Other variants of hyperIgM syndrome are due to intrinsic defects in the process of Bcell classswitch recombination. Patients having these defects are susceptible to severe extracellular bacterial infections, but because Tcell differentiation and function are spared, they do not show increased susceptibility to intracellular pathogens or opportunistic agents such as P. jirovecii. One classswitching defect is due to mutations in the gene for activationinduced cytidine deaminase (AID), which is required for both somatic hypermutation and class switching (see Section 107). Patients with autosomally inherited defects in the AID gene (AICDA) fail to switch antibody isotype and also have greatly reduced somatic hypermutation (see Fig. 13.5). Immature B cells accumulate in abnormal germinal centers, causing enlargement of the lymph nodes and spleen. Another variant of Bcellintrinsic hyperIgM syndrome was identified recently in a small number of patients with an autosomal recessive defect in the DNA repair enzyme uracilDNA glycosylase (UNG; see Section 1010), which is also involved in class switching; these patients have normal AID function and normal somatic hypermutation, but defective class switching.
Other examples of predominantly antibody deficiency include the most common forms of primary immunodeficiency, referred to as common variable immunodeficiencies (CVIDs). CVIDs are a clinically and genetically heterogeneous group of disorders that typically go undiagnosed until late childhood or adulthood, because the immune deficiency is relatively mild. Unlike other causes of immunoglobulin deficiency, patients with CVID can have defects in immunoglobulin production that are limited to one or more isotypes (see Fig. 13.5). IgA deficiency, the most common primary immunodeficiency, exists in both sporadic and familial forms, and both autosomal recessive and autosomal dominant inheritance have been described. The etiology of IgA deficiency in most patients is not understood, and these patients are asymptomatic. In IgAdeficient patients who do develop recurrent infections, an associated defect in one of the IgG subclasses is often found.
A small minority of CVID patients have mutations in the transmembrane protein TACI (TNFlike receptor transmembrane activator and CAML interactor), which is encoded by the gene TNFRSF13B. TACI is the receptor for the cytokines BAFF and APRIL, which are produced by T cells, dendritic cells, and macrophages, and which can provide costimulatory and survival signals for Bcell activation and class switching (see Section 103). Other patients with selective deficiencies in IgG subclasses have also been described. Bcell numbers are typically normal in these patients, but serum levels of the affected immunoglobulin isotype are depressed. Although some of these patients have recurrent bacterial infections, as in IgA deficiency, many are asymptomatic. CVID patients with other defects that affect immunoglobulin class switching have been identified. Included in this group are patients with inherited defects in CD19, which is a component of the Bcell coreceptor (see Fig. 13.5). A genetic defect that has been linked to a small percentage of people with CVID is deficiency of the costimulatory molecule ICOS. As described in Section 917, ICOS is upregulated on T cells when they are activated. The effects of ICOS deficiency have confirmed its essential role in Tcell help for the later stages of Bcell differentiation, including class switching and the formation of memory cells.