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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.

A 10-year-old female with a complete selective IgA deficiency and recurrent autoimmune disease (chronic active hepatitis, focal glomerulonephritis, hemolytic anemia and thrombopenic purpura) is presented. Both serum IgA and saliva secretory IgA were below the detection limit. The small bowel biopsy using a peroxidase-antiperoxidase technique showed absence of plasma cells secreting IgA. Circulating antibodies against mitochondria, microsomal thyroid antigen were detected as well as rheumatoid factor. Circulating immune complexes were present. A positive Coombs' test and a slightly positive reaction for cryoagglutinins were demonstrated. No alterations in cellular immunity were observed. Clinical and analytical improvement with prednisone and azathioprine was obtained.