434 aRT Iv The Immune System in Health and Disease immune response against specific agents. A variety of failures can lead to such immunodeficiency. Defective intercellular communication may be rooted in deleterious mutations of genes that encode cell-surface receptors or signal-transduction molecules; defects in the mechanisms of gene rearrangement X-linked chronic granulomatous disease(CGD) and other functions may prevent normal B- or T-cell re- Properdin deficiency sponses Figure 19-3 is an overview of the molecules involved Wiskott-Aldrich syndrome(WAS) in the more well-described interactions among t cells and Bcells that give rise to specific responses, with a focus on teins in which defects leading to immunodeficiency h X-linked severe combined immunodeficiency been identified SEVERE COMBINED IMMUNODEFICIENCY(SCID) X-linked agammaglobulinemia(Bruton's tyrosine kinase) The family of disorders termed SCID stems from defects in lymphoid development that affect either T cells or both T and B cells. All forms of SCiD have common features despite differences in the underlying genetic defects. Clinically, SCID is characterized by a very low number of circulating lympho- cytes. There is a failure to mount immune responses medi- ated by T cells. The thymus does not develop, and the few X-linked hyper-IgM syndrome (XHM) circulating T cells in the SCid patient do not respond to timulation by mitogens, indicating that they cannot prolif- erate in response to antigens. Myeloid and erythroid (red blood-cell precursors) cells appear normal in number and FIGURE.2 Several X-linked immunodeficiency diseases result function, indicating that only lymphoid cells are depleted in from defects in loci on the X chromosome. Data from the Natl. Cen. SCID ter for Biotechnology Information Web site SCID results in severe recurrent infections and is usually fatal in the early years of life. Although both the T and B lin eages may be affected, the initial manifestation of SCID inin fants is almost always infection by agents, such as fungi or Immunoglobulin deficiencies are associated primarily with viruses, that are normally dealt with by T-cell immunity. The recurrent infections by extracellular bacteria, but those af- B-cell defect is not evident in the first few months of the af- fected have normal responses to intracellular bacteria, as well fected infant's life because antibodies are passively obtained as viral and fungal infections. By contrast, defects in the cell- from transplacental circulation or from mother's milk SCID mediated system are associated with increased suscepti- infants suffer from chronic diarrhea, pneumonia, and skin, bility to viral, protozoan, and fungal infections. Intracellular mouth, and throat lesions as well as a host of other oppor- pathogens such as Candida albicans, Pneumocystis carinii, tunistic infections The immune system is so compromised and Mycobacteria are often implicated, reflecting the impor- that even live attenuated vaccines(such as the Sabin polio tance of T cells in eliminating intracellular pathogens. Infec- vaccine) can cause infection and disease. The life span of a tions with viruses that are rarely pathogenic for the normal SCiD patient can be prolonged by preventing contact with all individual( such as cytomegalovirus or even an attenuated potentially harmful microorganisms, for example by con- measles vaccine)may be life threatening for those with im- finement in a sterile atmosphere. However, extraordinary ef- paired cell-mediated immunity. Defects that cause decreased fort is required to prevent direct contact with other persons T-cell counts generally also affect the humoral system, be- and with unfiltered air; any object, including food, that cause of the requirement for TH cells in B-cell activation. Gen- comes in contact with the sequestered SCID patient must erally there is some decrease in antibody levels, particularly in first be sterilized. Such isolation is feasible only as a tempo- the production of specific antibody after immunization. ary measure, pending treatment. As one might expect, combined deficiencies of the humoral The search for defects that underlie SCID has revealed and cell-mediated branches are the most serious of the im- several different causes for this general failure of immunity. a munodeficiency disorders. The onset of infections begins early survey of 141 patients by rebecca Buckley indicated that the in infancy, and the prognosis for these infants is early death most common ca 4 cases) was deficiency of the com- less therapeutic intervention reconstitutes their defective im- mon gamma chain of the IL-2 receptor (IL-2Ry see Figure mune system As described below, there are increasing numbers 12-7). Defects in this chain impede signaling through of options for the treatment of immunodeficiencies receptors for IL-4, -7, -9, and-15 as well as the IL-2 receptor, The immunodeficiencies that affect lymphoid function because the chain is present in receptors for all of these cy have in common the inability to mount or sustain a complete tokines Deficiency in the kinase JAK-3, which has a similarImmunoglobulin deficiencies are associated primarily with recurrent infections by extracellular bacteria, but those af￾fected have normal responses to intracellular bacteria, as well as viral and fungal infections. By contrast, defects in the cell￾mediated system are associated with increased suscepti￾bility to viral, protozoan, and fungal infections. Intracellular pathogens such as Candida albicans, Pneumocystis carinii, and Mycobacteria are often implicated, reflecting the impor￾tance of T cells in eliminating intracellular pathogens. Infec￾tions with viruses that are rarely pathogenic for the normal individual (such as cytomegalovirus or even an attenuated measles vaccine) may be life threatening for those with im￾paired cell-mediated immunity. Defects that cause decreased T-cell counts generally also affect the humoral system, be￾cause of the requirement for TH cells in B-cell activation. Gen￾erally there is some decrease in antibody levels, particularly in the production of specific antibody after immunization. As one might expect, combined deficiencies of the humoral and cell-mediated branches are the most serious of the im￾munodeficiency disorders. The onset of infections begins early in infancy, and the prognosis for these infants is early death un￾less therapeutic intervention reconstitutes their defective im￾mune system.As described below, there are increasing numbers of options for the treatment of immunodeficiencies. The immunodeficiencies that affect lymphoid function have in common the inability to mount or sustain a complete immune response against specific agents. A variety of failures can lead to such immunodeficiency. Defective intercellular communication may be rooted in deleterious mutations of genes that encode cell-surface receptors or signal-transduction molecules; defects in the mechanisms of gene rearrangement and other functions may prevent normal B- or T-cell re￾sponses. Figure 19-3 is an overview of the molecules involved in the more well-described interactions among T cells and B cells that give rise to specific responses, with a focus on pro￾teins in which defects leading to immunodeficiency have been identified. SEVERE COMBINED IMMUNODEFICIENCY (SCID) The family of disorders termed SCID stems from defects in lymphoid development that affect either T cells or both T and B cells. All forms of SCID have common features despite differences in the underlying genetic defects. Clinically, SCID is characterized by a very low number of circulating lympho￾cytes. There is a failure to mount immune responses medi￾ated by T cells. The thymus does not develop, and the few circulating T cells in the SCID patient do not respond to stimulation by mitogens, indicating that they cannot prolif￾erate in response to antigens. Myeloid and erythroid (red￾blood-cell precursors) cells appear normal in number and function, indicating that only lymphoid cells are depleted in SCID. SCID results in severe recurrent infections and is usually fatal in the early years of life. Although both the T and B lin￾eages may be affected, the initial manifestation of SCID in in￾fants is almost always infection by agents, such as fungi or viruses, that are normally dealt with by T-cell immunity. The B-cell defect is not evident in the first few months of the af￾fected infant’s life because antibodies are passively obtained from transplacental circulation or from mother’s milk. SCID infants suffer from chronic diarrhea, pneumonia, and skin, mouth, and throat lesions as well as a host of other oppor￾tunistic infections. The immune system is so compromised that even live attenuated vaccines (such as the Sabin polio vaccine) can cause infection and disease. The life span of a SCID patient can be prolonged by preventing contact with all potentially harmful microorganisms, for example by con￾finement in a sterile atmosphere. However, extraordinary ef￾fort is required to prevent direct contact with other persons and with unfiltered air; any object, including food, that comes in contact with the sequestered SCID patient must first be sterilized. Such isolation is feasible only as a tempo￾rary measure, pending treatment. The search for defects that underlie SCID has revealed several different causes for this general failure of immunity. A survey of 141 patients by Rebecca Buckley indicated that the most common cause (64 cases) was deficiency of the com￾mon gamma chain of the IL-2 receptor (IL-2R; see Figure 12-7). Defects in this chain impede signaling through receptors for IL-4, -7, -9, and -15 as well as the IL-2 receptor, because the chain is present in receptors for all of these cy￾tokines. Deficiency in the kinase JAK-3, which has a similar 434 PART IV The Immune System in Health and Disease X-linked chronic granulomatous disease (CGD) Properdin deficiency Wiskott-Aldrich syndrome (WAS) X-linked severe combined immunodeficiency X-linked agammaglobulinemia (Bruton’s tyrosine kinase) X-linked hyper-IgM syndrome (XHM) FIGURE 19-2 Several X-linked immunodeficiency diseases result from defects in loci on the X chromosome. [Data from the Natl. Cen￾ter for Biotechnology Information Web site.]