Patients with primary immunodeficiency diseases (PID) often develop autoimmune complications and therefore provide rare opportunities to study the impact of specific gene mutations on the regulation of B-cell tolerance defective in patients with autoimmune diseases. The C104R and A181E mutations in the TNFRSF13B gene encoding TACI are associated with the development of common variable immunodeficiency disease (CVID) with autoimmune complications. We previously reported that mutations in TNFRSF13B gene impact B cell tolerance at 2 distinct steps during B cell development; they interfere with the removal of developing autoreactive B cells in the bone marrow and TACI mutations also induce the secretion of anti-nuclear antibodies (ANAs). Our latest investigation revealed that TNFRSF13B hemizygosity does not affect B cell tolerance, suggesting that the common C104R and A181 TACI mutations may encode dominant negative products. However, it remains unclear why TACI is required for B cell tolerance and how this molecule may contribute to self-antigen sensing during the central counterselection of developing autoreactive B cells or to ANA secretion in the periphery. The goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy subjects but may be defective in patients with autoimmune diseases. The working hypothesis is that TACI is required for B cell tolerance because it mediates in B cells the tolerogenic function of Toll-like receptors (TLRs), which control the removal of developing autoreactive B cells in the marrow and the periphery when co- triggered with B-cell receptors (BCRs). We will also further characterize the pathways integrating BCR and TLR/TACI signaling required for B cell tolerance by analyzing additional PID patients with novel gene mutations.
Our studies will investigate the mechanisms by which TACI is required for B cell tolerance, potentially by mediating in B cells the tolerogenic function of Toll-like receptors (TLRs), which control the removal of developing autoreactive B cells in the marrow and the periphery when co-triggered with B-cell receptors. The TACI/TLR pathway also regulates in the periphery the induction of somatic hypermutation required for optimal antibody responses and the containment of gut microbiota; its alteration in some CVID patients leads to a break in B cell tolerance and autoimmune condition.
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