436 aRT Iv The Immune System in Health and Disease immunity, characterized by susceptibility to viral infection. a treatment for this condition is periodic administration of recent case of SCID uncovered a defect in the gene for the immunoglobulin, but patients seldom survive past their cell-surface phosphatase CD45. Interestingly, this defect teens. There is a defect in B-cell signal transduction in this caus sed lack of aB T-cells but spared the y8 lineage disorder. due to a defect in a transduction molecule called Bruton's tyrosine kinase(Btk), after the investigator who de- WISKOTT-ALDRICH SYNDROME (WAS) scribed the syndrome. B cells in the Xla patient remain in The severity of this X-linked disorder increases with age and the pre-B stage with H chains rearranged but L chains in their usually results in fatal infection or lymphoid malignancy. Ini- germ-line configuration. The Clinical Focus in Chapter 11 tially, T and B lymphocytes are present in normal numbers. describes the discovery of this immunodeficiency and its un WAS first manifests itself by defective responses to bacterial derlying defect in detail. polysaccharides and by lower-than-average IgM levels. Other responses and effector mechanisms are normal in the early X-LINKED HYPER-1gMSYNDROME stages of the syndrome. As the WAS sufferer ages, there are re- a peculiar immunoglobulin deficiency first thought to result current bacterial infections and a gradual loss of humoral and from a B-cell defect has recently been shown to result instead cellular responses. The syndrome includes thrombocytopenia from a defect in a T-cell surface molecule. X-linked hyper (owered platelet count; the existing platelets are smaller than IgM(XHM) syndrome is characterized by a deficiency of usual and have a short half-life), which may lead to fatal bleed- IgG, IgA, and IgE, and elevated levels of IgM, sometimes as ing Eczema(skin rashes)in varying degrees of severity may high as 10 mg/ml (normal IgM concentration is 1.5 mg/ml) also occur, usually beginning around one year of age. The de- Although individuals with XHM have normal numbers of B fect in WAS has been mapped to the short arm of the X chro- cells expressing membrane- bound IgM or IgD, they appear mosome (see Table 19-1 and Figure 19-2)and involves a to lack b cells expressing membrane-bound IgG, IgA, or IgE. cytoskeletal glycoprotein present in lymphoid cells called XHM syndrome is generally inherited as an X-linked reces- sialophorin(CD43). The WAS protein is required for assembly sive disorder(see Figure 19-2), but some forms appear to be of actin filaments required for the formation of microvesicles. acquired and affect both men and women Affected individ uals have high counts of IgM-secreting plasma cells in their INTERFERON-GAMMA-RECEPTOR DEFECT peripheral blood and lymphoid tissue. In addition, XHM pa- a recently described immunodeficiency that falls into the tients often have high levels of autoantibodies to neutrophils mixed-cell category involves a defect in the receptor for in- platelets, and red blood cells. Children with XHM suffer re- terferon gamma(IFN-Y, see Chapter 12). This deficiency was current infections, especially respiratory infections; these are found in patients suffering from infection with atypical my. more severe than expected for a deficiency characterized by cobacteria(intracellular organisms related to the bacteria low levels of immunoglobulins that cause tuberculosis and leprosy). Most of those carrying The defect in XHM is in the gene encoding the CD40 lig- this autosomal recessive trait are from families with a history and(CD40L), which maps to the X chromosome. TH cells of inbreeding. The susceptibility to infection with mycobac- from patients with XHM fail to express functional CD40Lon teria is selective in that those who survive these infections are their membrane. Since an interaction between CD40 on the not unusually susceptible to other agents, including other in- B cell and CD40L on the TH cell is required for B-cell activa- tracellular bacteria. This immunodeficiency points to a spe- tion, the absence of this co-stimulatory signal inhibits the b- cific role for IFN-Y and its receptor in protection from cell response to T-dependent antigens (see Figures 19-3 and infection with mycobacteria 11-10).The B-cell response to T-independent antigens, how Whereas SCID and the related combined immunodef- ever, is unaffected by this defect, accounting for the produc ciencies affect T cells or all lymphoid cells, other primary im- tion of IgM antibodies. As described in Chapter 11,class munodeficiencies affect B-cell function and result in the switching and formation of memory b cells both require reduction or absence of some or all classes of immunoglobu- contact with TH cells by a CD40-CD40L interaction. The ab- lins. While the underlying defects have been identified for sence of this interaction in XHM results in the loss of class some of these, little information exists concerning the exact switching to IgG, IgA, or IgE isotypes and in a failure to pro- of some of the more common deficiencies such as com- duce memory B cells. In addition, XHM individuals fail to variable immunodeficiency and selective IgA deficiency. produce germinal centers during a humoral response, which highlights the role of the CD40-CD40L interaction in the X-LINKED AGAMMAGLOBULINEMIA generation of germinal centers A B-cell defect called X-linked agammaglobulinemia(XLA or Bruton's hypogammaglobulinemia is characterized by ex- COMMON VARIABLE IMMUNODEFICIENCY(CVI) tremely low IgG levels and by the absence of other im- CVi is characterized by a profound decrease in numbers of lunoglobulin classes. Individuals with XLA have antibody-producing plasma cells, low levels of most im- peripheral B cells and suffer from recurrent bacterial infec- munoglobulin isotypes(hypogammaglobulinemia), and re- tions, beginning at about nine months of age. a palliative current infections. The condition is usually manifested laterimmunity, characterized by susceptibility to viral infection. A recent case of SCID uncovered a defect in the gene for the cell-surface phosphatase CD45. Interestingly, this defect caused lack of  T-cells but spared the  lineage. WISKOTT-ALDRICH SYNDROME (WAS) The severity of this X-linked disorder increases with age and usually results in fatal infection or lymphoid malignancy. Ini￾tially, T and B lymphocytes are present in normal numbers. WAS first manifests itself by defective responses to bacterial polysaccharides and by lower-than-average IgM levels. Other responses and effector mechanisms are normal in the early stages of the syndrome. As the WAS sufferer ages, there are re￾current bacterial infections and a gradual loss of humoral and cellular responses. The syndrome includes thrombocytopenia (lowered platelet count; the existing platelets are smaller than usual and have a short half-life), which may lead to fatal bleed￾ing. Eczema (skin rashes) in varying degrees of severity may also occur, usually beginning around one year of age. The de￾fect in WAS has been mapped to the short arm of the X chro￾mosome (see Table 19-1 and Figure 19-2) and involves a cytoskeletal glycoprotein present in lymphoid cells called sialophorin (CD43). The WAS protein is required for assembly of actin filaments required for the formation of microvesicles. INTERFERON-GAMMA–RECEPTOR DEFECT A recently described immunodeficiency that falls into the mixed-cell category involves a defect in the receptor for in￾terferon gamma (IFN-, see Chapter 12). This deficiency was found in patients suffering from infection with atypical my￾cobacteria (intracellular organisms related to the bacteria that cause tuberculosis and leprosy). Most of those carrying this autosomal recessive trait are from families with a history of inbreeding. The susceptibility to infection with mycobac￾teria is selective in that those who survive these infections are not unusually susceptible to other agents, including other in￾tracellular bacteria. This immunodeficiency points to a spe￾cific role for IFN- and its receptor in protection from infection with mycobacteria. Whereas SCID and the related combined immunodefi￾ciencies affect T cells or all lymphoid cells, other primary im￾munodeficiencies affect B-cell function and result in the reduction or absence of some or all classes of immunoglobu￾lins. While the underlying defects have been identified for some of these, little information exists concerning the exact cause of some of the more common deficiencies, such as com￾mon variable immunodeficiency and selective IgA deficiency. X-LINKED AGAMMAGLOBULINEMIA A B-cell defect called X-linked agammaglobulinemia (XLA) or Bruton’s hypogammaglobulinemia is characterized by ex￾tremely low IgG levels and by the absence of other im￾munoglobulin classes. Individuals with XLA have no peripheral B cells and suffer from recurrent bacterial infec￾tions, beginning at about nine months of age. A palliative treatment for this condition is periodic administration of immunoglobulin, but patients seldom survive past their teens. There is a defect in B-cell signal transduction in this disorder, due to a defect in a transduction molecule called Bruton’s tyrosine kinase (Btk), after the investigator who de￾scribed the syndrome. B cells in the XLA patient remain in the pre-B stage with H chains rearranged but L chains in their germ-line configuration. (The Clinical Focus in Chapter 11 describes the discovery of this immunodeficiency and its un￾derlying defect in detail.) X-LINKED HYPER-IgM 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 reces￾sive disorder (see Figure 19-2), but some forms appear to be acquired and affect both men and women. Affected individ￾uals have high counts of IgM-secreting plasma cells in their peripheral blood and lymphoid tissue. In addition, XHM pa￾tients often have high levels of autoantibodies to neutrophils, platelets, and red blood cells. Children with XHM suffer re￾current 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 activa￾tion, 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, how￾ever, is unaffected by this defect, accounting for the produc￾tion 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 ab￾sence of this interaction in XHM results in the loss of class switching to IgG, IgA, or IgE isotypes and in a failure to pro￾duce 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. COMMON VARIABLE IMMUNODEFICIENCY (CVI) CVI is characterized by a profound decrease in numbers of antibody-producing plasma cells, low levels of most im￾munoglobulin isotypes (hypogammaglobulinemia), and re￾current infections. The condition is usually manifested later 436 PART IV The Immune System in Health and Disease