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IgH sequences in common variable immune deficiency reveal altered B cell development and selection

Deep sequence analysis of the IgH repertoires of common variable immune deficiency patients highlights phenotypic features of the disorder and potential disease mechanisms. Not immune to memory problems Although elderly patients typically lament loss of memory, Roskin et al. now highlight a different kind of memory problem plus developmental difficulties that bedevils the immune systems of children and young adults with common variable immune deficiency (CVID). These aberrations may drive a variety of outcomes, including impaired antibody responses to foreign antigens, generation of autoimmune responses, and lymphoid cancers. As the most common symptomatic primary immune deficiency, CVID affects nearly one in 25,000 persons, but the biological basis for the constellation of clinical phenotypes remains hazy. Genetic recombination in the V(D)J regions of immunoglobulin (Ig) genes, which occurs in developing lymphocytes during the early stages of B cell maturation, gives rise to the diverse repertoire of antibodies produced by activated B lymphocytes. This so-called Ig gene rearrangement—a seminal component of the adaptive immune system—gives rise to a broad range of amino acid sequences in the antigen-binding regions of Igs, which permits the recognition of antigens from many pathogens and abnormal cells (such as cancer cells) and subsequent activation of the immune response. The authors first used high-throughput genomic DNA sequencing to explore Ig heavy chain gene rearrangements in B cells from CVID patients versus control subjects. CVID patients displayed abnormal VDJ rearrangement and thus abnormal formation of complementarity determining region 3 (CDR3), which are part of the Ig variable chains and central to the ability of B cells to recognize a wide range of antigens. The authors then sorted B cell populations to retrieve, specifically, the naïve and memory B cells. They detected decreased selection against antibodies with long CDR3 regions in CVID memory repertoires and fewer of the antibody gene mutations that accompany the formation of immune memory. The unmutated naïve B cell pool displayed decreased diversity and abnormal clonal expansion. Together, these alterations could explain the immune deficiencies and autoimmune reactions detected in CVID patients, and suggest that CVID phenotypes stem from aberrant generation and selection of B cell repertoires. Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro–B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.