| First Author | Lindh E | Year | 2008 |
| Journal | Proc Natl Acad Sci U S A | Volume | 105 |
| Issue | 47 | Pages | 18466-71 |
| PubMed ID | 19011083 | Mgi Jnum | J:142232 |
| Mgi Id | MGI:3820757 | Doi | 10.1073/pnas.0808205105 |
| Citation | Lindh E, et al. (2008) AIRE regulates T-cell-independent B-cell responses through BAFF. Proc Natl Acad Sci U S A 105(47):18466-71 |
| abstractText | Autoimmune polyendocrine syndrome type I (APS I) results in multiple endocrine organ destruction and is caused by mutations in the autoimmune regulator gene (AIRE). APS I is characterized by circulating tissue-specific autoantibodies, and the presence of these antibodies is often predictive of organ destruction. The importance of AIRE in ensuring central tolerance by regulating the negative selection of autoreactive T cells has been shown clearly. However, in Aire(-/-) mice the phenotype (i.e., autoantibodies, liver infiltrates of B cells, splenomegaly, and marginal zone B-cell lymphoma) is predominantly B-cell mediated, suggesting an exaggerated activation of B cells. We have studied T-cell-independent B-cell responses in the absence of AIRE and found that Aire(-/-) mice have an increased response against T-cell-independent type II antigens. We linked this exaggerated response to the elevated serum levels of the B-cell-activating factor of the TNF family (BAFF) that were found both in APS I patients and in Aire(-/-) mice. Transfer of Aire(-/-) bone marrow into irradiated nude mice resulted in increased percentage of BAFF-expressing antigen-presenting cells compared with wt bone marrow, suggesting a T-cell-independent mechanism behind our findings. Furthermore, in vitro experiments showed that AIRE-deficient murine bone marrow-derived dendritic cells produced significantly more BAFF than wt cells when stimulated with IFN-gamma but not when stimulated with IL-10. Our results suggest a cell-intrinsic role for AIRE in peripheral dendritic cells by regulating IFN-gamma-receptor signaling and point toward complementary mechanisms by which AIRE is involved in maintaining tolerance. |
