AIRE regulates T-cell-independent B-cell responses through BAFF

Abstract

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 antigenpresenting 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 marrowderived dendritic cells produced significantly more BAFF than wt cells when stimulated with IFN-␥ but not when stimulated with IL-10. Our results suggest a cell-intrinsic role for AIRE in peripheral dendritic cells by regulating IFN-␥-receptor signaling and point toward complementary mechanisms by which AIRE is involved in maintaining tolerance.autoimmunity ͉ tolerance

IL-10 and Lymphotoxin-α Expression Profiles within Marginal Zone-Like B-Cell Populations Are Associated with Control of HIV-1 Disease Progression

“…Strikingly, these animals present an enlarged splenic marginal zone (MZ), in which accumulated myeloid dendritic cells (mDCs) likely contribute to MZ expansion, polyclonal B-cell activation and breakage of tolerance through delivery of excessive signals such as B lymphocyte stimulator (BLyS/BAFF) [4]–[5]. A similar B-cell profile was reported for BLyS/BAFF-Tg [6] and autoimmune-regulatory-(AIRE)-deficient mice, in which BLyS/BAFF is elevated in serum and over-expressed by DCs [7]–[8]. Accordingly, DCs play a pivotal role in regulating B-cell development, activation and survival mainly through production of growth factors such as BLyS/BAFF [9]–[11], known to highly influence the transitional immature (TI) and MZ B-cell pools [12]–[13].…”

AIRE deficiency leads to impaired iNKT cell development

“…However, Aire À/À mice develop autoimmunity against antigens that are normally expressed in Aire-deficient mTECs, suggesting alternative functions by which Aire maintains tolerance [8]. In addition, Aire has been shown to play a role in regulating peripheral tolerance mechanisms independent of TSA expression in the thymus [9][10][11]. Several reports have investigated the regulatory cell types of the immune system, such as the T regulatory cells (Tregs), gd T cells and iNKT cells, in APS I patients and various strains of Aire À/À mice.…”

Deciphering the role of NETs and networks in SLE

“…8 Around the world, most children with JIA have to rely on much less expensive drugs, such as methotrexate. Therefore, data regarding the efficacy of combination therapies comprising methotrexate and other synthetic DMARDs in compari son with metho trexate alone would be viewed with interest by rheuma tologists worldwide.…”