Xlinked HyperigM Syndrome

A peculiar immunoglobulin deficiency first thought to result from a B-cell defect has recently been shown to result instead from a defect in a T-cell surface molecule. X-linked hyper-IgM (XHM) syndrome is characterized by a deficiency of IgG, IgA, and IgE, and elevated levels of IgM, sometimes as high as 10 mg/ml (normal IgM concentration is 1.5 mg/ml). Although individuals with XHM have normal numbers of B cells expressing membrane-bound IgM or IgD, they appear to lack B cells expressing membrane-bound IgG, IgA, or IgE. XHM syndrome is generally inherited as an X-linked recessive disorder (see Figure 19-2), but some forms appear to be acquired and affect both men and women. Affected individuals have high counts of IgM-secreting plasma cells in their peripheral blood and lymphoid tissue. In addition, XHM patients often have high levels of autoantibodies to neutrophils, platelets, and red blood cells. Children with XHM suffer recurrent infections, especially respiratory infections; these are more severe than expected for a deficiency characterized by low levels of immunoglobulins.

The defect in XHM is in the gene encoding the CD40 lig-and (CD40L), which maps to the X chromosome. TH cells from patients with XHM fail to express functional CD40L on their membrane. Since an interaction between CD40 on the B cell and CD40L on the TH cell is required for B-cell activation, the absence of this co-stimulatory signal inhibits the B-cell response to T-dependent antigens (see Figures 19-3 and 11-10). The B-cell response to T-independent antigens, however, is unaffected by this defect, accounting for the production of IgM antibodies. As described in Chapter 11, class switching and formation of memory B cells both require contact with TH cells by a CD40-CD40L interaction. The absence of this interaction in XHM results in the loss of class switching to IgG, IgA, or IgE isotypes and in a failure to produce memory B cells. In addition, XHM individuals fail to produce germinal centers during a humoral response, which highlights the role of the CD40-CD40L interaction in the generation of germinal centers.

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Essentials of Human Physiology

Essentials of Human Physiology

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