《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

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 later

immunity, 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

AIDs and other Immunodeficiencies chaPter 19 437 in life than other deficiencies and is sometimes called late- subject to severe infection by agents such as meningococcus, onset hypogammaglobulinemia or, incorrectly, acquired which causes fatal disease. IgM deficiency may be accompa- hypogammaglobulinemia. However, CVI has a genetic nied by various malignancies or by autoimmune disease. IgG component and is considered a primary immunodeficiency, deficiencies are also rare. These are often not noticed until although the exact pattern of inheritance is not known. Be- adulthood and can be effectively treated by administration of cause the manifestations are very similar to those of acquired immunoglobulin hypogammaglobulinemia, there is some confusion between the two forms(see below). Infections in CVI sufferers ATAXIA TELANGIECTASIA most frequently bacterial and can be controlled by adminis tration of immunoglobulin In CVI patients, B cells fail to Although not classified primarily as an immunodeficiency. mature into plasma cells; however in vitro studies show that ataxia telangiectasia is a disease syndrome that includes defi- ate differentiation signals. The underlying defect in Cvl is the appearance of broken capillaries(telangiectasia)in the not known, but must involve either an in vivo blockage of the maturation of B cells to the plasma-cell stage or their inabil- eyes. The primary defect appears to be in a kinase involved in ity to produce the secreted form of immunoglobulins regulation of the cell cycle. The relationship between the im- mune deficiency and the other defects in ataxia telangiectasia remains obscure HYPER-IgE SYNDROME (OB SYNDROME) A primary immunodeficiency characterized by skin abcesses, IMMUNE DISORDERS INVOLVING THE THYMUS recurrent pneumonia, eczema, and elevated levels of IgE ac- Several immunodeficiency syndromes are grounded in fail companies facial abnormalities and bone fragility. This multi-system disorder is autosomal dominant and has vari- ure of the thymus to undergo normal development. Thymic able expressivity. The gene for hyper Ige syndrome, or hIes malfunction has a profound effect on T-cell function; all maps to chromosome 4 HIES immunologic signs include re- populations ofT cells, including helper, cytolytic, and regula current infection and eosinophilia in addition to elevated Ige tory varieties, are affected. Immunity to viruses and fungi levels is especially compromised in those suffering from these conditions DiGeorge syndrome, or congenital thymic aplasia, in its SELECTIVE DEFICIENCIES OF IMMUNOGLOBULIN CLASSES most severe form is the complete absence of a thymus. This A number of immunodeficiency states are characterized by developmental defect, which is associated with the dele- ignificantly lowered amounts of specific immunoglobulin tion in the embryo of a region on chromosome 22, causes isotypes. Of these, iga deficiency is by far the most common. immunodeficiency along with characteristic facial abnor- There are family-association data showing that Iga defi- malities, hypoparathyroidism, and congenital heart disease ciency prevails in the same families as CVl, suggesting a rela-( Figure 19-4). The stage at which the causative developmen tionship between these conditions. The spectrum of clinical tal defect occurs has been determined, and the syndrome is symptoms of igA deficiency is broad; many of those affected sometimes called the third and fourth pharyngeal pouch syn are asymptomatic, while others suffer from an assortment of drome to reflect its precise embryonic origin. The immune serious problems. Recurrent respiratory and genitourinary defect includes a profound depression of T-cell numbers and tract infections resulting from lack of secreted igA on mu- absence of T-cell responses. Although B cells are present in cosal surfaces are common. In addition, problems such as in- normal numbers, affected individuals do not produce anti- testinal malabsorption, allergic disease, and autoimmune body in response to immunization with specific antigens disorders may also be associated with low IgA levels. The rea- Thymic transplantation is of some value for correcting the sons for this variability in the clinical profile of IgA deficiency T-cell defects, but many DiGeorge patients have such severe not clear but may relate to the ability of some, but not all, heart disease that their chances for long-term survival are patients to substitute IgM for igA as a mucosal antibody. The poor, even if the immune defects are corrected. defect in igA deficiency is related to the inability of igA B cells Whereas the DiGeorge syndrome results from an in- to undergo normal differentiation to the plasma-cell stage. trauterine or developmental anomaly, thymic hypoplasia, or IgG2 and Ig G4 may also be deficient in IgA-deficient pa- the Nezelof syndrome, is an inherited disorder. The mode of tients. No causative defect in iga genes has been identified, inheritance for this rare disease is not known and its presen- and the surface igA molecules on these patients' B cells ap- tation varies, making it somewhat difficult to diagnose. As pear to be expressed normally. a gene outside of the im- the name implies, thymic hypoplasia is a defect in which a munoglobulin gene complex is suspected to be responsible vestigial thymus is unable to serve its function in T-cell de- for this fairly common syndrome velopment. In some patients, B cells are normal, whereas in Other immunoglobulin deficiencies have been reported, others a B-cell deficiency is secondary to the T-cell defect Af but these are rarer. An igm deficiency has been identified as fected individuals suffer from chronic diarrhea, viral and an autosomal recessive trait. victims of this condition are fungal infections, and a general failure to thrive

in life than other deficiencies and is sometimes called late￾onset hypogammaglobulinemia or, incorrectly, acquired hypogammaglobulinemia. However, CVI has a genetic component and is considered a primary immunodeficiency, although the exact pattern of inheritance is not known. Be￾cause the manifestations are very similar to those of acquired hypogammaglobulinemia, there is some confusion between the two forms (see below). Infections in CVI sufferers are most frequently bacterial and can be controlled by adminis￾tration of immunoglobulin. In CVI patients, B cells fail to mature into plasma cells; however in vitro studies show that CVI B cells are capable of maturing in response to appropri￾ate differentiation signals. The underlying defect in CVI is not known, but must involve either an in vivo blockage of the maturation of B cells to the plasma-cell stage or their inabil￾ity to produce the secreted form of immunoglobulins. HYPER-IgE SYNDROME (JOB SYNDROME) A primary immunodeficiency characterized by skin abcesses, recurrent pneumonia, eczema, and elevated levels of IgE ac￾companies facial abnormalities and bone fragility. This multi-system disorder is autosomal dominant and has vari￾able expressivity. The gene for hyper IgE syndrome, or HIES, maps to chromosome 4. HIES immunologic signs include re￾current infection and eosinophilia in addition to elevated IgE levels. SELECTIVE DEFICIENCIES OF IMMUNOGLOBULIN CLASSES A number of immunodeficiency states are characterized by significantly lowered amounts of specific immunoglobulin isotypes. Of these, IgA deficiency is by far the most common. There are family-association data showing that IgA defi￾ciency prevails in the same families as CVI, suggesting a rela￾tionship between these conditions. The spectrum of clinical symptoms of IgA deficiency is broad; many of those affected are asymptomatic, while others suffer from an assortment of serious problems. Recurrent respiratory and genitourinary tract infections resulting from lack of secreted IgA on mu￾cosal surfaces are common. In addition, problems such as in￾testinal malabsorption, allergic disease, and autoimmune disorders may also be associated with low IgA levels. The rea￾sons for this variability in the clinical profile of IgA deficiency are not clear but may relate to the ability of some, but not all, patients to substitute IgM for IgA as a mucosal antibody. The defect in IgA deficiency is related to the inability of IgA B cells to undergo normal differentiation to the plasma-cell stage. IgG2 and IgG4 may also be deficient in IgA-deficient pa￾tients. No causative defect in IgA genes has been identified, and the surface IgA molecules on these patients’ B cells ap￾pear to be expressed normally. A gene outside of the im￾munoglobulin gene complex is suspected to be responsible for this fairly common syndrome. Other immunoglobulin deficiencies have been reported, but these are rarer. An IgM deficiency has been identified as an autosomal recessive trait. Victims of this condition are subject to severe infection by agents such as meningococcus, which causes fatal disease. IgM deficiency may be accompa￾nied by various malignancies or by autoimmune disease. IgG deficiencies are also rare. These are often not noticed until adulthood and can be effectively treated by administration of immunoglobulin. ATAXIA TELANGIECTASIA Although not classified primarily as an immunodeficiency, ataxia telangiectasia is a disease syndrome that includes defi￾ciency of IgA and sometimes of IgE. The syndrome is charac￾terized by difficulty in maintaining balance (ataxia) and by the appearance of broken capillaries (telangiectasia) in the eyes. The primary defect appears to be in a kinase involved in regulation of the cell cycle. The relationship between the im￾mune deficiency and the other defects in ataxia telangiectasia remains obscure. IMMUNE DISORDERS INVOLVING THE THYMUS Several immunodeficiency syndromes are grounded in fail￾ure of the thymus to undergo normal development. Thymic malfunction has a profound effect on T-cell function; all populations of T cells, including helper, cytolytic, and regula￾tory varieties, are affected. Immunity to viruses and fungi is especially compromised in those suffering from these conditions. DiGeorge syndrome, or congenital thymic aplasia, in its most severe form is the complete absence of a thymus. This developmental defect, which is associated with the dele￾tion in the embryo of a region on chromosome 22, causes immunodeficiency along with characteristic facial abnor￾malities, hypoparathyroidism, and congenital heart disease (Figure 19-4). The stage at which the causative developmen￾tal defect occurs has been determined, and the syndrome is sometimes called the third and fourth pharyngeal pouch syn￾drome to reflect its precise embryonic origin. The immune defect includes a profound depression of T-cell numbers and absence of T-cell responses. Although B cells are present in normal numbers, affected individuals do not produce anti￾body in response to immunization with specific antigens. Thymic transplantation is of some value for correcting the T-cell defects, but many DiGeorge patients have such severe heart disease that their chances for long-term survival are poor, even if the immune defects are corrected. Whereas the DiGeorge syndrome results from an in￾trauterine or developmental anomaly, thymic hypoplasia, or the Nezelof syndrome, is an inherited disorder. The mode of inheritance for this rare disease is not known and its presen￾tation varies, making it somewhat difficult to diagnose. As the name implies, thymic hypoplasia is a defect in which a vestigial thymus is unable to serve its function in T-cell de￾velopment. In some patients, B cells are normal, whereas in others a B-cell deficiency is secondary to the T-cell defect. Af￾fected individuals suffer from chronic diarrhea, viral and fungal infections, and a general failure to thrive. AIDS and Other Immunodeficiencies CHAPTER 19 437

438 PART IV The Immune System in Health and Disease in the bone marrow but rarely differentiate beyond the promyelocyte stage. As a result, children born with this con- dition show severe neutropenia, with counts of less than 200 ils/mm. These children suffer from frequent bacte rial infections beginning as early as the first month of life; normal infants are protected at this age by maternal antibody as well as by innate immune mechanisms, including neu trophils. Experimental evidence suggests that this genetic defect results in decreased production of granulocyte colony stimulating factor(G-CSF)and thus in a failure of the myeloid stem cell to differentiate along the granulocytic lineage(see Figure 2-1) Neutrophils have a short life span, and their precursors must divide rapidly in the bone marrow to maintain levels of these cells in the circulation. For this reason, agents such as radiation and certain drugs(e. g, chemotherapeutic drugs) that specifically damage rapidly dividing cells are likely to cause neutropenia. Occasionally, neutropenia develops in such autoimmune diseases as Sjogrens syndrome orsystemi lupus erythematosus; in these conditions, autoantibodies de stroy the neutrophils. Transient neutropenia often develops after certain bacterial or viral infections, but neutrophil FIGURE 19.4 A child with DiGeorge syndrome showing character. counts return to normal as the infection is cleared istic dysplasia of ears and mouth and abnormally long distance be tween the eyes. R Kretschmer et al., 1968, New Engl J Med. 279: 1295 photograph courtesy of F S. Rosen./ CHRONIC GRANULOMATOUS DISEASE(CGD) CGD is a genetic disease that has at least two distinct forms an X-linked form that occurs in about 70% of patients and an Immunodeficiencies of the myeloid autosomal recessive form found in the rest this disease is Lineage Affect Innate Immunity rooted in a defect in the oxidative pathway by which phago- cytes generate hydrogen peroxide and the resulting reactive Immunodeficiencies of the lymphoid lineage affect adaptive products, such as hypochlorous acid, that kill phagocytosed immunity. By contrast, defects in the myeloid cell lineage af- bacteria. CGD sufferers undergo excessive inflammatory fect the innate immune functions(see Figure 19-1). Most of reactions that result in gingivitis, swollen lymph nodes, these defects result in impaired phagocytic processes that are and nonmalignant granulomas(lumpy subcutaneous cell manifested by recurrent microbial infection of greater masses); they are also susceptible to bacterial and fungal in lesser severity. There are several stages at which the phago- fection CGD patients are not subject to infection by those cytic processes may be faulty; these include cell motility, ad- bacteria, such as pneumococcus, that generate their own hy herence to and phagocytosis of organisms, and killing by drogen peroxide. In this case, the myeloperoxidase in the host macrophages cell can use the bacterial hydrogen peroxide to generate enough hypochlorous acid to thwart infection. Several re REDUCTION IN NEUTROPHIL COUNT lated defects may lead to CGD; these include a missing or de- fective cytochrome(cyt b558)that functions in an oxidati As described in Chapter 2, neutrophils are circulating granu- pathway and defects in proteins (phagocyte oxidases, locytes with phagocytic function. Quantitative deficiencies in phox) that stabilize the cytochrome. In addition to the gen- eutrophils can range from an almost complete absence of eral defect in the killer function of phagocytes, there is also a cells, called agranulocytosis, to a reduction in the concentra- decrease in the ability of mononuclear cells to serve as APCs tion of peripheral blood neutrophils below 1500/mm, called Both processing and presentation of antigen are impaired. granulocytopenia or neutropenia. These quantitative defi- Increased amounts of antigen are required to trigger T-cell iencies may result from congenital defects or may be help when mononuclear cells from CGD patients are used as quired through extrinsic factors. Acquired neutropenias APCs much more common than congenital ones The addition of IFN-y has been shown to restore function ongenital neutropenia is often due to a genetic defect to CGd granulocytes and monocytes in vitro. This observa- that affects the myeloid progenitor stem cell; it results in re- tion prompted clinical trials of IFN-y for CGD patients. En duced production of neutrophils during hematopoiesis. In couraging increases in oxidative function and restoration congenital agranulocytosis, myeloid stem cells are present of cytoplasmic cytochrome have been reported in these

Immunodeficiencies of the Myeloid Lineage Affect Innate Immunity Immunodeficiencies of the lymphoid lineage affect adaptive immunity. By contrast, defects in the myeloid cell lineage af￾fect the innate immune functions (see Figure 19-1). Most of these defects result in impaired phagocytic processes that are manifested by recurrent microbial infection of greater or lesser severity. There are several stages at which the phago￾cytic processes may be faulty; these include cell motility, ad￾herence to and phagocytosis of organisms, and killing by macrophages. REDUCTION IN NEUTROPHIL COUNT As described in Chapter 2, neutrophils are circulating granu￾locytes with phagocytic function. Quantitative deficiencies in neutrophils can range from an almost complete absence of cells, called agranulocytosis, to a reduction in the concentra￾tion of peripheral blood neutrophils below 1500/mm3 , called granulocytopenia or neutropenia. These quantitative defi￾ciencies may result from congenital defects or may be ac￾quired through extrinsic factors. Acquired neutropenias are much more common than congenital ones. Congenital neutropenia is often due to a genetic defect that affects the myeloid progenitor stem cell; it results in re￾duced production of neutrophils during hematopoiesis. In congenital agranulocytosis, myeloid stem cells are present in the bone marrow but rarely differentiate beyond the promyelocyte stage. As a result, children born with this con￾dition show severe neutropenia, with counts of less than 200 neutrophils/mm3 . These children suffer from frequent bacte￾rial infections beginning as early as the first month of life; normal infants are protected at this age by maternal antibody as well as by innate immune mechanisms, including neu￾trophils. Experimental evidence suggests that this genetic defect results in decreased production of granulocyte colony￾stimulating factor (G-CSF) and thus in a failure of the myeloid stem cell to differentiate along the granulocytic lineage (see Figure 2-1). Neutrophils have a short life span, and their precursors must divide rapidly in the bone marrow to maintain levels of these cells in the circulation. For this reason, agents such as radiation and certain drugs (e.g., chemotherapeutic drugs) that specifically damage rapidly dividing cells are likely to cause neutropenia. Occasionally, neutropenia develops in such autoimmune diseases as Sjögren’s syndrome or systemic lupus erythematosus; in these conditions, autoantibodies de￾stroy the neutrophils. Transient neutropenia often develops after certain bacterial or viral infections, but neutrophil counts return to normal as the infection is cleared. CHRONIC GRANULOMATOUS DISEASE (CGD) CGD is a genetic disease that has at least two distinct forms: an X-linked form that occurs in about 70% of patients and an autosomal recessive form found in the rest. This disease is rooted in a defect in the oxidative pathway by which phago￾cytes generate hydrogen peroxide and the resulting reactive products, such as hypochlorous acid, that kill phagocytosed bacteria. CGD sufferers undergo excessive inflammatory reactions that result in gingivitis, swollen lymph nodes, and nonmalignant granulomas (lumpy subcutaneous cell masses); they are also susceptible to bacterial and fungal in￾fection. CGD patients are not subject to infection by those bacteria, such as pneumococcus, that generate their own hy￾drogen peroxide. In this case, the myeloperoxidase in the host cell can use the bacterial hydrogen peroxide to generate enough hypochlorous acid to thwart infection. Several re￾lated defects may lead to CGD; these include a missing or de￾fective cytochrome (cyt b558) that functions in an oxidative pathway and defects in proteins (phagocyte oxidases, or phox) that stabilize the cytochrome. In addition to the gen￾eral defect in the killer function of phagocytes, there is also a decrease in the ability of mononuclear cells to serve as APCs. Both processing and presentation of antigen are impaired. Increased amounts of antigen are required to trigger T-cell help when mononuclear cells from CGD patients are used as APCs. The addition of IFN- has been shown to restore function to CGD granulocytes and monocytes in vitro. This observa￾tion prompted clinical trials of IFN- for CGD patients. En￾couraging increases in oxidative function and restoration of cytoplasmic cytochrome have been reported in these 438 PART IV The Immune System in Health and Disease FIGURE 19-4 A child with DiGeorge syndrome showing character￾istic dysplasia of ears and mouth and abnormally long distance be￾tween the eyes. [R. Kretschmer et al., 1968, New Engl. J. Med. 279:1295; photograph courtesy of F. S. Rosen.]

AIDS and other Immunodeficiencies cHAPTER 19 439 patients. In addition, knowledge of the precise gene defects localized to the common p chain and affects expression of all underlying CGD makes it a candidate for gene therapy, and three of the molecules that use this chain. This defect, called replacement of the defective cytochrome has had promising leukocyte adhesion deficiency(lad), causes susceptibility to results(see below) infection with both gram-positive and gram-negative bacte ria as well as various fungi. Impairment of adhesion of leuko- CHEDIAK-HIGASHI SYNDROME tes to vascular endothelium limits recruitment of cells to This autosomal recessive disease is characterized by recurrent sites of inflammation. Viral immunity is somewhat impaired. bacterial infections, partial oculo-cutaneous albinism (lack as would be predicted from the defective T-B cell cooperation of skin and eye pigment), and aggressive but nonmalignant arising from the adhesion defect. LAD varies in its severity infiltration of organs by lymphoid cells. Phagocytes from pa- some affected individuals die within a few years, others sur tients with this immune defect contain giant granules but do vive into their forties. The reason for the variable disease phe- not have the ability to kill bacteria. The molecular basis of the pe in this disorder is not known. LAD is the subject of a defect is a mutation in a protein (LySt) involved in the regu- Clinical Focus in Chapter 15 lation of intracellular trafficking. The mutation impairs the targeting of proteins to secretory lysosomes, which makes Complement Defects Result them unable to lyse bacteria. in Immunodeficiency or LEUKOCYTE ADHESION DEFICIENCY(LAD) Immune-Complex Disease As described in Chapter 15, cell-surface molecules belonging Immunodeficiency diseases resulting from defects in the to the integrin family of proteins function as adhesion mole- complement system are described in Chapter 13. Many com cules and are required to facilitate cellular interaction. Three plement deficiencies are associated with increased suscepti of these, LFA-1, Mac-1, and gp150/95(CDlla, b, and c, re- bility to bacterial infections and/or immune-complex spectively) have a common B chain(CD18)and are variably diseases. One of these complement disorders, a deficiency in present on different monocytic cells; CDlla is also expressed properdin, which stabilizes the C3 convertase in the alterna on B cells(Table 19-2). An immunodeficiency related to tive complement pathway, is caused by a defect in a gene lo- dysfunction of the adhesion molecules is rooted in a defect cated on the X chromosome(see Figure 19-2) TABLE 19-2 Properties of integrin molecules that are absent in leukocyte-adhesion deficiency INTEGRIN MOLECULES. LFA-1 CR4 CD designation CDlla/CD18 CD11b/CD18 CD11c/CD18 Subunit composition aXB2 Subunit molecular mass(kDa) a chain 175000 B chain 95000 95,000 95,000 Cellular expression Lymphocytes Mo Monocytes Monocytes Macrophages Granulocytes Granulocytes Natural killer cells Natural killer cells Ligand ICAM-1 C3b ICAM-2 Functions inhibited with monoclonal Extravasation Opsonization Granulocyte adherence CTL killing Granulocyte adherence. and aggregation T-B conjugate formation ADCC chemotaxis aDcc CR3= type 3 complement receptor, also known as Mac-1: CR4= type 4 complement receptor, also known as gp150/95: LFA-1, CR3, and CR4 are heterodimers containing a common B chain but different a chains designated L, M, and x, respectively

patients. In addition, knowledge of the precise gene defects underlying CGD makes it a candidate for gene therapy, and replacement of the defective cytochrome has had promising results (see below). CHEDIAK-HIGASHI SYNDROME This autosomal recessive disease is characterized by recurrent bacterial infections, partial oculo-cutaneous albinism (lack of skin and eye pigment), and aggressive but nonmalignant infiltration of organs by lymphoid cells. Phagocytes from pa￾tients with this immune defect contain giant granules but do not have the ability to kill bacteria. The molecular basis of the defect is a mutation in a protein (LYST) involved in the regu￾lation of intracellular trafficking. The mutation impairs the targeting of proteins to secretory lysosomes, which makes them unable to lyse bacteria. LEUKOCYTE ADHESION DEFICIENCY (LAD) As described in Chapter 15, cell-surface molecules belonging to the integrin family of proteins function as adhesion mole￾cules and are required to facilitate cellular interaction. Three of these, LFA-1, Mac-1, and gp150/95 (CD11a, b, and c, re￾spectively) have a common  chain (CD18) and are variably present on different monocytic cells; CD11a is also expressed on B cells (Table 19-2). An immunodeficiency related to dysfunction of the adhesion molecules is rooted in a defect localized to the common  chain and affects expression of all three of the molecules that use this chain. This defect, called leukocyte adhesion deficiency (LAD), causes susceptibility to infection with both gram-positive and gram-negative bacte￾ria as well as various fungi. Impairment of adhesion of leuko￾cytes to vascular endothelium limits recruitment of cells to sites of inflammation.Viral immunity is somewhat impaired, as would be predicted from the defective T-B cell cooperation arising from the adhesion defect. LAD varies in its severity; some affected individuals die within a few years, others sur￾vive into their forties. The reason for the variable disease phe￾notype in this disorder is not known. LAD is the subject of a Clinical Focus in Chapter 15. Complement Defects Result in Immunodeficiency or Immune-Complex Disease Immunodeficiency diseases resulting from defects in the complement system are described in Chapter 13. Many com￾plement deficiencies are associated with increased suscepti￾bility to bacterial infections and/or immune-complex diseases. One of these complement disorders, a deficiency in properdin, which stabilizes the C3 convertase in the alterna￾tive complement pathway, is caused by a defect in a gene lo￾cated on the X chromosome (see Figure 19-2). AIDS and Other Immunodeficiencies CHAPTER 19 439 TABLE 19-2 Properties of integrin molecules that are absent in leukocyte-adhesion deficiency INTEGRIN MOLECULES* Property LFA-1 CR3 CR4 CD designation CD11a/CD18 CD11b/CD18 CD11c/CD18 Subunit composition L2 M2 X2 Subunit molecular mass (kDa)  chain 175,000 165,000 150,000  chain 95,000 95,000 95,000 Cellular expression Lymphocytes Monocytes Monocytes Monocytes Macrophages Macrophages Macrophages Granulocytes Granulocytes Granulocytes Natural killer cells Natural killer cells Ligand ICAM-1 C3bi C3bi ICAM-2 Functions inhibited with monoclonal Extravasation Opsonization Granulocyte adherence antibody CTL killing Granulocyte adherence, and aggregation T-B conjugate formation aggregation, and ADCC chemotaxis ADCC *CR3 type 3 complement receptor, also known as Mac-1; CR4 type 4 complement receptor, also known as gp150/95; LFA-1, CR3, and CR4 are heterodimers containing a common  chain but different  chains designated L, M, and X, respectively.

40 aRT Iv The Immune System in Health and Disease Immunodeficiency Disorders Are Treated it is not known whether transplantation cures the immuno- by Replacement of the Defective Element deficiency permanently. A variation of bone-marrow trans- plantation is the injection of paternal CD34 cells in utero Although there are no cures for immunodeficiency disor- when the birth of an infant with SCID is expected. Two in- ders, there are several treatment possibilities. In addition to fants born after this procedure had normal T-cell function the drastic option of total isolation from exposure to any mi- and did not develop the infections that characterize SCID crobial agent, treatment options for the immunodeficiencies If a single gene defect has been identified, as in adenosine nclude deaminase deficiency or chronic granulomatous disease, re- s replacement of a missing protein placement of the defective gene may be a treatment option Clinical tests of such therapy are underway for SCID caused a replacement of a missing cell type or lineage by ada deficiency and for chronic granulomatous disease a replacement of a missing or defective gene with defective p67Pn0, with promising initial results. Disease remission for up to 18 months was seen in the SCid patients For disorders that impair antibody production, the classic and up to 6 months in the Cgd patients. a similar procedure course of treatment is administration of the missing protein was used in both trials. It begins with obtaining cells(CD34+ immunoglobulin Pooled human gamma globulin given ei- stem cells are usually selected for these procedures) from the ther intravenously or subcutaneously protects against recur- patient and transfecting them with a normal copy of the de- rent infection in many types of immunodeficiency. Main- fective gene. The transfected cells are then returned to the pa- tenance of reasonably high levels of serum immunoglobulin tient. As this treatment improves, it will become applicable to (5 mg/ml serum) will prevent most common infections in a number of immunodeficiencies for which a genetic defect the agammaglobulinemic patient. This is generally accom- is well defined. As mentioned above, these include defects plished by the administration of immunoglobulin that has in genes that encode the y chain of the IL-2 receptor, JAK-3 been selected for antibodies directed against a particular or- and ZAP-70, all of which give rise to SCiD ganism. Recent advances in the preparation of human mon clonal antibodies and in the ability to genetically engineer Experimental Models of Immunodeficiency chimeric antibodies with mouse V regions and human- derived C regions make it possible to prepare antibodies spe- Include Genetically Altered Animals cific for important pathogens(see Chapter 5) Advances in molecular biology make it possible to clone Immunologists use two well-studied animal models of pri- mary immunodeficiency for a variety of experimental pur the genes that encode other immunologically important pro- poses. One of these is the athymic, or nude, mouse; the teins, such as cytokines, and to express these genes in vitro sing bacterial or eukaryotic expression systems. The avail is the severe combined immunodeficiency, or SCID, mor ability of such proteins allows new modes of therapy in which immunologically important proteins may be replace NUDE(ATHYMIC)MICE or their concentrations increased in the patient. For example, A genetic trait designated nu, which is controlled by a reces- the administration of recombinant IFN-y has proven effec- sive gene on chromosome 11, was discovered in certain mice tive for patients with CGD, and the use of recombinant IL-2 Mice homozygous for this trait(nw/nu) are hairless and have may help to restore immune function in AIDS patients. Re- a vestigial thymus(Figure 19-5). Heterozygotic, nu/+, litter combinant adenosine deaminase has been successfully ad- mates have hair and a normal thymus. It is not known ministered to ada deficient SCID patient whether the hairlessness and the thymus defect are caused by Cell replacement as therapy for immunodeficiencies has the same gene. It is possible that two very closely linked genes been made possible by recent progress in bone-marrow trans- control these defects, which, although unrelated, appear to- plantation(see Chapter 21). Replacement of stem cells with gether in this mutant mouse. a gene that controls develop- those from an immunocompetent donor allows development ment may be involved, since the pathway that leads to the of a functional immune system(see Clinical Focus Chapter differential development of the thymus is related to the one 2). High rates of success have been reported for those who are that controls the skin epithelial cells. The nw/nu mouse can- fortunate enough to have an HLA-identical donor. Careful not easily survive; under normal conditions, the mortality is matching of patients with donors and the ability to manipu- 100% within 25 weeks and 50% die within the first two weeks late stem-cell populations to select CD34 precursor cells after birth. Therefore, when these animals are to be used fo continues to minimize the risk in this procedure, even when experimental purposes, they must be maintained under con- o ideal donor exists. These procedures have been highly suc- ditions that protect them from infection. Precautions include cessful with SCiD infants when haploidentical(complete use of sterilized food, water, cages, and bedding. The cages match of one hla gene set or haplotype) donor marrow is are protected from dust by placing them in a laminar flow usedT cells are depleted and CD34 stem cells are enriched rack or by the use of air filters fitted over the individual cages before introducing the donor bone marrow into the SCID in Nude mice lack cell-mediated fant. Because this therapy has been used only in recent years, they are unable to make antibodies to most antigens. The

Immunodeficiency Disorders Are Treated by Replacement of the Defective Element Although there are no cures for immunodeficiency disor￾ders, there are several treatment possibilities. In addition to the drastic option of total isolation from exposure to any mi￾crobial agent, treatment options for the immunodeficiencies include: ■ replacement of a missing protein ■ replacement of a missing cell type or lineage ■ replacement of a missing or defective gene For disorders that impair antibody production, the classic course of treatment is administration of the missing protein immunoglobulin. Pooled human gamma globulin given ei￾ther intravenously or subcutaneously protects against recur￾rent infection in many types of immunodeficiency. Main￾tenance of reasonably high levels of serum immunoglobulin (5 mg/ml serum) will prevent most common infections in the agammaglobulinemic patient. This is generally accom￾plished by the administration of immunoglobulin that has been selected for antibodies directed against a particular or￾ganism. Recent advances in the preparation of human mon￾oclonal antibodies and in the ability to genetically engineer chimeric antibodies with mouse V regions and human￾derived C regions make it possible to prepare antibodies spe￾cific for important pathogens (see Chapter 5). Advances in molecular biology make it possible to clone the genes that encode other immunologically important pro￾teins, such as cytokines, and to express these genes in vitro, using bacterial or eukaryotic expression systems. The avail￾ability of such proteins allows new modes of therapy in which immunologically important proteins may be replaced or their concentrations increased in the patient. For example, the administration of recombinant IFN- has proven effec￾tive for patients with CGD, and the use of recombinant IL-2 may help to restore immune function in AIDS patients. Re￾combinant adenosine deaminase has been successfully ad￾ministered to ADA deficient SCID patients. Cell replacement as therapy for immunodeficiencies has been made possible by recent progress in bone-marrow trans￾plantation (see Chapter 21). Replacement of stem cells with those from an immunocompetent donor allows development of a functional immune system (see Clinical Focus Chapter 2). High rates of success have been reported for those who are fortunate enough to have an HLA-identical donor. Careful matching of patients with donors and the ability to manipu￾late stem-cell populations to select CD34 precursor cells continues to minimize the risk in this procedure, even when no ideal donor exists. These procedures have been highly suc￾cessful with SCID infants when haploidentical (complete match of one HLA gene set or haplotype) donor marrow is used. T cells are depleted and CD34 stem cells are enriched before introducing the donor bone marrow into the SCID in￾fant. Because this therapy has been used only in recent years, it is not known whether transplantation cures the immuno￾deficiency permanently. A variation of bone-marrow trans￾plantation is the injection of paternal CD34 cells in utero when the birth of an infant with SCID is expected. Two in￾fants born after this procedure had normal T-cell function and did not develop the infections that characterize SCID. If a single gene defect has been identified, as in adenosine deaminase deficiency or chronic granulomatous disease, re￾placement of the defective gene may be a treatment option. Clinical tests of such therapy are underway for SCID caused by ADA deficiency and for chronic granulomatous disease with defective p67phox, with promising initial results. Disease remission for up to 18 months was seen in the SCID patients and up to 6 months in the CGD patients. A similar procedure was used in both trials. It begins with obtaining cells (CD34 stem cells are usually selected for these procedures) from the patient and transfecting them with a normal copy of the de￾fective gene. The transfected cells are then returned to the pa￾tient. As this treatment improves, it will become applicable to a number of immunodeficiencies for which a genetic defect is well defined. As mentioned above, these include defects in genes that encode the chain of the IL-2 receptor, JAK-3, and ZAP-70, all of which give rise to SCID. Experimental Models of Immunodeficiency Include Genetically Altered Animals Immunologists use two well-studied animal models of pri￾mary immunodeficiency for a variety of experimental pur￾poses. One of these is the athymic, or nude, mouse; the other is the severe combined immunodeficiency, or SCID, mouse. NUDE (ATHYMIC) MICE A genetic trait designated nu, which is controlled by a reces￾sive gene on chromosome 11, was discovered in certain mice. Mice homozygous for this trait (nu/nu) are hairless and have a vestigial thymus (Figure 19-5). Heterozygotic, nu/, litter mates have hair and a normal thymus. It is not known whether the hairlessness and the thymus defect are caused by the same gene. It is possible that two very closely linked genes control these defects, which, although unrelated, appear to￾gether in this mutant mouse. A gene that controls develop￾ment may be involved, since the pathway that leads to the differential development of the thymus is related to the one that controls the skin epithelial cells. The nu/nu mouse can￾not easily survive; under normal conditions, the mortality is 100% within 25 weeks and 50% die within the first two weeks after birth. Therefore, when these animals are to be used for experimental purposes, they must be maintained under con￾ditions that protect them from infection. Precautions include use of sterilized food, water, cages, and bedding. The cages are protected from dust by placing them in a laminar flow rack or by the use of air filters fitted over the individual cages. Nude mice lack cell-mediated immune responses, and they are unable to make antibodies to most antigens. The 440 PART IV The Immune System in Health and Disease