A diverse antibody repertoire is paramount to an effective adaptive immune response in
higher eukaryotes. This diversity is generated through the orchestrated introduction of somatic DNA
mutations, rearrangements, and deletions in specific regions of the B cell genome. Class switch
recombination (CSR) is the process by which a B cell alters its antibody-encoding DNA to produce a
new class (isotype) of antibodies with a different effector function. This is accomplished by replacing
the μ constant region (encoding for the IgM antibody isotype) with a downstream α, γ, or ε constant
region (encoding for IgA, IgG, or IgE, respectively). The study of inherited antibody deficiency
syndromes has provided valuable insight into the signaling cascades that stimulate CSR and the DNA
metabolism machinery that coordinates CSR at the molecular level. The goal of this thesis was to
improve our understanding of the molecular events of CSR through the study of two antibody
deficiency syndromes, IgA deficiency (IgAD) and common variable immunodeficiency (CVID).
The tumor necrosis factor-like B cell surface receptor, TACI, is important for B cell
activation independent of stimulation by T cells. Through a large-scale genetic association study of
non-synonymous TACI polymorphisms, I provided evidence that the heterozygous TACI sequence
variants p.C104R, p.A181E, and c.204insA constitute risk factors for the development of CVID, but
likely have only a minor role, if any, in the development of IgAD.
Next, prompted by the knowledge that a subset of well characterized antibody deficiencies
(termed hyper-IgM syndromes) were due to defects in the DNA metabolism genes AID and UNG2, I
hypothesized that a subset a IgAD and CVID cases could be due to defects in additional DNA repair
genes. In an association study of 27 DNA metabolism genes, I noted significant association with
IgAD and/or CVID for markers in AID and genes of the mismatch repair pathways (MSH2 and
MLH1), the MRN complex (MRE11-RAD50-NBS1), and the homologous recombination pathway. Subsequent resequencing of associated pathways yielded a number of novel non-synonymous alleles
in MSH2, MLH1, RAD50, and NBS1 that were IgAD/CVID-specific.