Functions of the Activation Induced Cytidine Deaminase (AID) and Toll-like Receptors (TLR) on Regulation of the Central B cell Tolerance Checkpoint

Abstract

Çakan, E., Functions of the Activation Induced Cytidine Deaminase (AID) and Toll-Like Receptors (TLR) on Regulation of the Central B Cell Tolerance Checkpoint, Hacettepe University Graduate School Health Sciences Program of Tumor Biology and Immunology Doctor of Philosophy Thesis, Ankara, 2021. In this study, we aimed to investigate the mechanism regulating the central B cell tolerance checkpoint. Activation induced cytidine deaminase (AID) enzyme is expressed at high levels during germinal center reactions and plays role in somatic hypermutation and class switch recombination reactions. Dr. Meffre and colleagues defined a new mutation in exon 14 of the CTNNBL1 gene in a unique CVID patient and they found decreased frequencies of somatic hypermutation in the IgG+ B cells from patient’s blood. Using Ramos WT and Ramos CTNNBL1 466v/v cell lines and CTNNBL1 WT and CTNNBL1 466V lentiviruses, we investigated the effect of the mutation and found that it leads to a 2-to-3-fold reduction in somatic hypermutation. Cantaert et al. (1) and Kuroaka et al. (2) showed that establishment of central B cell tolerance requires AID expression in human B cell precursors. Activation of both B cell receptor and Toll like receptors are necessary for AID induction in immature B cells. We showed that TLR9 but not the TLR7 is a key molecule for the elimination of autoreactive B cells. We also showed that the scleroderma patients who have dysfunctional defective central B cell tolerance checkpoints (3) have non-functional TLR9. We demonstrated that the CXCL4– which is involved in the pathogenesis of the scleroderma patients- sequesters TLR9 ligands away from the endosomal compartment and leads to an inhibition of TLR9 function and AID induction after B cell stimulation. Therefore, CXCL4 contributes to the broken central B cell tolerance in systemic sclerosis patients.