Patients present with recurrent pyogenic infections because of low levels of opsonizing IgG antibodies. Those with CD40L mutations also are susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because CD40L-mediated macrophage activation, a key reaction of cell-mediated immunity, is compromised. Occasionally, the IgM antibodies react with blood cells, giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. In older patients, there may be a proliferation of IgM-producing plasma cells that infiltrate the mucosa of the gastrointestinal tract.
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This relatively frequent but poorly defined entity encompasses a heterogeneous group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG. The diagnosis of common variable immunodeficiency is based on exclusion of other well-defined causes of decreased antibody production. The estimated prevalence of the disease is about 1 in 50,000.
Although most patients have normal numbers of mature B cells, plasma cells are absent, suggesting a block in B-cell differentiation. In keeping with this idea, B cell areas of the lymphoid tissues (i.e., lymphoid follicles in nodes, spleen, and gut) tend to be hyperplastic. The enlargement of B cell areas may reflect incomplete activation, such that B cells can proliferate in response to antigen but do not differentiate into antibody-producing plasma cells. The defective antibody production has been variably attributed to intrinsic B-cell defects, deficient T-cell help, or excessive T-cell suppressive activity. Paradoxically, these patients are prone to develop a variety of autoimmune disorders (hemolytic anemia, pernicious anemia) as well as lymphoid tumors. Common variable immunodeficiency may be genetic or acquired. Different genetic causes have been discovered, including mutations in a receptor for BAFF, a cytokine that promotes the survival and differentiation of B cells, and in a molecule called ICOS (inducible costimulator), a homologue of CD28 that contributes to the function of T follicular helper cells. However, in the majority of cases, the genetic basis is unknown.
Patients typically present with recurrent sinopulmonary bacterial infections. About 20% of patients have recurrent herpesvirus infections, and serious enterovirus infections causing meningoencephalitis also may occur. Individuals with this disorder also are prone to the development of persistent diarrhea caused by G. lamblia. In contrast to X-linked agammaglobulinemia, common variable immunodeficiency affects both sexes equally, and the onset of symptoms is later, in childhood or adolescence. As in X-linked agammaglobulinemia, these patients have a high frequency of autoimmune diseases (approximately 20%), including rheumatoid arthritis. The risk for lymphoid malignancy also is increased, and an increase in gastric cancer has been reported.
This is the most common primary immune deficiency disease, affecting about 1 in 700 whites. As noted previously, IgA is the major immunoglobulin in mucosal secretions and is thus involved in defending the airways and the gastrointestinal tract. Weakened mucosal defenses due to IgA deficiency predispose patients to recurrent sinopulmonary infections and diarrhea. There also is a significant (but unexplained) association with autoimmune diseases. The pathogenesis of IgA deficiency seems to involve a block in the terminal differentiation of IgA-secreting B cells to plasma cells; IgM and IgG subclasses of antibodies are present in normal or even supranormal levels. The molecular basis for this defect is not understood.