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Review
. 2022 Jul 7:13:912876.
doi: 10.3389/fimmu.2022.912876. eCollection 2022.

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Connor Cole  1 , Keshavamurthy Vinay  2 , Luca Borradori  3 , Kyle T Amber  1   4
Affiliations
Review

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Connor Cole et al. Front Immunol. .

Abstract

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. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

Keywords: BP180; BP230; autoimmune blistering diseases; bullous pemphigoid; complement - immunological terms; eosinophils – immunology; igE (Immunoglobulin E).

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Conflict of interest statement

KA has served as a consultant for AstraZeneca, Akari Therapeutics, Argenx, as well as received research support from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Keratinocyte mediated, complement-independent pathways in bullous pemphigoid. (A) IgG autoantibodies targeting BP180 bind to the epidermal basement membrane. IgG-BP180 complexes undergo macropinocytosis as shown by immunostain for EEA-1. (B) Internalized IgG-BP180 complexes lead to both loss of cellular BP180 and increased expression of proinflammatory mediators such as IL-6 and IL-8, resulting in both (C) pauci-inflammatory and pro-inflammatory complement-independent mechanisms.
Figure 2
Figure 2
IgE- and eosinophil-mediated complement-independent pathways in bullous pemphigoid. (A) BP180 IgE autoantibodies and BP180-IgE complexes bind to the cutaneous basement membrane and the FcϵR1 on eosinophils as well as mast cells and basophils. This results in release of proteases (e.g. MMP9), eosinophil granule proteins (ECP, EDN), eosinophil extracellular traps, as well as reactive nitric oxide-derived oxidants (NOS). (B) Keratinocytes release IL-5, RANTES, and eotaxin-1 as a response to eosinophil granule proteins. (C) this positive feedback loop results in an increase in tissue eosinophilia and eosinophilic spongiosis. Inhibitory therapeutic antibodies are shown in boxes with red arrows leading to their downstream target.
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