Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

Abstract

Pemphigus vulgaris (PV) is considered as a model for an autoantibody-mediated organ-specific autoimmune disorder. IgG autoantibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epidermal keratinocyte adhesion, resulting in blisters and erosions of the skin and mucous membranes. The association of human autoimmune diseases with distinct HLA alleles is a well-known phenomenon, such as the association with HLA-DRB1*04:02 in PV. However, direct evidence that HLA-DRB1*04:02–restricted autoreactive CD4+ T cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing. In this study, we show in a humanized HLA-DRB1*04:02–transgenic mouse model that HLA-DRB1*04:02–restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG Abs that induce loss of epidermal adhesion, a hallmark in the immune pathogenesis of PV. Activation of Dsg3-reactive CD4+ T cells by distinct human Dsg3 peptides that bind to HLA-DRβ1*04:02 is tightly regulated by the HLA-DRB1*04:02 allele and leads, via CD40-CD40L–dependent T cell–B cell interaction, to the production of IgG Abs that recognize both N- and COOH-terminal epitopes of the human Dsg3 ectodomain. These findings demonstrate key cellular and humoral immune events in the autoimmune cascade of PV in a humanized HLA-transgenic mouse model. We show that CD4+ T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DRB1*04:02 induce the secretion of Dsg3-specific IgG in vivo. Finally, these results identify Dsg3-reactive CD4+ T cells as potential therapeutic targets in the future.

Pemphigus

“…5b). Another approach is a mouse model with a MHC class II-null background that expresses the pemphigus-associated HLA-DRB1*0402 allele 109 (FIG. 5c).…”

Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

“…Analysis of the peptides that these Dsg3-specific T cells recognize showed that they derive mostly from the amino-terminal extracellular domain of Dsg3 and share anchor residues at relative positions 1, 4, and 6 (position 4 being positively charged and critical for binding to the negatively charged p4 binding pocket of DRB1*0402) (74). The relevance of the restriction of the Dsg3-specific CD4+ T cell response to HLA-DRB1*0402 for human disease pathophysiology was demonstrated in vivo by immunization of mice transgenic for HLA-DRB1*0402 with such peptides, in which case anti-Dsg3 pathogenic antibodies were produced; however, such peptides do not produce autoantibodies in HLA-DRB1*0401-transgenic mice, and Dsg3 peptides that do not bind the HLA-DRB1*0402 pocket also do not produce autoantibodies in HLA-DRB1*0402-transgenic mice (75). Finally, CD4+CD25+ regulatory T cells have been implicated in maintaining peripheral tolerance to Dsg3 in mice, and in healthy human carriers of the PV-associated HLA-DRB1*0402 and DQB1*0503 alleles, through the suppression of CD4+ effector T cells (76, 77).…”

A reciprocal HLA-Disease Association in Rheumatoid Arthritis and Pemphigus Vulgaris

“…Using a humanized HLA-DRB1*04:02 transgenic mouse model, it was recently shown that T cell recognition of Dsg3 is tightly associated with the HLA-DRB1*04:02 transgene. Additionally, it was shown that T cell–dependent B cell activation was critical for the induction of pathogenic IgG antibodies (34). However, as correctly stated by the authors, this mouse model is only suitable for investigating the effector phase of the autoimmune response in PV.…”

“…However, in the absence of T cells there was no detectable autoantibody production by B cells (38), suggesting that T cells are necessary for the anti-Dsg3 antibody production by B cells. Indeed, recent in vitro and in vivo studies have shown that an interaction between T cells and B cells was necessary for autoantibody production in PV (34, 39). In addition, Dsg3-specific T cells have been shown to be present at higher levels in the peripheral blood of PV patients compared to healthy controls (40).…”