title: Anti-islet autoantibodies trigger autoimmune diabetes in the presence of an increased frequency of islet-reactive CD4 T cells.
abstract: OBJECTIVE
  To define cellular mechanisms by which B cells promote type 1 diabetes.
  
  
  METHODS
  The study measured islet-specific CD4 T cell regulation in T-cell receptor transgenic mice with elevated frequencies of CD4 T cells recognizing hen egg lysozyme (HEL) autoantigen expressed in islet β-cells and thymic epithelium under control of the insulin-gene promoter. The effects of a mutation in Roquin that dysregulates T follicular helper (Tfh) cells to promote B-cell activation and anti-islet autoantibodies were studied, as were the effects of HEL antigen-presenting B cells and passively transferred or maternally transmitted anti-islet HEL antibodies.
  
  
  RESULTS
  Mouse anti-islet IgG antibodies-either formed as a consequence of excessive Tfh activity, maternally transmitted, or passively transferred-caused a breakdown of tolerance in islet-reactive CD4(+) cells and fast progression to diabetes. Progression to diabetes was ameliorated in the absence of B cells or when the B cells could not secrete islet-specific IgG. Anti-islet antibodies increased the survival of proliferating islet-reactive CD4(+) T cells. FcγR blockade delayed and reduced the incidence of autoimmune diabetes.
  
  
  CONCLUSIONS
  B cells can promote type 1 diabetes by secreting anti-islet autoantibodies that act in an FcγR-mediated manner to enhance the expansion of islet-reactive CD4 T cells and cooperate with inherited defects in thymic and peripheral CD4 T-cell tolerance. Cooperation between inherited variants affecting CD4 T-cell tolerance and anti-islet autoantibodies should be examined in epidemiological studies and in studies examining the efficacy of B-cell depletion.
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Diego G
authors.initials: DG
authors.lastname: Silva
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Daley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hogan
authors.forename: Sau K
authors.initials: SK
authors.lastname: Lee
authors.forename: Charis E
authors.initials: CE
authors.lastname: Teh
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Hu
authors.forename: Kong-Peng
authors.initials: KP
authors.lastname: Lam
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D001323:Autoantibodies; D011948:Receptors, Antigen, T-Cell