Loss of B Cell tolerance in Primary Immune Deficiency

导致原发性免疫缺陷病（PID）的免疫功能受损通常与反常的自身免疫并发症相关。PID患者提供了难得的机会，研究特定的缺陷基因对调节B细胞耐受性的影响，并在人类发展自身反应性B细胞的去除。缺乏功能性BTK、CDI 9或介导Toll样受体（TLR）信号传导的分子如IRAK-4、MyD 88和ILK-93 B的患者中B细胞受体（BCR）信号传导的改变导致有缺陷的中心检查点和未能反选择发育中的自身反应性B细胞。实际上，自身抗原与自身反应性BCR和TLR的结合不能在所有这些患者的发育中的B细胞中诱导耐受机制，并且自身反应性B细胞从骨髓泄漏到外周。我们最近的工作表明，突变的基因编码的跨膜激活剂和钙调节亲环蛋白配体相互作用（TACI），其功能涉及MyD 88，也影响早期B细胞耐受性检查点。此外，我们确定了一个主要的和以前未被怀疑的作用激活诱导的胞苷脱氨酶（AID），类转换重组（CSR）和体细胞超突变（SHM）所需的酶，在消除发展中的自身反应性B细胞在人类。最后， CDI 9、TACI和IRAK 4基因也改变一些记忆B细胞的产生，但它们参与人类活化B细胞克隆的选择仍有待确定。 这项研究的长期目标是进一步确定在健康人中调节B细胞耐受性的机制，但在PID患者中可能存在缺陷。工作假设是TACI与TLR 7、TLR 9和MyD 88以及AID交织在一起，在BCR、TLR 9和/或TACI触发后，其表达在未成熟B细胞中被诱导，TACI在去除发育中的自身反应性B细胞中起重要作用。此外，我们还将重点分析TLR、TACI、MyD 88和AID的机制，以及通过这些机制在记忆B细胞区室中选择发育中的突变克隆。

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.