Autoantibodies to the extracellular and intracellular domain of bullous pemphigoid 180, the putative key autoantigen in bullous pemphigoid, belong predominantly to the IgG1 and IgG4 subclasses

Abstract

Consistent with prior evidence indicating that subepidermal blister formation in BP is dependent upon complement activation, the frequent finding of complement-fixing IgG1 autoantibodies to both the ECD and ICD of BP180 might have pathogenic relevance in BP. These findings provide new insights relevant for our understanding of the immune response to BP180, the putative key autoantigen in BP.

Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model

“…In this study, we have directly demonstrated that anti-hCOL17 NC16A IgG1 mAb has pathogenic activity in vivo by using COL17-humanized (COL17 m2/2, h+ ) BP model mice. As previous clinical studies on BP (5,7,28), our results further support the notion that IgG1 autoantibodies against hCO17 are potent and possibly the main pathogenic IgG autoantibodies in BP.…”

“…IgG1 and IgG3 are the most effective complement activators, whereas IgG4 is not capable of fixing complements (40). Previous clinical studies demonstrated that IgG1 and IgG4 autoantibodies are major IgG subclasses of BP patient autoantibodies and that IgG2 and IgG3 are minor subclasses of BP patient autoantibodies (5,7,28). In vitro analysis using cryosections of human skin and leukocytes from healthy volunteers demonstrated that IgG1 autoantibodies purified from BP sera showed much stronger pathogenic activity than that of IgG4 autoantibodies (41).…”

“…Circulating autoantibodies target human type XVII collagen (human collagen 17 [hCOL17]), also known as BP Ag 2 (BPAG2) or BP180, which is a major component in hemidesmosome-anchoring filament complexes at the epidermal basement membrane zone (BMZ) (3)(4)(5)(6)(7)(8)(9). The major pathogenic epitope of BP autoantibodies is present at the extracellular noncollagenous 16A (NC16A) domain, which has distinctive diversity among different species (10)(11)(12).…”

“…Clinical studies have shown a preferential detection of hCOL17-specific IgG1 and IgG4 autoantibodies in BP sera, with IgG2 and IgG3 being detected in a minority of patients (5,7,28). Eighty-five percent and 46% of BP sera contained IgG1 and IgG4 Abs against hCOL17, respectively (6).…”

IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin

“…Indeed, the pathogenic role of autoreactive IgG4 is suspected in several autoimmune diseases, particularly dermatological bullous diseases. IgG4 towards the major autoantigens of such diseases were reported to be associated to clinical features: to disease progression and severity in Pemphigus vulgaris [53,54], to progression from a preclinical to a clinical form in P. foliaceus [55], and to a long disease duration in bullous pemphigoid [56]. Finally, IgG1 in mice (the human IgG4 counterpart) may trigger immune effector functions via FcgRIII [42], supporting our hypothesis that a particular interaction between AhFibA subclasse(s) and particular type(s) of IgG receptors may be critical in the self-maintenance of inflammation.…”