| First Author | Silva DG | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 8 | Pages | 2102-11 |
| PubMed ID | 21788582 | Mgi Jnum | J:186792 |
| Mgi Id | MGI:5433251 | Doi | 10.2337/db10-1344 |
| Citation | Silva DG, et al. (2011) Anti-islet autoantibodies trigger autoimmune diabetes in the presence of an increased frequency of islet-reactive CD4 T cells. Diabetes 60(8):2102-11 |
| abstractText | 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 beta-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. FcgammaR 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 FcgammaR-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. |
