All ETDs from UAB

Advisory Committee Chair

Harry W Schroeder Jr

Advisory Committee Members

Thomas P Atkinson

Elizabeth E Brown

Peter D Burrows

John E Volanakis

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Depressed serum immunoglobulin levels and recurrent sinopulmonary infections mark Common Variable Immune Deficiency (CVID). Many family members of CVID patients also suffer Recurrent Sino-Pulmonary Infection (RESPI) but have normal serum immunoglobulins. We identified HLAB44 positive identical female twins who suffer sinopulmonary infections and are discordant for CVID and RESPI. Flow cytometry subsets showed equivalent numbers of immature B cells (BC) in both twins, but lower numbers of transitional and mature BC in the CVID twin. Presented is an in-depth comparison of V (D) J gene usage, hydrophobicity, length, DH reading frame, and amino acid usage between µ H chain repertoires expressed by transitional, mature, memory IgD+, memory IgD-, and plasmacytes isolated from the blood of a healthy control subject and the identical twins that are discordant for RESPI and CVID in order to further investigate the antibody repertoire. Our analysis illustrates the process of somatic selection of the repertoire that occurs as B cells progress through development. Deep sequencing of the immunoglobulin repertoires expressed by the transitional and mature BC showed a significant divergence in the utilization of VH1 and VH4 family gene segments, with CVID favoring VH4 and RESPI VH1. RESPI twin used JH6 more frequently, whereas CVID twin used JH3. The amino acid composition of CDR-H3 repertoire was compared with a control; the twin and control tyrosine usage in transitional BC was similar (~15%) but greatly diverged in mature BC (control 15%, RESPI 25%, CVID < 10%). Whole genome sequencing revealed homozygosity for a rare CD21 S639N polymorphism and heterozygosity for CD19 L174V. These findings suggest that in addition to an acquired block in BC development at the transitional stage, the CVID twin produces an Ig repertoire that is markedly depleted of tyrosine. This may explain why the function of the Ig repertoire in CVID is more impaired than what might be expected by serum immunoglobulin levels alone.

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