kappa beta and STAT3. […] Hence, it is plausible that both complement-dependent and independent mechanisms play a collaborative role in triggering and perpetuating bullous pemphigoid. […] The fundamental initial process in the development of bullous pemphigoid is the generation of autoantibodies targeting hemidesmosomal proteins. […] The dysfunction of Treg cells has been identified in BP. This malfunction can result in the suppression of self-tolerance and subsequently the formation of autoreactive T helper 2 (Th2) lymphocytes mediated by STAT6. Autoreactive Th2 cells are able to activate and sensitize B cells and generate antibodies against self-components.
#2
https://link.springer.com/article/10.1007/s12325-024-02992-w
The involvement of mast cells in BP pathophysiology is well documented, although their precise role is likely highly complex. […] Additionally, mast cells may be involved in recruiting other inflammatory cells into lesional skin; studies show that mast cell activation precedes neutrophil and eosinophil infiltration, and inhibition of mast cell degranulation in mice prevents neutrophil infiltration and subsequent blister formation. […] Eosinophils may amplify local type 2 inflammation in BP skin lesions by releasing cytokines and chemokines (eotaxin and MCP-4) that act in a positive feedback loop by recruiting more eosinophils. […] Studies show that eosinophils are necessary for anti-BP180 IgE-mediated skin blistering, and that eosinophils participate in dermal-epidermal junction separation through the generation of reactive oxygen species, eosinophilic granule release, and eosinophil extracellular trap formation.
#2 Targeting Type 2 Inflammation for Treatment of Bullous Pemphigoid
https://www.dermatoljournal.com/articles/targeting-type-2-inflammation-for-treatment-of-bullous-pemphigoid.html
While anti-BP180 and anti-BP230 IgG autoantibodies are well-established drivers of BP pathogenesis, IgE antibodies against these epitopes have also been shown to play an important role. […] Elevated serum IgE is a hallmark of type 2 inflammation and is present in patients with BP, and increased IgE auto-antibodies targeting the NC16a domain of BP180 correlate with disease severity. […] Further studies have shown that eosinophils are necessary for anti-BP180 IgE-mediated skin blistering and participate in dermal epidermal junction (DEJ) separation through reactive oxygen species generation, release of eosinophilic granules, and eosinophil extracellular trap formation. […] Dupilumab may help maintain or re-establish immune tolerance by preventing excessive IL-4R mediated T cell subversion.
#2 Bullous pemphigoid* | Anais Brasileiros de Dermatologia
https://www.anaisdedermatologia.org.br/en-bullous-pemphigoid-articulo-S0365059620305778
Bullous pemphigoid is characterized by autoantibodies that recognize self-antigens at the basement membrane zone (BMZ), known as BP180 (180kDa) or BPAG2, and BP230 (230kDa) or BPAG1. Both antigens are key components of the hemidesmosome, which is responsible for the adhesion between the epidermis and dermis. […] Once anti-NC16A autoantibodies bind to BP180, several pathways are activated, including complement activation and deposition, neutrophilic chemotaxis with release of proteases and elastases that promote the disruption of the BMZ leading to blister formation. […] Disease activity correlates with circulating levels of anti–BP180 IgG and potentially to serum levels of anti-BP180 IgE. […] Eosinophilic infiltration is a main histopathologic finding in BP. […] Messingham et al. proposed two IgE-mediated mechanisms of blister formation: IgE may interact with the FcRI receptors on mast cells and promote their cross-linking through binding of the NC16A domain of BP180, followed by the degranulation of histamine and cytokines and chemotaxis of eosinophils and neutrophils; in addition, IgE may also bind directly to the NC16A domain of BP180 expressed on keratinocytes; the internalization of this immune complex leads to the release of IL-6 and IL-8, which recruit additional immune cells.
#2 Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease | Nature Communications
https://www.nature.com/articles/s41467-024-50283-3
Importantly, the dominant role of Th2-mediated immunity in the pathophysiological mechanisms of BP has been widely emphasized. […] This suggests that IL-13 might be a more important mediator for Th2 immunity in skin-related conditions. […] However, the specific mechanisms underlying the interactions between IL-13-producing cells and IL-13-responsive cells are not yet fully understood. […] Our findings advance the understanding of immune-fibroblast communication and emphasize the role of the IL13-IL13RA1 axis in Th2-mediated immunity in BP patients, with potential implications for broader research in autoimmune diseases. […] The analysis demonstrated that genes with type 2 inflammation (POSTN and TNC), the inflammatory cytokines and chemokines (CCL26 and CCL19) were upregulated in lesional BP versus controls.
#2 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses
https://www.scielo.br/j/abd/a/3yskKs9VzYCcjh8VWrFmhxq/
In the etiopathogenesis of BP, IgG autoantibodies are produced against antigens of the basement membrane zone (BMZ)-180kDa and 230kDa -collagen XVII, COL17 or BPAg2, and BPAg1, respectively. BP180 is the most relevant antigenic determinant, whereas BP230 appears to be more related to cytoskeletal function and signaling of the dermoepidermal transition. The involvement of mast cells and IgE in the development of BP lesions has recently been described. […] Of greater interest, BP has been associated with neurological diseases, such as dementia, stroke, multiple sclerosis, epilepsy, and Parkinson disease, but the underlying pathophysiological mechanism is not completely understood. It is possible that the BP antigens BPA1 and BPA2 act as autoreactive antigens in the central nervous system and in tegument.
#2 Bullous Pemphigoid – Dermatology – Diseases – McMaster Textbook of Internal Medicine
https://empendium.com/mcmtextbook/chapter/B31.II.856.1.
Bullous pemphigoid (BP) is a chronic autoimmune skin disease characterized by generalized, pruritic, tense bullae. […] The hallmark of BP is the presence of circulating and tissue-bound autoantibodies against hemidesmosomal proteins BP180 (type XVII collagen or BPAG2) or less commonly against BP230 (BPAG1), which are structural components of the basement membrane zone at the dermo-epidermal junction. […] Approximately 85% to 90% of the antibodies target the juxtamembranous extracellular noncollagenous 16th A (NC16A) domain of BP180. […] BP may be induced by drugs. […] Several agents have been implicated to cause drug-induced BP, including diuretics (furosemide, spironolactone) and angiotensin-converting enzyme inhibitors (captopril, enalapril, lisinopril). […] Newer classes of drugs have also been associated with the induction of BP, such as dipeptidyl peptidase4 inhibitors (eg, linagliptin, sitagliptin) and programmed death1 (PD-1) and programmed death ligand1 (PD-L1) checkpoint inhibitors (eg, nivolumab).
#2 Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC9300999/
Patients sera recognize multiple antigenic regions on both target antigens, although the NC16A domain, on the extracellular membrane of BP180, contains the immunodominant antigenic determinants. The autoreactive B and T cell response in BP is primarily directed at this region of BP180. BP autoantibodies lead to an inflammatory response with a large number of eosinophils and, to a lesser degree, neutrophils, migrating to the dermis and degranulating. These cells contain and release upon activation dozens of cytokines, chemokines, hydrolytic degrading enzymes, including matrix metalloprotease 9 (MMP9) and neutrophil elastase, as well reactive oxygen species. This inflammatory cascade ultimately leads to tissue damage and subepidermal blister formation. […] In vitro and in vivo studies have allowed the characterization of several pathways critically involved in BP pathogenesis that directly contribute to tissue damage. Among these, activation of the complement system with production of anaphylatoxins, and activation of the innate immune response with subsequent recruitment and activation of basophils, eosinophils, neutrophils, monocytes/macrophages, and mast cells, play a key role in BP.
#2 From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid
https://www.mdpi.com/1422-0067/24/23/16786
Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. […] The underlying mechanisms of BP remain largely unknown. However, it seems to rely upon the interaction between predisposing and triggering factors. […] The pathogenesis initiates with the binding of autoantibodies against the hemidesmosomes in the basement membrane zone (BMZ). This binding activates multiple pathways, both complement-mediated and non-mediated, leading to the release of cytokines and proteases and the chemotaxis of neutrophils and eosinophils. Proteolytic cleavage at the BMZ induces dermalâepidermal separation and blister formation, with the subsequent dispersion of hemidesmosome-associated protein fragments. These fragments may interact with autoreactive lymphocytes, intensifying the inflammatory response.
#3 Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid – UpToDate
https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-bullous-pemphigoid-and-mucous-membrane-pemphigoid/print
Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune subepithelial blistering diseases that most frequently arise in older adults and are characterized by the presence of cutaneous bullae and erosive mucosal lesions. Significant progress has been made in understanding the pathogenesis of these diseases. Multiple events, including the binding of immunoglobulins to basement membrane zone components, the subsequent activation of complement, and the migration of inflammatory cells into the subepithelial tissue, likely contribute to the clinical manifestations of bullous pemphigoid and MMP. […] The epidemiology and pathogenesis of bullous pemphigoid and MMP will be reviewed here. […] Pemphigoid disorders, which include bullous pemphigoid, MMP, anti-laminin 332 pemphigoid (also known as anti-epiligrin cicatricial pemphigoid), pemphigoid gestationis, Brunsting-Perry pemphigoid, and anti-laminin gamma-1 (anti-p200) pemphigoid, are characterized clinically by the presence of inflammatory, blistering, and/or erosive mucocutaneous lesions and immunohistopathologically by subepithelial cleavage and immunoglobulin G (IgG) and/or complement deposits in a linear pattern at the epidermal basement membrane zone. The location of blistering and immunoglobulin deposition distinguishes pemphigoid disorders from pemphigus. […] MMP is not a single disease, rather it represents a group of heterogeneous, chronic subepithelial blistering diseases that primarily affect mucosal surfaces.
#3 Targeting Type 2 Inflammation for Treatment of Bullous Pemphigoid
https://www.dermatoljournal.com/articles/targeting-type-2-inflammation-for-treatment-of-bullous-pemphigoid.html
Bullous pemphigoid (BP) is an autoimmune blistering condition, often presenting in elderly individuals with pruritis and tense bullae. […] Here, we discuss how the reported efficacy of dupilumab and certain other biologics in treating BP implicates type 2 inflammation as an important driver of BP pathogenesis. […] Dupilumab is a human monoclonal IL-4R antibody approved for treatment of atopic dermatitis (AD), asthma, and chronic sinusitis with nasal polyposis, which modulates type 2 inflammation through inhibition of IL-4 and IL-13 signaling. […] Several lines of evidence point to a prominent type 2 inflammatory response in BP, which include important roles of TH2 cytokines and chemokines, eosinophils, and IgE. […] These observations have sparked interest in eosinophils as well as the cytokines and chemokines that regulate their biological functions in BP pathogenesis.
#3 Drug-Associated Bullous Pemphigoid | Encyclopedia MDPI
https://encyclopedia.pub/entry/52465
It is well accepted that bullous pemphigoid arises from a loss of immune tolerance, resulting in the production of autoantibodies against BP180 and BP230. These antibodies trigger an inflammatory reaction, attracting numerous neutrophils, eosinophils and mast cells, which migrate to the dermis and release a wide range of cytokines and proteases, responsible for dermoepidermal cleavage and blister formation. […] Until the last decade, complement was believed to be a prerequisite for blister formation by autoantibodies. Complement components are present along the dermoepidermal junction in patients with BP, as demonstrated with direct immunofluorescence (DIF), which shows linear C3 deposition in 83â84% of BP cases. […] Nonetheless, more recent studies have questioned its major pathogenic role in bullous pemphigoid, proposing the existence of complement-independent mechanisms mediating blister formation.
#3 From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid
https://www.mdpi.com/1422-0067/24/23/16786
It is well accepted that bullous pemphigoid arises from a loss of immune tolerance, resulting in the production of autoantibodies against BP180 and BP230. These antibodies trigger an inflammatory reaction, attracting numerous neutrophils, eosinophils and mast cells, which migrate to the dermis and release a wide range of cytokines and proteases, responsible for dermoepidermal cleavage and blister formation. […] Until the last decade, a complement was believed to be a prerequisite for blister formation by autoantibodies. […] Nonetheless, more recent studies have questioned its major pathogenic role in bullous pemphigoid, proposing the existence of complement-independent mechanisms mediating blister formation. […] The binding of autoantibodies to BP180 in hemidesmosomes results in the internalization of BP180 into basal keratinocytes, so the adhesive strength of the dermoepidermal junction decreases. This appears to be an early event in disease pathogenesis, followed by an inflammatory response that finally causes dermoepidermal separation.
#3 FDA Drug Approval Decisions Expected in June 2025 – The Cardiology Advisor
https://www.thecardiologyadvisor.com/news/fda-drug-approval-decisions-expected-in-june-2025/
Dupilumab is designed to target 2 key inflammatory cytokines, interleukin-4 and interleukin-13, thereby reducing type 2 inflammation in these patients. […] Findings showed more patients treated with dupilumab experienced sustained disease remission at week 36 compared with those who received placebo (20% vs 4%, respectively; P =.0114). Sustained disease remission was defined as complete clinical remission with oral corticosteroid (OCS) taper completed by 16 weeks without relapse and no rescue therapy use during the treatment period. A greater improvement with dupilumab vs placebo was also observed in key secondary endpoints including pruritus reduction and decreased OCS use.
#3
https://link.springer.com/article/10.1007/s12325-024-02992-w
Bullous pemphigoid (BP) is an autoimmune blistering disease that most often affects elderly individuals and has a significant negative impact on quality of life. The disease is characterized primarily by autoantibodies to hemidesmosomal proteins BP180 and/or BP230, and an inflammatory reaction with notable features of type 2 inflammation, including elevated serum IgE, increased numbers of eosinophils in lesions and peripheral blood, and elevated expression of type 2 cytokines and chemokines in skin lesions. […] BP pathophysiology is not completely understood but is characterized primarily by the production of immunoglobin G (IgG) autoantibodies directed against hemidesmosomal anchoring proteins BP antigen 180 (BP180) and/or BP antigen 230 (BP230). Several lines of evidence also suggest a prominent type 2 inflammatory response in BP. Type 2 inflammation predominantly involves the activation of group 2 innate lymphoid cells, T helper type 2 cells, eosinophils, and inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13.