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


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.
Ruan
Qingguo
Q
Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Zheng
Shi-Jun
SJ
Palmer
Scott
S
Carmody
Ruaidhri J
RJ
Chen
Youhai H
YH
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002454:Cell Differentiation; D018925:Chemokines / Q000235:genetics; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology* / Q000517:prevention & control; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008156:Luciferases / Q000235:genetics; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D018925:Chemokines; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D008156:Luciferases