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ABSTRACT: Objective
To define cellular mechanisms by which B cells promote type 1 diabetes.Research design and 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 ?-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. Fc?R 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 Fc?R-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.
SUBMITTER: Silva DG
PROVIDER: S-EPMC3142068 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
Silva Diego G DG Daley Stephen R SR Hogan Jennifer J Lee Sau K SK Teh Charis E CE Hu Daniel Y DY Lam Kong-Peng KP Goodnow Christopher C CC Vinuesa Carola G CG
Diabetes 20110801 8
<h4>Objective</h4>To define cellular mechanisms by which B cells promote type 1 diabetes.<h4>Research design and methods</h4>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 ...[more]