AIRE regulates T-cell-independent B-cell responses through BAFF.
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.
Lindh
Emma
E
Clinical Allergy Research Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
Lind
Sara M
SM
Lindmark
Evelina
E
Hässler
Signe
S
Perheentupa
Jaakko
J
Peltonen
Leena
L
Winqvist
Ola
O
Karlsson
Mikael C I
MC
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D053264:B-Cell Activating Factor / Q000097:blood / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000096927:AIRE Protein
D001324:Autoantigens; D053264:B-Cell Activating Factor; D017931:DNA Primers; D017471:Receptors, Interferon; D014157:Transcription Factors; D000096927:AIRE Protein; C505719:TNFSF13B protein, human