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Roles of Bcl-3 in the Pathogenesis of Murine Type 1 Diabetes.
- Source :
- Diabetes; Oct2010, Vol. 59 Issue 10, p2549-2557, 9p, 1 Color Photograph, 7 Graphs
- Publication Year :
- 2010
-
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. 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. 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. 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. Diabetes 59:25492557, 2010 [ABSTRACT FROM AUTHOR]
- Subjects :
- DIABETES
B cell lymphoma
NF-kappa B
MORPHOGENESIS
AUTOIMMUNITY
IMMUNODEFICIENCY
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 59
- Issue :
- 10
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 57312548
- Full Text :
- https://doi.org/10.2337/db10-0480