All ETDs from UAB

Advisory Committee Chair

Robert Kimberly

Advisory Committee Members

Peter Burrows

Stuart Frank

Louis Justment

Rosa Serra

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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.

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