The relevance of complement in pemphigoid diseases: A critical appraisal

Abstract

Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies.

What's new in the pathogeneses and triggering factors of bullous pemphigoid

“…The latter has been thoroughly investigated based on animal models and patient samples, and the complement‐dependent and ‐independent pathways have been well elucidated. 80 As shown in this review, an improved understanding of the epitope‐spreading phenomenon and the pathogenicity of anti‐BP230 autoantibodies may elucidate the mechanism behind disease progression and the chronic disease course of BP. In addition, type 2 immune reactions, eosinophils, mast cells, granzymes, IgE autoantibodies, and Fc receptors have been attracting researchers' interest.…”

“…There are two major focuses of BP research: (1) the mechanism behind the breakdown of immune tolerance to BP antigens (COL17 and BP230) and (2) the molecular and immunological pathways of blister formation and inflammation triggered by BP autoantibodies. The latter has been thoroughly investigated based on animal models and patient samples, and the complement‐dependent and ‐independent pathways have been well elucidated 80 . As shown in this review, an improved understanding of the epitope‐spreading phenomenon and the pathogenicity of anti‐BP230 autoantibodies may elucidate the mechanism behind disease progression and the chronic disease course of BP.…”

“…The latter has been thoroughly investigated based on animal models and patient samples, and the complement-dependent and -independent pathways have been well elucidated. 80 F I G U R E 4 Our hypothesis on the pathogenesis of bullous pemphigoid (BP). We hypothesize that the patient's background, such as genetic background, Treg cell dysfunction and aging, as well as triggers such as trauma, irradiation, infection, neurological diseases, hematological malignancies, DPP-4 inhibitors, immune checkpoint inhibitors, and the like, cooperatively or synergistically induce the breakdown of immune tolerance to COL17, resulting in the production of autoantibodies and the development of BP.…”

The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets

“…It is worth noting that loss of dermal-epidermal adhesion in BP may also occur via complement-independent mechanisms ( 76 , 81 , 82 ), which are thought to be preponderant during early and non-blistering phases of BP, where non-fixing complement IgG4 subclasses are predominant ( 83 – 85 ). These mechanisms include (i) internalization of BP180 from the surface of keratinocytes after IgG binding to BP180 ( 86 ); (ii) direct release of cytokines, e.g., IL-6 and IL-8, from keratinocytes ( 87 ); (iii) induction of MC degranulation and eosinophil activation by IgE autoantibodies ( 88 ).…”

“…It is thus possible that both complement-dependent and complement-independent mechanisms work together in inducing and perpetuating BP inflammation and blistering ( 85 ).…”