title: Induction of T regulatory cells by the superagonistic anti-CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA-transgenic mouse model of pemphigus vulgaris.
abstract: Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune disease of the skin and mucous membranes. Its pathogenesis is based on IgG autoantibodies that target the desmosomal cadherins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) and induce intra-epidermal loss of adhesion. Although the PV pathogenesis is well-understood, therapeutic options are still limited to immunosuppressive drugs, particularly corticosteroids, which are associated with significant side effects. Dsg3-reactive T regulatory cells (Treg) have been previously identified in PV and healthy carriers of PV-associated HLA class II alleles. Ex vivo, Dsg3-specific Treg cells down-regulated the activation of pathogenic Dsg3-specific T-helper (Th) 2 cells. In this study, in a HLA-DRB1*04:02 transgenic mouse model of PV, peripheral Treg cells were modulated by the use of Treg-depleting or expanding monoclonal antibodies, respectively. Our findings show that, in vivo, although not statistically significant, Treg cells exert a clear down-regulatory effect on the Dsg3-driven T-cell response and, accordingly, the formation of Dsg3-specific IgG antibodies. These observations confirm the powerful immune regulatory functions of Treg cells and identify Treg cells as potential therapeutic modulators in PV.
authors.affiliation: Department of Dermatology and Allergology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of Dermatology and Allergology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Willenborg
authors.affiliation: Institute of Virology and Immunobiology, Department of Immunology, Julius-Maximilians University Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.affiliation: Department of Ophthalmology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Cornelia A
authors.initials: CA
authors.lastname: Deeg
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Grete
authors.initials: G
authors.lastname: Sonderstrup
authors.affiliation: Department of Dermatology and Allergology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hertl
authors.affiliation: Department of Dermatology and Allergology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Eming
mesh_terms: D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001323:Autoantibodies / Q000737:chemistry*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D051183:Desmoglein 1 / Q000235:genetics; D051184:Desmoglein 3 / Q000235:genetics*; D015536:Down-Regulation; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D010392:Pemphigus / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D018106:CD28 Antigens; D051183:Desmoglein 1; D051184:Desmoglein 3; D059811:HLA-DRB1 Chains; C553506:HLA-DRB1*04:02 antigen; D007074:Immunoglobulin G; D011994:Recombinant Proteins
keywords: CD28 superagonist; Dsg3-specific IgG; T regulatory cells (Treg); anti-CD25 monoclonal antibody; pemphigus vulgaris