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Review
. 2022 Mar;142(3 Pt B):907-914.
doi: 10.1016/j.jid.2021.04.040. Epub 2021 Oct 29.

Pemphigus and Pemphigoid: From Disease Mechanisms to Druggable Pathways

Christoph T Ellebrecht  1 , Damian Maseda  1 , Aimee S Payne  2
Affiliations
Review

Pemphigus and Pemphigoid: From Disease Mechanisms to Druggable Pathways

Christoph T Ellebrecht et al. J Invest Dermatol. 2022 Mar.

Abstract

Pemphigus and pemphigoid are paradigms for understanding the mechanisms of antibody-mediated autoimmune disease in humans. In pemphigus, IgG4-predominant autoantibodies cause intraepidermal blistering by direct interference with desmoglein interactions and subsequent disruption of desmosomes and signaling pathways. In pemphigoid, IgG1, IgG4, and IgE autoantibodies against basement membrane zone antigens directly interfere with hemidesmosomal adhesion, activating complement and Fc receptor‒mediated effector pathways. Unraveling disease mechanisms in pemphigus and pemphigoid has identified numerous opportunities for clinical trials, which hold promise to identify safer and more effective therapies for these potentially life-threatening diseases.

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Conflict of interest statement

CONFLICT OF INTEREST

A.S.P. reports equity (Cabaletta Bio), patent licensing (Cabaletta Bio, Novartis, Tmunity), grant support (Cabaletta Bio), consultant fees (Cabaletta Bio, Villaris).

C.T.E. reports equity (Cabaletta Bio), patent licensing (Cabaletta Bio, Novartis, Tmunity)

D.M. reports no conflicts of interest.

Figures

Figure 1.
Figure 1.. Disease pathways in pemphigus.
Desmogleins interact with cytoplasmic plaque proteins and engage in trans-interactions with desmocollins on neighboring keratinocytes, predominantly through residues in the extracellular cadherin 1 domain, to mediate desmosomal adhesion. Autoantibody binding to DSGs can directly interfere with cis- or trans-adhesive interactions, weakening desmosomal adhesion. DSG clusters in response to pemphigus IgG binding and internalizes in a p38MAPK-dependent process. DSG trafficking is most directly regulated by p38MAPK and protein kinase C; other signaling pathways may synergize to augment blister formation. DSG clustering and endocytosis impairs desmosome assembly and promotes disassembly, leading to DSG-depleted desmosomes, weakened desmosomal adhesion, and acantholysis.
Figure 2.
Figure 2.. Disease pathways in pemphigoid.
a. B-cells in skin-draining lymph nodes and possibly dermis secrete IgG1/IgG4/IgE autoantibodies that bind the BMZ, triggering both Fc-independent and Fc-dependent effects. Fc-effector functions include complement activation, FcγR and/or FcεR engagement on neutrophils (N), Langerhans cells (LC), mast cells (M), eosinophils (E), and endothelial cells (Ec). b. Fc-dependent effects: C3a/C5a, as well as FcγR/FcεR engagement by IgG1/IgE, induce chemotaxis, activation and inflammation. C3d binds B-cell complement receptor 2 (CR2) to promote autoantibody production. c. Fc-independent effects: IgG4 autoantibodies cause internalization of BP180 on basal keratinocytes, leading to dermal-epidermal detachment. Loss of BMZ anchorage activates keratinocyte signaling pathways to induce secretion of IL-6, which promotes inflammation and antibody secretion by activated B-cells, as well as IL-8, a neutrophil chemoattractant.
See this image and copyright information in PMC

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