《免疫学》（英文版） Chapter 19 AlDS and other Immunodeficiencies

chapter 19 AlDS and other Immunodeficiencies IKE ANY COMPLEX MULTI-COMPONENT SYSTEM, THE immune system is subject to failure of some or all of its parts. This failure can have dire consequences Nude Mouse(nu/nu) When the system loses its sense of self and begins to attack host cells and tissues, the result is autoimmunity, which is a Primary Immunodeficiencies described in Chapter 20. When the system errs by failing to protect the host from disease-causing agents or from malig- a AIDS and Other Acquired or Secondary nant cells, the result is immunodeficiency, which is the sub immunodeficiencies ject of this chapter. A condition resulting from a genetic or devel I de- fect in the immune system is called a primary immunodef altho y. In such a condition, the defect is present at birth hough it may not manifest itself until later in life. Sec ondary immunodeficiency, or acquired immunodeficiency, is the loss of immune function and results from exposure to various agents. By far the most common secondary immun- differentiated from immunodeficiencies in which the non- deficiency is acquired immunodeficiency syndrome specific mediators of innate immunity, such as phagocytes or AIDS, which results from infection with the human immun- complement, are impaired. Immunodeficiencies are conve deficiency virus 1(HIV-1). In the year 2000, AIDS killed ap- niently categorized by the type or the developmental stage of proximately 3 million persons, and HIV infection continues the cells involved. Figure 19-1 reviews the overall cellular de- to spread to an estimated 15,000 persons per day. AIDS pa- velopment in the immune system, showing the locations of tients, like other individuals with severe immunodeficiency, defects that give rise to primary immunodeficiencies. As are at risk of infection with so-called opportunistic agents. Chapter 2 explained, the two main cell lineages important to These are microorganisms that healthy individuals can har- immune function are lymphoid and myeloid. Most defects bor with no ill consequences but that cause disease in those that lead to immunodeficiencies affect either one or the with impaired immune function. other. The lymphoid cell disorders may affect T cells, B cells, The first part of this chapter describes the common pri- or, in combined immunodeficiencies, both B and T cells. The mary immunodeficiencies, examines progress in identifying myeloid cell disorders affect phagocytic function. Most of the the genetic defects that underlie these disorders, and consid- primary immunodeficiencies are inherited, and the precise ers approaches to their treatment, including innovative uses molecular variations and the genetic defects that lead to of gene therapy. Animal models of primary immunodef- many of these dysfunctions have been determined (Table ciency are also described. The rest of this chapter describes 19-1 and Figure 19-2). In addition, there are immunodef- acquired immunodeficiency, with a strong focus on HIV in- ciencies that stem from developmental defects that impair fection, AIDS, and the current status of therapeutic and proper function of an organ of the immune system prevention strategies for combating this fatal acquired im- The of primary immunodeficiency deper munodeficiency on the number and type of immune system components in- volved. Defects in components early in the hematopoietic de- velopmental scheme affect the entire immune system. In this Primary Immunodeficiencies category is reticular dysgenesis, a stem-cell defect that affects the maturation of all leukocytes; the resulting general failure a primary immunodeficiency may affect either adaptive or of immunity leads to susceptibility to infection by a variety of innate immune functions. Deficiencies involving compo- microorganisms Without aggressive treatment, the affected nents of adaptive immunity, such as T or B cells, are thus individual usually dies young from severe infection. In the

differentiated from immunodeficiencies in which the non￾specific mediators of innate immunity, such as phagocytes or complement, are impaired. Immunodeficiencies are conve￾niently categorized by the type or the developmental stage of the cells involved. Figure 19-1 reviews the overall cellular de￾velopment in the immune system, showing the locations of defects that give rise to primary immunodeficiencies. As Chapter 2 explained, the two main cell lineages important to immune function are lymphoid and myeloid. Most defects that lead to immunodeficiencies affect either one or the other. The lymphoid cell disorders may affect T cells, B cells, or, in combined immunodeficiencies, both B and T cells. The myeloid cell disorders affect phagocytic function. Most of the primary immunodeficiencies are inherited, and the precise molecular variations and the genetic defects that lead to many of these dysfunctions have been determined (Table 19-1 and Figure 19-2). In addition, there are immunodefi￾ciencies that stem from developmental defects that impair proper function of an organ of the immune system. The consequences of primary immunodeficiency depend on the number and type of immune system components in￾volved. Defects in components early in the hematopoietic de￾velopmental scheme affect the entire immune system. In this category is reticular dysgenesis, a stem-cell defect that affects the maturation of all leukocytes; the resulting general failure of immunity leads to susceptibility to infection by a variety of microorganisms. Without aggressive treatment, the affected individual usually dies young from severe infection. In the chapter 19 ■ Primary Immunodeficiencies ■ AIDS and Other Acquired or Secondary Immunodeficiencies AIDS and Other Immunodeficiencies L   - ,  immune system is subject to failure of some or all of its parts. This failure can have dire consequences. When the system loses its sense of self and begins to attack host cells and tissues, the result is autoimmunity, which is described in Chapter 20. When the system errs by failing to protect the host from disease-causing agents or from malig￾nant cells, the result is immunodeficiency, which is the sub￾ject of this chapter. A condition resulting from a genetic or developmental de￾fect in the immune system is called a primary immunodefi￾ciency. In such a condition, the defect is present at birth although it may not manifest itself until later in life. Sec￾ondary immunodeficiency, or acquired immunodeficiency, is the loss of immune function and results from exposure to various agents. By far the most common secondary immun￾odeficiency is acquired immunodeficiency syndrome, or AIDS, which results from infection with the human immun￾odeficiency virus 1 (HIV-1). In the year 2000, AIDS killed ap￾proximately 3 million persons, and HIV infection continues to spread to an estimated 15,000 persons per day. AIDS pa￾tients, like other individuals with severe immunodeficiency, are at risk of infection with so-called opportunistic agents. These are microorganisms that healthy individuals can har￾bor with no ill consequences but that cause disease in those with impaired immune function. The first part of this chapter describes the common pri￾mary immunodeficiencies, examines progress in identifying the genetic defects that underlie these disorders, and consid￾ers approaches to their treatment, including innovative uses of gene therapy. Animal models of primary immunodefi￾ciency are also described. The rest of this chapter describes acquired immunodeficiency, with a strong focus on HIV in￾fection, AIDS, and the current status of therapeutic and prevention strategies for combating this fatal acquired im￾munodeficiency. Primary Immunodeficiencies A primary immunodeficiency may affect either adaptive or innate immune functions. Deficiencies involving compo￾nents of adaptive immunity, such as T or B cells, are thus Nude Mouse (nu/nu)

432 PART I The Immune System in Health and Disease VISUALIZING CONCEPTS Reticular dysgenes Lymphoid ◎ immunodeficiency Congenital granulomatous Monocyte Pre-B cell Pre-T cell X-linked Severe deficiency In uno Mature Mature t cell Common variable B cell X-linked e Plasma celll Memory b cell IGURE 19-1 Congenital defects that interrupt hematopoiesis ciencies, green humoral deficiencies, red= cell-mediated or impair functioning of immune-system cells result in various ciencies, and purple combined immunodeficiencies, de immunodeficiency diseases. (Orange boxes= phagocytic defi- that affect more than one cell lineage. more restricted case of defective phagocytic function, the and usually less severe. For example, an individual with selec quence is susceptibility to bacterial infection. tive Iga deficiency may enjoy a full life span, troubled only by Defects in more highly differentiated compartments of the a greater than normal susceptibility to infections of the respi immune system have consequences that are more specific ratory and genitourinary tracts

more restricted case of defective phagocytic function, the major consequence is susceptibility to bacterial infection. Defects in more highly differentiated compartments of the immune system have consequences that are more specific 432 PART IV The Immune System in Health and Disease and usually less severe. For example, an individual with selec￾tive IgA deficiency may enjoy a full life span, troubled only by a greater than normal susceptibility to infections of the respi￾ratory and genitourinary tracts. VISUALIZING CONCEPTS FIGURE 19-1 Congenital defects that interrupt hematopoiesis or impair functioning of immune-system cells result in various immunodeficiency diseases. (Orange boxes phagocytic defi￾ciencies, green humoral deficiencies, red cell-mediated defi￾ciencies, and purple combined immunodeficiencies, defects that affect more than one cell lineage.) Neutrophil Plasma cell Mature B cell Monocyte Stem cell Lymphoid progenitor cell Pre–B cell Pre–T cell Memory B cell Mature T cell Myeloid progenitor cell Thymus Severe combined immuno￾deficiency X-linked agammaglobulinemia Reticular dysgenesis Severe combined immunodeficiency (SCID) Congenital agranulocytosis Leukocyte-adhesion deficiency Bare-lymphocyte syndrome Selective immunoglobulin deficiency Common variable hypogammaglobulinemia X-linked hyper-IgM syndrome DiGeorge syndrome Chronic granulomatous disease Wiskott-Aldrich syndrome

AIDS and Other Immunodeficiencies CHAPTER 19 433 TABLE 19-1 Some primary human immunodeficiency diseases and underlying genetic defects Immunodeficiency Inheritance Chromosomal disease Specific defect mpaired function Severe combined RAG-1/RAG-2 deficiency No TCR or lg gene 11p13 immunodeficiency rearrangement ADA deficiency Toxic metabolite in T 20q13 PNP deficiency 14q13 JAK-3 deficiency Defective signals from 19p13 IL-2Ry-deficiency lL2,4,7.9.15 Xq13 ZAP-70 deficiency Defective signal from 2q12 Bare lymphocyte Defect in MHc class ll No class I mHc 6p13 Wiskott-Aldrich Cytoskeletal protein(CD43) Defective T cells and A platelets Interferon gamma IFN-y-receptor defect Impaired immunity to q23 DiGeorge syndrome Thymic aplasia T-and B-cell development 22q11 Ataxia telangiectasia Defective cell-cycle kinase Low IgA, igE 11q22 ammaglobulinemias X-linked gammaglobulin Btk): no mature B cells X-linked hyper-IgM Defective CD40 ligand syndrome Common variable Low IgG, IgA; variable immunodeficiency Selective IgA deficiency Low or no IgA Complex Chronic granulomatous Cyt p67 No oxidative burst Cyt p22 for bacterial killing Chediak-Higashi syndrome Defective intracellular Inability to lyse bacteria transport protein(LYST) Leukocyte-adhesion defect Defective integrinβ2 Leukocyte extravasation 21q22 .AR= autosomal recessive: AD= autosomal dominant; XL= x linked; Complex "indicates conditions for which precise genetic data are not available and that may involve several interacting loci Lymphoid Immunodeficiencies May immunoglobulins. Patients with these disorders usually are Involve b cells T Cells, or Both subject to recurrent bacterial infections but display normal immunity to most viral and fungal infections, because the t- The combined forms of lymphoid immunodeficiency affect cell branch of the immune system is largely unaffected. Most both lineages and are generally lethal within the first few common in patients with humoral immunodeficiencies are years of life; these arise from defects early in developmental infections by such encapsulated bacteria as staphylococci, pathways. They are less common than conditions, usually less streptococci, and pneumococci, because antibody is critical severe, that result from defects in more highly differentiated for the opsonization and clearance of these organisms lymphoid cells Because of the central role of t cells in the immune B-cell immunodeficiency disorders make up a diverse tem, a T-cell deficiency can affect both the humoral and the spectrum of diseases ranging from the complete absence of cell-mediated responses. The impact on the cell-mediated mature recirculating B cells, plasma cells, and immuno- system can be severe, with a reduction in both delayed-type globulin to the selective absence of only certain classes of hypersensitive responses and cell-mediated cytotoxicity

Lymphoid Immunodeficiencies May Involve B Cells, T Cells, or Both The combined forms of lymphoid immunodeficiency affect both lineages and are generally lethal within the first few years of life; these arise from defects early in developmental pathways. They are less common than conditions, usually less severe, that result from defects in more highly differentiated lymphoid cells. B-cell immunodeficiency disorders make up a diverse spectrum of diseases ranging from the complete absence of mature recirculating B cells, plasma cells, and immuno￾globulin to the selective absence of only certain classes of AIDS and Other Immunodeficiencies CHAPTER 19 433 immunoglobulins. Patients with these disorders usually are subject to recurrent bacterial infections but display normal immunity to most viral and fungal infections, because the T￾cell branch of the immune system is largely unaffected. Most common in patients with humoral immunodeficiencies are infections by such encapsulated bacteria as staphylococci, streptococci, and pneumococci, because antibody is critical for the opsonization and clearance of these organisms. Because of the central role of T cells in the immune sys￾tem, a T-cell deficiency can affect both the humoral and the cell-mediated responses. The impact on the cell-mediated system can be severe, with a reduction in both delayed-type hypersensitive responses and cell-mediated cytotoxicity. TABLE 19-1 Some primary human immunodeficiency diseases and underlying genetic defects Immunodeficiency Inheritance Chromosomal disease Specific defect Impaired function mode* defect Severe combined RAG-1/RAG-2 deficiency No TCR or Ig gene AR 11p13 immunodeficiency rearrangement (SCID) ADA deficiency Toxic metabolite in T AR 20q13 PNP deficiency and B cells AR 14q13 JAK-3 deficiency Defective signals from AR 19p13 IL-2R-deficiency IL-2, 4, 7, 9, 15, XL Xq13 ZAP-70 deficiency Defective signal from AR 2q12 TCR Bare lymphocyte Defect in MHC class II No class II MHC AR 16p13 syndrome gene promoter molecules Wiskott-Aldrich Cytoskeletal protein (CD43) Defective T cells and XL Xp11 syndrome (WAS) platelets Interferon gamma IFN-–receptor defect Impaired immunity to AR 6q23 receptor mycobacteria DiGeorge syndrome Thymic aplasia T- and B-cell development AD 22q11 Ataxia telangiectasia Defective cell-cycle kinase Low IgA, IgE AR 11q22 Gammaglobulinemias X-linked Bruton’s tyrosine kinase XL Xq21 agammaglobulinemia (Btk); no mature B cells X-linked hyper-IgM Defective CD40 ligand XL Xq26 syndrome Common variable Low IgG, IgA; variable Complex immunodeficiency IgM Selective IgA deficiency Low or no IgA Complex Chronic granulomatous Cyt p91phox XL Xp21 disease Cyt p67phox No oxidative burst AR 1q25 Cyt p22phox for bacterial killing AR 16q24 Chediak-Higashi syndrome Defective intracellular Inability to lyse bacteria AR 1q42 transport protein (LYST) Leukocyte-adhesion defect Defective integrin 2 Leukocyte extravasation AR 21q22 (CD18) *AR autosomal recessive; AD autosomal dominant; XL X linked; “Complex” indicates conditions for which precise genetic data are not available and that may involve several interacting loci. } } } } } }

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 similar

Immunoglobulin 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.]

AIDS and other Immunodeficiencies cHAPTER 19 43 DEf rosine L-R (XHM) kinase (XLa) CD4OL CD40 Class lI mhc T cell B cell Defect in DEfective recombination- tivating genes f Class lI mhc RAG-1/2) FIGURE Defects in cell interaction and signaling can lead to of receptors for IL-2, 4, 7, 9, and 15(IL-RY): (3)JAK-3, which trans- severe immunodeficiency. The interaction of T cell and B cell is duces signals from the gamma chain of the cytokine receptor: or(4) shown here with a number of the components important to the intra- expression of the class ll MHC molecule(bare lymphocyte syn- and extracellular signaling pathways. A number of primary immuno- drome). XLA results from defective transduction of activating signals deficiencies are rooted in defects in these interactions. SCID may re- from the cell-surface IgM by Bruton's tyrosine kinase( Btk). XHM re- lt from defects in (1)the recombination-activating genes(RAG-1 sults from defects in CD40L that preclude normal maturation of B and) required for synthesis of the functional immunoglobulins and lls. Adapted from B. A. Smart and H. D. Ochs, 1997, Curr. Opin T-cell receptors that characterize mature B and T cells: (2)the y chain Pediatr. 9: 570. phenotype because the Il receptors signal through this mol- nucleoside phosphorylase(PNP)causes immunodeficiency ecule, accounted for 9 of the cases(see Figure 12-10). A rare by a mechanism similar to the ADa defect. As described in defect found in only 2 of the patients involved the IL-7 recep- Chapters 5 and 9, both immunoglobulin and T-cell receptor tor;these patients have impaired T and B cells but normal genes undergo rearrangement to express the active forms of NK cells. Another common defect is the adenosine deami- these molecules. a defect in the genes that encode mediators nase or ada deficiency found in 22 patients. Adenosine of the rearrangement processes (recombination-activating deaminase catalyzes conversion of adenosine to inosine, and proteins RAG-1 and RAG-2)precludes development of B and its deficiency results in accumulation of adenosine, which in- T cells with functional receptors and leads to SCID terferes with purine metabolism and DNA synthesis. The a defect leading to general failure of immunity similar to remaining cases included single instances of reticular dysge- SCID is failure to transcribe the genes that encode class II nesis and cartilage hair dysplasia or were classified as autos- MHC molecules. Without these molecules, the patient's lym- mal recessive defects not related to known IL-2Ry or JAK-3 phocytes cannot participate in cellular interactions with T mutations. Thirteen of the 141 cases were of unknown ori- helper cells. This type of immunodeficiency is also called the gin, with no apparent genetic defect or family history of im- bare-lymphocyte syndrome. Molecular studies of a class II munodeficien MHC deficiency revealed a defective interaction between a 5 There are other known defects that give rise to SCID. There promoter sequence of the gene for the class ll MHC molecule is a defect characterized by depletion of CD8* T cells that in- and a DNA-binding protein necessary for gene transcription. volves the tyrosine kinase ZAP-70, an important element in Other patients with SCID-like symptoms lack class I MHC T-cell signal transduction(see Figures 10-11 and 10-12). In- molecules. This rare variant of immunodeficiency was fants with defects in ZAP-70 may have normal levels of im- ascribed to mutation in the taP genes that are vital to anti- munoglobulin and CD4 lymphocytes, but their CD4 t gen processing by class I MHc molecules(see Clinical Focus cells are nonfunctional. a deficiency in the enzyme purine Chapter 8). This defect causes a deficit in CD8-mediated

phenotype because the IL receptors signal through this mol￾ecule, accounted for 9 of the cases (see Figure 12-10). A rare defect found in only 2 of the patients involved the IL-7 recep￾tor; these patients have impaired T and B cells but normal NK cells. Another common defect is the adenosine deami￾nase or ADA deficiency found in 22 patients. Adenosine deaminase catalyzes conversion of adenosine to inosine, and its deficiency results in accumulation of adenosine, which in￾terferes with purine metabolism and DNA synthesis. The remaining cases included single instances of reticular dysge￾nesis and cartilage hair dysplasia or were classified as autoso￾mal recessive defects not related to known IL-2R or JAK-3 mutations. Thirteen of the 141 cases were of unknown ori￾gin, with no apparent genetic defect or family history of im￾munodeficiency. There are other known defects that give rise to SCID. There is a defect characterized by depletion of CD8 T cells that in￾volves the tyrosine kinase ZAP-70, an important element in T-cell signal transduction (see Figures 10-11 and 10-12). In￾fants with defects in ZAP-70 may have normal levels of im￾munoglobulin and CD4 lymphocytes, but their CD4 T cells are nonfunctional. A deficiency in the enzyme purine nucleoside phosphorylase (PNP) causes immunodeficiency by a mechanism similar to the ADA defect. As described in Chapters 5 and 9, both immunoglobulin and T-cell receptor genes undergo rearrangement to express the active forms of these molecules. A defect in the genes that encode mediators of the rearrangement processes (recombination-activating proteins RAG-1 and RAG-2) precludes development of B and T cells with functional receptors and leads to SCID. A defect leading to general failure of immunity similar to SCID is failure to transcribe the genes that encode class II MHC molecules. Without these molecules, the patient’s lym￾phocytes cannot participate in cellular interactions with T helper cells. This type of immunodeficiency is also called the bare-lymphocyte syndrome. Molecular studies of a class II MHC deficiency revealed a defective interaction between a 5 promoter sequence of the gene for the class II MHC molecule and a DNA-binding protein necessary for gene transcription. Other patients with SCID-like symptoms lack class I MHC molecules. This rare variant of immunodeficiency was ascribed to mutation in the TAP genes that are vital to anti￾gen processing by class I MHC molecules (see Clinical Focus Chapter 8). This defect causes a deficit in CD8-mediated AIDS and Other Immunodeficiencies CHAPTER 19 435 FIGURE 19-3 Defects in cell interaction and signaling can lead to severe immunodeficiency. The interaction of T cell and B cell is shown here with a number of the components important to the intra￾and extracellular signaling pathways. A number of primary immuno￾deficiencies are rooted in defects in these interactions. SCID may re￾sult from defects in (1) the recombination-activating genes (RAG-1 and -2) required for synthesis of the functional immunoglobulins and T-cell receptors that characterize mature B and T cells; (2) the chain of receptors for IL-2, 4, 7, 9, and 15 (IL-R); (3) JAK-3, which trans￾duces signals from the gamma chain of the cytokine receptor; or (4) expression of the class II MHC molecule (bare lymphocyte syn￾drome). XLA results from defective transduction of activating signals from the cell-surface IgM by Bruton’s tyrosine kinase (Btk). XHM re￾sults from defects in CD40L that preclude normal maturation of B cells. [Adapted from B. A. Smart and H. D. Ochs, 1997, Curr. Opin. Pediatr. 9:570.] IL-2, IL-4, IL-7, IL-9, IL-15 IL-Rγ IL-Rγ Ag IgM Ig B7 CD28 CD4 Class II MHC CD40L CD40 TCR T cell B cell Btk RAG-1/2 RAG-1/2 JAK-3 Deficiency in JAK-3 pathway Defect in CD40L (XHM) Defect in Bruton's tyrosine kinase (XLA) Defect in recombination￾activating genes (RAG-1/2) Defective expression of Class II MHC (bare lymphocyte syndrome) Defect in γ chain of receptors for IL-2, 4, 7, 9, 15