Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 38, Issue 8, Pages 2219-2228Publisher
WILEY
DOI: 10.1002/eji.200738113
Keywords
Act1; autoimmunity; B cells; Sjogren's syndrome; systemic lupus erythematosus
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Funding
- NIAID NIH HHS [R01 AI065470, R01 AI065470-04, R01 AI065470-05, AI 065470, T32 AI007051] Funding Source: Medline
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CD40L and B lymphocyte-activating factor (BAFF), members of the TNF superfamily, play critical roles in B cell survival and activation, and in the regulation of humoral immunity. We previously reported that the adaptor molecule Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival. Here we demonstrated that mice deficient in Act1 developed systemic autoimmune disease with histological and serological features of human Sjogren's syndrome (SS), in association with systemic lupus erythematosus-like nephritis. Analyses of Act1(-/-)CD40(-/-) and Act1(-/-)BAFF(-/-) double-deficient mice revealed that Act1 regulates different stages of the disease development through its impact on both CD40- and BAFF-mediated pathways. We found that Act1 modulates the survival of autoreactive B cells mainly through its negative regulatory role in BAFF-mediated cell survival, while the effect of Act1 on autoantibody production is likely through modulation of CD40-mediated T cell-dependent antibody response. The impact of Act1 on both BAFF and CD40 pathways establishes Act1-deficient mice as a unique model to study distinct steps of autoimmunity and regulation of self tolerance.
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