Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris

Eur J Immunol. 2002 Mar;32(3):627-33. doi: 10.1002/1521-4141(200203)32:3<627::AID-IMMU627>3.0.CO;2-1.

Abstract

Mechanisms of tolerance break against desmoglein 3 (Dsg3) in patients with pemphigus vulgaris (PV) producing pathogenic anti-Dsg3 IgG autoantibodies are unclear. In this study, using a novel PV mouse model involving Dsg3 knockout mice, we investigated the mechanisms leading to production of autoantibodies against Dsg3. Adoptive transfer of Dsg3(-/-) splenocytes immunized with recombinant mouse Dsg3 to Rag2(-/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3(-/-), Dsg3(+/-) or Dsg3(+/+) mice were mixed with various combinations and transferred to Rag2(-/-) mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3(-/-) T and Dsg3(-/-) B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantibodies / biosynthesis*
  • Autoantibodies / immunology
  • Autoantigens / immunology*
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / transplantation
  • Cadherins / immunology*
  • Cell Line
  • Crosses, Genetic
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Desmoglein 3
  • Disease Models, Animal
  • Epidermis / pathology
  • Female
  • Flow Cytometry
  • Humans
  • Immunization
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / immunology
  • Keratinocytes / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mouth Mucosa / pathology
  • Nuclear Proteins
  • Pemphigus / immunology*
  • Phenotype
  • Recombinant Fusion Proteins / immunology
  • Self Tolerance*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / transplantation

Substances

  • Autoantibodies
  • Autoantigens
  • Cadherins
  • DNA-Binding Proteins
  • DSG3 protein, human
  • Desmoglein 3
  • Immunoglobulin G
  • Nuclear Proteins
  • RAG2 protein, human
  • Rag2 protein, mouse
  • Recombinant Fusion Proteins
  • V(D)J recombination activating protein 2