title: 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 anti-Dsg3 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.
authors: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors: Kazuyuki
authors: K
authors: Tsunoda
authors: Takayuki
authors: T
authors: Ota
authors: Masataka
authors: M
authors: Saito
authors: Tsuyoshi
authors: T
authors: Hata
authors: Atsushi
authors: A
authors: Shimizu
authors: Akira
authors: A
authors: Ishiko
authors: Taketo
authors: T
authors: Yamada
authors: Taneaki
authors: T
authors: Nakagawa
authors: Andrew P
authors: AP
authors: Kowalczyk
authors: Masayuki
authors: M
authors: Amagai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001768:Blister / Q000276:immunology; D002448:Cell Adhesion; D051184:Desmoglein 3 / Q000737:chemistry*; D005434:Flow Cytometry / Q000379:methods; D006825:Hybridomas / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry*; D007075:Immunoglobulin M / Q000737:chemistry* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010392:Pemphigus / Q000276:immunology*
chemical_list: D051184:Desmoglein 3; D007074:Immunoglobulin G; D007075:Immunoglobulin M