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. Initially, 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 recurrent 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 bleeding. Eczema (skin rashes) in varying degrees of severity may also occur, usually beginning around one year of age. The defect in WAS has been mapped to the short arm of the X chromosome (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 interferon gamma (IFN-, see Chapter 12). This deficiency was found in patients suffering from infection with atypical mycobacteria (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 mycobacteria is selective in that those who survive these infections are not unusually susceptible to other agents, including other intracellular bacteria. This immunodeficiency points to a specific role for IFN- and its receptor in protection from infection with mycobacteria. Whereas SCID and the related combined immunodeficiencies affect T cells or all lymphoid cells, other primary immunodeficiencies affect B-cell function and result in the reduction or absence of some or all classes of immunoglobulins. 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 common 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 extremely low IgG levels and by the absence of other immunoglobulin classes. Individuals with XLA have no peripheral B cells and suffer from recurrent bacterial infections, 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 described 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 underlying 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 hyperIgM (XHM) syndrome is characterized by a deficiency of IgG, IgA, and IgE, and elevated levels of IgM, sometimes as high as 10 mg/ml (normal IgM concentration is 1.5 mg/ml). Although individuals with XHM have normal numbers of B cells expressing membrane-bound IgM or IgD, they appear to lack B cells expressing membrane-bound IgG, IgA, or IgE. XHM syndrome is generally inherited as an X-linked recessive disorder (see Figure 19-2), but some forms appear to be acquired and affect both men and women. Affected individuals have high counts of IgM-secreting plasma cells in their peripheral blood and lymphoid tissue. In addition, XHM patients often have high levels of autoantibodies to neutrophils, platelets, and red blood cells. Children with XHM suffer recurrent infections, especially respiratory infections; these are more severe than expected for a deficiency characterized by low levels of immunoglobulins. The defect in XHM is in the gene encoding the CD40 ligand (CD40L), which maps to the X chromosome. TH cells from patients with XHM fail to express functional CD40L on their membrane. Since an interaction between CD40 on the B cell and CD40L on the TH cell is required for B-cell activation, the absence of this co-stimulatory signal inhibits the Bcell response to T-dependent antigens (see Figures 19-3 and 11-10). The B-cell response to T-independent antigens, however, is unaffected by this defect, accounting for the production of IgM antibodies. As described in Chapter 11, class switching and formation of memory B cells both require contact with TH cells by a CD40–CD40L interaction. The absence of this interaction in XHM results in the loss of class switching to IgG, IgA, or IgE isotypes and in a failure to produce memory B cells. In addition, XHM individuals fail to produce germinal centers during a humoral response, which highlights the role of the CD40–CD40L interaction in the generation of germinal centers. COMMON VARIABLE IMMUNODEFICIENCY (CVI) CVI is characterized by a profound decrease in numbers of antibody-producing plasma cells, low levels of most immunoglobulin isotypes (hypogammaglobulinemia), and recurrent 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 lateonset 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. Because 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 administration 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 appropriate 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 inability 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 accompanies facial abnormalities and bone fragility. This multi-system disorder is autosomal dominant and has variable expressivity. The gene for hyper IgE syndrome, or HIES, maps to chromosome 4. HIES immunologic signs include recurrent 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 deficiency prevails in the same families as CVI, suggesting a relationship 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 mucosal surfaces are common. In addition, problems such as intestinal malabsorption, allergic disease, and autoimmune disorders may also be associated with low IgA levels. The reasons 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 patients. No causative defect in IgA genes has been identified, and the surface IgA molecules on these patients’ B cells appear to be expressed normally. A gene outside of the immunoglobulin 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 accompanied 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 deficiency of IgA and sometimes of IgE. The syndrome is characterized 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 immune deficiency and the other defects in ataxia telangiectasia remains obscure. IMMUNE DISORDERS INVOLVING THE THYMUS Several immunodeficiency syndromes are grounded in failure 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 regulatory 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 deletion in the embryo of a region on chromosome 22, causes immunodeficiency along with characteristic facial abnormalities, hypoparathyroidism, and congenital heart disease (Figure 19-4). The stage at which the causative developmental defect occurs has been determined, and the syndrome is sometimes called the third and fourth pharyngeal pouch syndrome 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 antibody 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 intrauterine 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 presentation 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 development. In some patients, B cells are normal, whereas in others a B-cell deficiency is secondary to the T-cell defect. Affected 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 affect 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 phagocytic processes may be faulty; these include cell motility, adherence to and phagocytosis of organisms, and killing by macrophages. REDUCTION IN NEUTROPHIL COUNT As described in Chapter 2, neutrophils are circulating granulocytes with phagocytic function. Quantitative deficiencies in neutrophils can range from an almost complete absence of cells, called agranulocytosis, to a reduction in the concentration of peripheral blood neutrophils below 1500/mm3 , called granulocytopenia or neutropenia. These quantitative deficiencies may result from congenital defects or may be acquired 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 reduced 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 condition show severe neutropenia, with counts of less than 200 neutrophils/mm3 . These children suffer from frequent bacterial 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 neutrophils. Experimental evidence suggests that this genetic defect results in decreased production of granulocyte colonystimulating 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 destroy 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 phagocytes 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 infection. CGD patients are not subject to infection by those bacteria, such as pneumococcus, that generate their own hydrogen 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 related defects may lead to CGD; these include a missing or defective 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 general 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 observation prompted clinical trials of IFN- for CGD patients. Encouraging 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 characteristic dysplasia of ears and mouth and abnormally long distance between 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 patients 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 regulation 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 molecules and are required to facilitate cellular interaction. Three of these, LFA-1, Mac-1, and gp150/95 (CD11a, b, and c, respectively) 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 bacteria as well as various fungi. Impairment of adhesion of leukocytes 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 survive into their forties. The reason for the variable disease phenotype 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 complement deficiencies are associated with increased susceptibility to bacterial infections and/or immune-complex diseases. One of these complement disorders, a deficiency in properdin, which stabilizes the C3 convertase in the alternative complement pathway, is caused by a defect in a gene located 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 disorders, there are several treatment possibilities. In addition to the drastic option of total isolation from exposure to any microbial 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 either intravenously or subcutaneously protects against recurrent infection in many types of immunodeficiency. Maintenance of reasonably high levels of serum immunoglobulin (5 mg/ml serum) will prevent most common infections in the agammaglobulinemic patient. This is generally accomplished by the administration of immunoglobulin that has been selected for antibodies directed against a particular organism. Recent advances in the preparation of human monoclonal antibodies and in the ability to genetically engineer chimeric antibodies with mouse V regions and humanderived C regions make it possible to prepare antibodies specific for important pathogens (see Chapter 5). Advances in molecular biology make it possible to clone the genes that encode other immunologically important proteins, such as cytokines, and to express these genes in vitro, using bacterial or eukaryotic expression systems. The availability 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 effective for patients with CGD, and the use of recombinant IL-2 may help to restore immune function in AIDS patients. Recombinant adenosine deaminase has been successfully administered to ADA deficient SCID patients. Cell replacement as therapy for immunodeficiencies has been made possible by recent progress in bone-marrow transplantation (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 manipulate 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 successful 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 infant. Because this therapy has been used only in recent years, it is not known whether transplantation cures the immunodeficiency permanently. A variation of bone-marrow transplantation is the injection of paternal CD34 cells in utero when the birth of an infant with SCID is expected. Two infants 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, replacement 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 defective gene. The transfected cells are then returned to the patient. 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 primary immunodeficiency for a variety of experimental purposes. 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 recessive 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 together in this mutant mouse. A gene that controls development 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 cannot 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 conditions 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