Impaired immune functions leading to primary immunodeficiency diseases (PID) often correlate with paradoxical autoimmune complications. PID patients provide rare opportunities to study the impact of specific defective genes on the regulation of B cell tolerance and the removal of developing autoreactive B cells in humans. Alterations in B cell receptor (BCR) signaling in patients lacking functional BTK, CDI 9, or molecules mediating Toll-like receptor (TLR) signaling such as IRAK-4, MyD88, and UNC-93B result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells. Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms in all these patients'developing B cells and autoreactive B cells leaks from the bone marrow into the periphery. Our recent work demonstrates that mutations in the gene encoding the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) whose functions involve MyD88, also affect early B cell tolerance checkpoints. In addition, we identified a major and previously unsuspected role for activation-induced cytidine deaminase (AID), an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), in the removal of developing autoreactive B cells in humans. Finally, mutations in CDI 9, TACI and IRAK4 genes also alter the production of some memory B cells yet their involvement in the selection of activated B cell clones in humans remained to be determined. The long range goal ofthe proposed research is to further determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in PID patients. The working hypothesis is that TACI, intertwined with TLR7,TLR9, and MyD88 as well as AID, whose expression is induced in immature B cells after BCR, TLR9 and/or TACI triggering, play essential roles in the removal of developing autoreactive B cells. In addition, we will focus on the analysis ofthe mechanisms involving TLRs, TACI, MyD88 and AID and by which developing mutating clones are selected in the memory B cell compartments.

Public Health Relevance

Understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies. In addition, anti-B cell therapies effective at blocking autoimmune disease progression may be useful for delaying or preventing the development of other disorders potentially affecting patients with primary immune deficiency.

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Icahn School of Medicine at Mount Sinai
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