Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

Abstract

Pemphigus vulgaris is an autoimmune disease caused by IgG antibodies against desmoglein 3 (Dsg3). Previously, we isolated a pathogenic mAb against Dsg3, AK23 IgG, which induces a pemphigus vulgaris-like phenotype characterized by blister formation. In the present study, we generated a transgenic mouse expressing AK23 IgM to examine B-cell tolerance and the pathogenic role of IgM. Autoreactive transgenic B cells were found in the spleen and lymph nodes, whereas antiDsg3 AK23 IgM was detected in the cardiovascular circulation. The transgenic mice did not develop an obvious pemphigus vulgaris phenotype, however, even though an excess of AK23 IgM was passively transferred to neonatal mice. Similarly, when hybridoma cells producing AK23 IgM were inoculated into adult mice, no blistering was observed. Immunoelectron microscopy revealed IgM binding at the edges of desmosomes or interdesmosomal cell membranes, but not in the desmosome core, where AK23 IgG binding has been frequently detected. Furthermore, in an in vitro dissociation assay using cultured keratinocytes, AK23 IgG and AK23 IgM F(ab=) 2 fragments, but not AK23 IgM, induced fragmentation of epidermal sheets. Together, these observations indicate that antibodies must gain access to Dsg3 integrated within desmosomes to induce the loss of keratinocyte cell-cell adhesion. These findings provide an important framework for improved understanding of B-cell tolerance and the pathophysiology of blister formation in pemphigus. Pemphigus vulgaris (PV) is a life-threatening, organ-specific autoimmune blistering disease of the skin and mucous membranes. It is characterized clinically by painful oral erosions and flaccid skin blisters, histologically by suprabasal acantholysis (ie, loss of cell-cell adhesion between suprabasal keratinocytes), and immunopathologically by IgG autoantibodies against desmoglein 3 (Dsg3), a cadherin-type cell-cell adhesion molecule found in desmosomes.1,2 Compelling evidence indicates that IgG autoantibodies against Dsg3 are pathogenic and play a primary role in inducing blister formation in pemphigus. IgGs affinity-purified from the sera of PV patients using the extracellular domain of Dsg3 cause suprabasal acantholysis when injected into neonatal mice.3 When anti-Dsg3 IgG is immunoadsorbed from the sera of PV patients using the same Dsg3 domain, those sera lose their ability to cause blister formation in neonatal mice. 4 Furthermore, monoclonal antibodies (mAbs) against Dsg3 from a model mouse and from PV patients induce the formation in mice of blisters with typical PV histology. 5,6 The pathogenic roles of autoantibodies against nondesmoglein molecules remain to be clarified. 7,8 We previously developed a PV model mouse by the adoptive transfer of lymphocytes from Dsg3 Ϫ/Ϫ mice immunized with rDsg3 to Rag2 Ϫ/Ϫ mice that express Dsg3. 9Recipient mice showed stable anti-Dsg3 IgG production and developed a PV phenotype characterized by mucosal erosions and acantholytic blisters, similar to those seen in PV patients. We subsequently isolated AK...

Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

“…However, our immunoprecipitation experiments also revealed that the complex is not detectable exclusively in the soluble pool but also within desmosomes. Moreover, AK23, which induces p38 MAPK activation (20), has been shown to also bind to Dsg3 within desmosomes (42). Thus, the contribution of desmosomal versus non-desmosomal Dsg3 to signaling events needs to be clarified further.…”

Development of a Disease Registry for Autoimmune Bullous Diseases: Initial Analysis of the Pemphigus Vulgaris Subset

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