Roles of Bcl-3 in the pathogenesis of murine type 1 diabetes

Ruan, Q., Zheng, S.-J., Palmer, S., Carmody, R.J. and Chen, Y.H. (2010) Roles of Bcl-3 in the pathogenesis of murine type 1 diabetes. Diabetes, 59(10), pp. 2549-2557. (doi: 10.2337/db10-0480)

Abstract

OBJECTIVE: It has long been recognized that autoimmunity is often associated with immunodeficiency. The mechanism underlying this paradox is not well understood. Bcl-3 (B-cell lymphoma 3) is an atypical member of the IκB (inhibitor of the nuclear factor-κB) family that is required for lymphoid organogenesis and germinal center responses. Mice deficient in Bcl-3 are immunodeficient because of the microarchitectural defects of their lymphoid organs. The goal of this study is to define the potential roles of Bcl-3 in type 1 diabetes. <p/>RESEARCH DESIGN AND METHODS: Bcl-3–deficient NOD mice were generated by backcrossing Bcl-3–deficient C57BL/6 mice to NOD mice. Spontaneous and induced type 1 diabetes were studied in these mice by both pathologic and immunologic means. The effect of Bcl-3 on inflammatory gene transcription was evaluated in a promoter reporter assay. <p/>RESULTS: We found that Bcl-3–deficient NOD and C57BL/6 mice were, paradoxically, more susceptible to autoimmune diabetes than wild-type mice. The increase in diabetes susceptibility was caused by Bcl-3 deficiency in hematopoietic cells but not nonhematopoietic cells. Bcl-3 deficiency did not significantly affect anti-islet Th1 or Th2 autoimmune responses, but markedly increased inflammatory chemokine and T helper 17 (Th17)-type cytokine expression. Upon transfection, Bcl-3 significantly inhibited the promoter activities of inflammatory chemokine and cytokine genes. <p/>CONCLUSIONS: These results indicate that in addition to mediating lymphoid organogenesis, Bcl-3 prevents autoimmune diabetes by inhibiting inflammatory chemokine and cytokine gene transcription. Thus, a single Bcl3 gene mutation leads to both autoimmunity and immunodeficiency.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carmody, Dr Ruaidhri
• Authors: Ruan, Q., Zheng, S.-J., Palmer, S., Carmody, R.J., and Chen, Y.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Diabetes
• Publisher: American Diabetes Association
• ISSN: 0012-1797
• Published Online: 09 July 2010
• Copyright Holders: Copyright © 2010 American Diabetes Association
• First Published: First published in Diabetes 59(10):2549-2557
• Publisher Policy: Reproduced under a Creative Commons License