AIDs and ot munodeficiencies cHAPTER 19 RE19. A nude mouse(nu/nu). This defect leads to ab- munodeficiency / Courtesy of the Jackson Laboratory, Bar Harbor, of a thymus or a vestigial thymus and cell-mediated im- Maine. immunodeficiency in the nude mouse can be reversed by a finding suggests that the defective enzyme can function thymic transplant. Because they can permanently tolerate partly in T-and B-cell development, allowing normal differ- both allografts and xenografts, they have a number of practi- entiation of a small percentage of precursor cells. More cal experimental uses. For example, hybridomas or solid tu- recently, immunodeficient SCID-Ilike mice have been devel mors from any origin may be grown as ascites or as oped by deletion of the recombination-activating enzy implanted tumors in a nude mouse. It is known that the nude (RAG-1 and rAg-2) responsible for the rearrangement of mouse does not completely lack T cells; rather, it has a lim- immunoglobulin or T-cell-receptor genes in both B-andt ited population that increases with age. The source of theset cell precursors(RAG knockout mice). This gives rise to a de- cells is not known; an intriguing possibility is that there is an fect in both B and T cells of the mouse; neither can rearrange extrathymic source of mature T cells. However, it is more the genes for their receptor and thus neither proceeds along a likely that the T cells arise from the vestigial thymus. The ma- normal developmental path. Because cells with abnormal re- jority of cells in the circulation of a nude mouse carry T-cell arrangements are eliminated in vivo, both B and T cells are receptors of the y8 type instead of the aB type that prevails absent from the lymphoid organs of the RAG knockout in the circulation of a normal mouse mouse. In addition to providing a window into possible causes of combined T-and B-cell immunodeficiency, the THE SCID MOUSE SCID mouse has proven extremely useful in studies of cellu In 1983, Melvin and Gayle Bosma and their colleagues de- lar immunology. Because its rejection mechanisms do not scribed an autosomal recessive mutation in mice that gave operate, the SCID mouse can be used for studies on cells or rise to a severe deficiency in mature lymphocytes. They des- organs from various sources. For example, immune precur- ignated the trait sCID because of its similarity to human se- sor cells from human sources may be used to reestablish the shown to have early B- and T-lineage cells, but there was elop in a normal fashion and, as a result, the SCid mouse virtual absence of lymphoid cells in the thymus, spleen, circulation will contain immunoglobulin of human origi lymph nodes, and gut tissue, the usual locations of functional In one important application, these SCID mice are infected Tand B cells. The precursor T and B cells in the SCID mouse with HIV-1. Although normal mice are not susceptible to appeared to be unable to differentiate into mature functional HIV-1 infection, the SCID mouse reconstituted with human B and T lymphocytes. Inbred mouse lines carrying the SCID lymphoid tissue (SCID-Hu mouse) provides an animal defect have been derived and studied in great detail. The model in which to test therapeutic or prophylactic strategies SCID mouse can neither make antibody nor carry out against Hiv infection of the transplanted human lymphoid delayed-type hypersensitivity(DTH) or graft-rejection re- actions. If the animals are not kept in an extremely clean environment, they succumb to infection early in life. Cells other than lymphocytes develop normally in the SCid mouse;red blood cells, monocytes, and granulocytes are AIDS and other Acquired or sent and functional SCID mice may be rendered immuno- Secondary Immunodeficiencies normal mice As described above, a variety of defects in the immune sys- The mutation in a DNa protein kinase that causes mouse tem give rise to immunodeficiency. In addition to the pri- SCID is a so-called"leaky"mutation, because a certain num- mary immunodeficiencies, there ber of SCid mice do produce immunoglobulin. About half secondary, immunodeficiencies. One that has been known of these leaky SCid mice can also reject skin allografts. This for some time is called acquired hypogammaglobulinemia
immunodeficiency in the nude mouse can be reversed by a thymic transplant. Because they can permanently tolerate both allografts and xenografts, they have a number of practical experimental uses. For example, hybridomas or solid tumors from any origin may be grown as ascites or as implanted tumors in a nude mouse. It is known that the nude mouse does not completely lack T cells; rather, it has a limited population that increases with age. The source of these T cells is not known; an intriguing possibility is that there is an extrathymic source of mature T cells. However, it is more likely that the T cells arise from the vestigial thymus. The majority of cells in the circulation of a nude mouse carry T-cell receptors of the type instead of the type that prevails in the circulation of a normal mouse. THE SCID MOUSE In 1983, Melvin and Gayle Bosma and their colleagues described an autosomal recessive mutation in mice that gave rise to a severe deficiency in mature lymphocytes. They designated the trait SCID because of its similarity to human severe combined immunodeficiency. The SCID mouse was shown to have early B- and T-lineage cells, but there was a virtual absence of lymphoid cells in the thymus, spleen, lymph nodes, and gut tissue, the usual locations of functional T and B cells. The precursor T and B cells in the SCID mouse appeared to be unable to differentiate into mature functional B and T lymphocytes. Inbred mouse lines carrying the SCID defect have been derived and studied in great detail. The SCID mouse can neither make antibody nor carry out delayed-type hypersensitivity (DTH) or graft-rejection reactions. If the animals are not kept in an extremely clean environment, they succumb to infection early in life. Cells other than lymphocytes develop normally in the SCID mouse; red blood cells, monocytes, and granulocytes are present and functional. SCID mice may be rendered immunologically competent by transplantation of stem cells from normal mice. The mutation in a DNA protein kinase that causes mouse SCID is a so-called “leaky” mutation, because a certain number of SCID mice do produce immunoglobulin. About half of these leaky SCID mice can also reject skin allografts. This finding suggests that the defective enzyme can function partly in T- and B-cell development, allowing normal differentiation of a small percentage of precursor cells. More recently, immunodeficient SCID-like mice have been developed by deletion of the recombination-activating enzymes (RAG-1 and RAG-2) responsible for the rearrangement of immunoglobulin or T-cell–receptor genes in both B- and Tcell precursors (RAG knockout mice). This gives rise to a defect in both B and T cells of the mouse; neither can rearrange the genes for their receptor and thus neither proceeds along a normal developmental path. Because cells with abnormal rearrangements are eliminated in vivo, both B and T cells are absent from the lymphoid organs of the RAG knockout mouse. In addition to providing a window into possible causes of combined T- and B-cell immunodeficiency, the SCID mouse has proven extremely useful in studies of cellular immunology. Because its rejection mechanisms do not operate, the SCID mouse can be used for studies on cells or organs from various sources. For example, immune precursor cells from human sources may be used to reestablish the SCID mouse’s immune system. These human cells can develop in a normal fashion and, as a result, the SCID mouse circulation will contain immunoglobulin of human origin. In one important application, these SCID mice are infected with HIV-1. Although normal mice are not susceptible to HIV-1 infection, the SCID mouse reconstituted with human lymphoid tissue (SCID-Hu mouse) provides an animal model in which to test therapeutic or prophylactic strategies against HIV infection of the transplanted human lymphoid tissue. AIDS and Other Acquired or Secondary Immunodeficiencies As described above, a variety of defects in the immune system give rise to immunodeficiency. In addition to the primary immunodeficiencies, there are also acquired, or secondary, immunodeficiencies. One that has been known for some time is called acquired hypogammaglobulinemia. AIDS and Other Immunodeficiencies CHAPTER 19 441 FIGURE 19-5 A nude mouse (nu/nu). This defect leads to absence of a thymus or a vestigial thymus and cell-mediated immunodeficiency. [Courtesy of the Jackson Laboratory, Bar Harbor, Maine.]
442 PART IV The Immune System in Health and Disease (As mentioned above, this condition is sometimes confused tered opportunistic infections. More complete evaluation of with common variable immunodeficiency, a condition that the patients showed that they had in common a marked defi- shows genetic predisposition. The origin of acquired hy- ciency in cellular immune responses and a significant de- pogammaglobulinemia is unknown, and its major symptom, crease in the subpopulation of T cells that carry the Cd4 recurrent infection, manifests itself in young adults. The pa- marker(T helper cells. When epidemiologists examined the tients generally have very low but detectable levels of total background of the first patients with this new syndrome, it immunoglobulin. T-cell numbers and function may be was found that the majority of those afflicted were homosex ormal. but there are some cases with t-celll defects and these ual males as the number of aids cases increased and the may grow more severe as the disease progresses. The disease disease was recognized throughout the world, persons found is generally treated by immunoglobulin therapy, allowing pa- to be at high risk for AIDS were homosexual males, promis- tients to survive into their seventh and eighth decades. Unlike cuous heterosexual individuals of either sex and their part- similar deficiencies described above there is no evidence for ners, intravenous drug users, persons who received blood or genetic transmission of this disease. Mothers with acquired blood products prior to 1985, and infants born to HIv- hypogammaglobulinemia deliver normal infants. Howev infected mothe at birth the infants will be deficient in circulating im Since its discovery in 1981, AIDS has increased to epi munoglobulin, because the deficiency in maternal circula- demic proportions throughout the world. As of December tion is reflected in the infant 2000, the cumulative total number of persons in the United Another form of secondary immunodeficiency, known as States reported to have AIdS was 688, 200, and of these ap- gent-induced immunodeficiency, results from exposure to proximately 420,000 have died. Although reporting of AIDS any of a number of chemical and biological agents that in- cases is mandatory, many states do not require reporting of duce an immunodeficient state. Certain of these are drugs cases of Hiv infection that have not yet progressed to aIDS used to combat autoimmune diseases such as rheumatoid Therefore there is no official count of the number of hiv- arthritis or lupus erythematosis. Corticosteroids, which are infected individuals; as many as 1 million Americans are esti commonly used for autoimmune disorders, interfere with mated to be infected. Although the death rate from AIdS has the immune response in order to relieve disease symptoms. decreased in recent years because of improved treatments, Similarly, a state of immunodeficiency is deliberately in- AIDS remains among the leading killers of persons in the duced in transplantation patients who are given immuno- 25-44-year-old age range in this country( Figure 19-6). The suppressive drugs, such as cyclosporin A, in order to blunt fact that the number of yearly aids deaths has leveled off is the attack of the immune system on transplanted organs. As encouraging, but does not indicate an end to the epidemic in will be described in Chapter 21, there are recent efforts to use this country; there were an estimated 45,000 persons newly more specific means of inducing tolerance to allografts to infected in 2000 circumvent the unwanted side effects of general immuno- suppression. The mechanism of action of the immunosup- In addition, cytotoxic drugs or radiation treatments given to treat various forms of cancer frequently damage the dividing cells in the body, including those of the immune system, and 30 induce a state of immunodeficiency as an unwanted conse- 3 Cancer quence. Patients undergoing such therapy must be moni- a tored closely and treated with antibiotics or immunoglob- 20 Heart disease ulin if infection appears HIV/AIDS Has Claimed Millions HIV infection of Lives Worldwide In recent years, all other forms of immunodeficiency have been overshadowed by an epidemic of severe immunodef 84858687888990919293949596979899° ciency caused by the infectious agent called human immun deficiency virus 1, or HIV-1. The disease that HIv-1 causes. acquired immunodeficiency syndrome(AIDS)was first re- FIGURE 19-6 Death rates of the leading causes of death in per ported in the United States in 1981 in Los angeles, New York, sons aged 25-44 years in the United States for the years 1982-99 mocystis carinii, which causes a pneumonia called PCP(P. death in this ag the period 1993 to 1995. The recent carinii pneumonia) in persons with immunodeficiency. In decrease in AIDS deaths in the United States is attributed to im- addition to PCP, some patients had Kaposi's sarcoma, an provements in anti-HIV drug therapy, which prolongs the lives of pa- extremely rare skin tumor, as well as other, rarely encoun- tients /National Vital Statistics Report 1
(As mentioned above, this condition is sometimes confused with common variable immunodeficiency, a condition that shows genetic predisposition.) The origin of acquired hypogammaglobulinemia is unknown, and its major symptom, recurrent infection, manifests itself in young adults. The patients generally have very low but detectable levels of total immunoglobulin. T-cell numbers and function may be normal, but there are some cases with T-cell defects and these may grow more severe as the disease progresses. The disease is generally treated by immunoglobulin therapy, allowing patients to survive into their seventh and eighth decades. Unlike similar deficiencies described above, there is no evidence for genetic transmission of this disease. Mothers with acquired hypogammaglobulinemia deliver normal infants. However, at birth the infants will be deficient in circulating immunoglobulin, because the deficiency in maternal circulation is reflected in the infant. Another form of secondary immunodeficiency, known as agent-induced immunodeficiency, results from exposure to any of a number of chemical and biological agents that induce an immunodeficient state. Certain of these are drugs used to combat autoimmune diseases such as rheumatoid arthritis or lupus erythematosis. Corticosteroids, which are commonly used for autoimmune disorders, interfere with the immune response in order to relieve disease symptoms. Similarly, a state of immunodeficiency is deliberately induced in transplantation patients who are given immunosuppressive drugs, such as cyclosporin A, in order to blunt the attack of the immune system on transplanted organs. As will be described in Chapter 21, there are recent efforts to use more specific means of inducing tolerance to allografts to circumvent the unwanted side effects of general immunosuppression. The mechanism of action of the immunosuppressive agents varies, although T cells are a common target. In addition, cytotoxic drugs or radiation treatments given to treat various forms of cancer frequently damage the dividing cells in the body, including those of the immune system, and induce a state of immunodeficiency as an unwanted consequence. Patients undergoing such therapy must be monitored closely and treated with antibiotics or immunoglobulin if infection appears. HIV/AIDS Has Claimed Millions of Lives Worldwide In recent years, all other forms of immunodeficiency have been overshadowed by an epidemic of severe immunodeficiency caused by the infectious agent called human immunodeficiency virus 1, or HIV-1. The disease that HIV-1 causes, acquired immunodeficiency syndrome (AIDS) was first reported in the United States in 1981 in Los Angeles, New York, and San Francisco. A group of patients displayed unusual infections, including the opportunistic fungal pathogen Pneumocystis carinii, which causes a pneumonia called PCP (P. carinii pneumonia) in persons with immunodeficiency. In addition to PCP, some patients had Kaposi’s sarcoma, an extremely rare skin tumor, as well as other, rarely encountered opportunistic infections. More complete evaluation of the patients showed that they had in common a marked deficiency in cellular immune responses and a significant decrease in the subpopulation of T cells that carry the CD4 marker (T helper cells.) When epidemiologists examined the background of the first patients with this new syndrome, it was found that the majority of those afflicted were homosexual males. As the number of AIDS cases increased and the disease was recognized throughout the world, persons found to be at high risk for AIDS were homosexual males, promiscuous heterosexual individuals of either sex and their partners, intravenous drug users, persons who received blood or blood products prior to 1985, and infants born to HIVinfected mothers. Since its discovery in 1981, AIDS has increased to epidemic proportions throughout the world. As of December 2000, the cumulative total number of persons in the United States reported to have AIDS was 688,200, and of these approximately 420,000 have died. Although reporting of AIDS cases is mandatory, many states do not require reporting of cases of HIV infection that have not yet progressed to AIDS. Therefore, there is no official count of the number of HIVinfected individuals; as many as 1 million Americans are estimated to be infected. Although the death rate from AIDS has decreased in recent years because of improved treatments, AIDS remains among the leading killers of persons in the 25–44-year-old age range in this country (Figure 19-6). The fact that the number of yearly AIDS deaths has leveled off is encouraging, but does not indicate an end to the epidemic in this country; there were an estimated 45,000 persons newly infected in 2000. 442 PART IV The Immune System in Health and Disease 40 35 30 25 20 15 10 5 0 Deaths /100,000 population Year 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99* Unintentional injuries Cancer Heart disease Suicide Homicide Liver disease Stroke Diabetes HIV infection FIGURE 19-6 Death rates of the leading causes of death in persons aged 25–44 years in the United States for the years 1982–99 (* preliminary data). The heavy line shows that the death rate per 100,000 persons caused by AIDS surpassed any other single cause of death in this age range during the period 1993 to 1995. The recent decrease in AIDS deaths in the United States is attributed to improvements in anti-HIV drug therapy, which prolongs the lives of patients. [National Vital Statistics Report.]