Defects in B Cell Differentiation Common Variable Immunodeficiency

Common variable immunodeficiency is a group of heterogeneous disorders defined by reduced levels of serum Ig, impaired antibody responses to infection or vaccines, and increased incidence of infections. The diagnosis is usually one of exclusion when other primary immunodeficiency diseases are ruled out. The presentation and pathogenesis are, as the name implies, highly variable. Although Ig deficiency and associated pyogenic infections, typically with Haemophilus influenzae and Streptococcus pneumoniae, are major components of these disorders, autoimmune diseases, including pernicious anemia, hemolytic anemia, inflammatory bowel disease, and rheumatoid arthritis, may be just as clinically significant. A high incidence of malignant tumors, particularly lymphomas, is also associated with common variable immunodeficiency. These disorders may be diagnosed early in childhood or late in life. Both sporadic and familial cases occur, the latter with both autosomal dominant and recessive inheritance patterns. Mature B lymphocytes are present in these patients, but plasma cells are absent in lymphoid tissues, which suggests a block in B cell differentiation to antibody-secreting cells. The defective antibody production has been attributed to multiple abnormalities, including intrinsic B cell defects, deficient T cell help, and excessive "suppressor cell" activity. A small proportion of patients with common variable immunodeficiency have a mutation in the ICOS (inducible T cell costimulator) gene. ICOS is required for T follicular helper cell generation (see Chapter 11). A more common cause of this syndrome is the existence of mutations in TACI, described before in the context of selective IgA deficiency. A few cases of common variable immunodeficiency are linked to mutations in the CD19 gene. CD19 is a signaling component of the CR2 (CD21) coreceptor complex (see Chapter 7).

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