title: Immune dysregulation of pemphigus in humans and mice.
abstract: Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by immunoglobulin (Ig)G autoantibodies against the cadherin-type adhesion molecule desmoglein (Dsg)3 expressed on stratified epithelial cells. Interaction between antigen-specific T and B cells, which is selectively achieved through T-cell receptor/major histocompatibility complex-peptide complex association and subsequently corroborated by co-stimulatory molecules such as CD40/CD154, is required for production of pathological anti-desmoglein 3 antibody. Some genetically and environmentally susceptible individuals harbor desmoglein reactive B and T cells, and anti-desmoglein antibodies were detected in their serum. Analysis of the anti-desmoglein antibody clones derived from pemphigus patients or pemphigus model mice revealed that pathogenic antibodies mostly react with conformational epitopes on mature form desmogleins, whereas non-pathogenic ones tend to react with non-conformational epitopes. Surprisingly, antibodies to the Dsg1 precursor pro-protein are also cloned from individuals without pemphigus. These observations suggest that active suppression by regulatory cell subsets is dominant in these susceptible individuals. In fact, Dsg-reactive T-inducible regulatory type 1 (Tr1) cells are readily detected in healthy carriers of pemphigus-related human leukocyte antigen haplotypes, but rarely in pemphigus patients. These Tr1 cells can be functionally converted to T-helper 2-like cells which secrete interleukin-2 by inactivation of Foxp3 through antisense oligonucleotides. Thus, delicate balance between self-reactive lymphocytes and regulatory T cells may be a key element in determining whether individuals produce pathogenic antibodies and develop pemphigus phenotypes or not.
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001768:Blister / Q000276:immunology* / Q000473:pathology*; D019013:CD40 Antigens; D051184:Desmoglein 3 / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D010392:Pemphigus / Q000276:immunology* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D019013:CD40 Antigens; D051184:Desmoglein 3; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D007376:Interleukin-2