Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
B cell development, maturation and proliferation are all strictly regulated processes. Disruption of the regulatory network at any step would lead to immune disorders. The regulatory system of B cells can be considered as two layers: a general homeostasis regulation system and a specificity-based control system. General regulation of B cell homeostasis is mastered by BLyS (B Lymphocyte Stimulator) and several other BLyS family cytokines, which serve as a crucial survival factor for which transitional and mature B cells compete. Specificity-based control is achieved via B cell antigen receptors (BCRs), which serve as a determinant of whether an antigen-specific B cell will survive negative and positive selection and successfully mature. As one would expect, mechanisms that can regulate either BLyS levels or BCR signaling strength can impact B cell destiny and the shape of adaptive immune system. In this work, we uncovered two new mechanisms that contribute to B cell regulation: Fcγ receptors boosting soluble BLyS levels, and enhancing BCR signaling. (1) Both IgG and CRP, immune system opsonins, induced rapid and significant shedding of membrane-bound BLyS on human myeloid cells. The shed BLyS promotes long-term (days) B cell survival. Furthermore, using direct anti-receptor mAb cross-linking, we ii demonstrated that this effect was preferentially mediated by FcγRI compared to FcγRIIA. (2) We identified FcγRIIC as a second FcγR on human B cells besides FcγRIIB. Its expression is determined by a single nucleotide polymorphism in amino acid codon 13 in its first extracellular domain. This SNP encodes either a stop codon or an open reading frame (allele frequency 0.12). In transduced cells, co-ligation of FcγRIIC and BCR led to FcγRIIC tyrosine phosphorylation, as well as enhanced B cell activation, reflected by amplified global tyrosine phosphorylation and increased phosphorylation of a series of key molecules in the BCR signaling cascade, and enhanced calcium flux. Therefore, in carriers of the open reading frame allele, FcγRIIC is expressed on B cells and would set up a new activation threshold, potentially slanting B cells towards hyper-activation.
Li, Xinrui, "Regulation of B Cell Biology by FCγ Receptors" (2009). All ETDs from UAB. 228.