* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Secondary Immunodeficiency I
Survey
Document related concepts
Gluten immunochemistry wikipedia , lookup
Hospital-acquired infection wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Immune system wikipedia , lookup
DNA vaccination wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Adaptive immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Innate immune system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
X-linked severe combined immunodeficiency wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Transcript
Immunodeficiency: Secondary Secondary article Article Contents . Introduction Sudhir Gupta, University of California, Irvine, California, USA Gabriel Fernandes, University of Texas, San Antonio, Texas, USA . Malnutrition . Malignancy . Infections Immune deficiencies that develop in previously immunologically intact individuals are called secondary immunodeficiencies; they are a result of diverse external factors (infections, surgery and trauma, malnutrition, drugs) and a number of human diseases, including malignancy, nephrotic syndrome and protein-losing enteropathy. Immunodeficiencies render the host markedly susceptible to viral and bacterial infections. Introduction Immune deficiencies that develop in previously immunologically intact individuals are called secondary immunodeficiencies; they are a result of diverse external factors (infections, surgery and trauma, malnutrition, drugs) and a number of human diseases, including malignancy, nephrotic syndrome and protein-losing enteropathy. Immunodeficiencies render the host markedly susceptible to viral and bacterial infections. Malnutrition Malnutrition is the most common cause of secondary immunodeficiency in the world. It is a serious problem, particularly among young children in most developing nations. In malnutrition, inadequacy of essential nutrients results in alterations in immune functions. The nutritional deficiencies usually involve varying degrees of protein and calorie deprivation (protein–calorie malnutrition). Based on the predominant deficiency, protein–calorie malnutrition has been divided into marasmus (caloric deficiency due to decreased intake of all food) and kwashiorkor (a deficiency of protein in a diet usually high in calories). Marasmus usually occurs early in infancy. The patients are grossly underweight and wasted; however, the oedema and skin changes observed in kwashiorkor are absent in marasmus. Kwashiorkor is more common during the second year of life and is characterized by the presence of growth retardation, dermatitis, oedema, moon facies, hepatomegaly and abnormal hair. There is an overlap between the two syndromes. Therefore, immunological changes in both syndromes will be discussed together as changes in protein–calorie malnutrition. In protein–calorie malnutrition, the thymus is atrophic and fibrotic. Changes are preferentially in the cortex; the number of thymocytes is markedly reduced, as is thymic . Drugs and Other Treatments . Nephrotic Syndrome . Protein-losing Enteropathy hormone production. Varying degrees of germinal centre depletion and depletion of paracortical cells in peripheral lymphoid tissue are observed. Other T cell-mediated changes include impaired delayed-type hypersensitivity (DTH) reaction; reduced lymphocyte proliferation in response to mitogens and antigens; decreased proportions and numbers of cluster of differentiation (CD) 41 T cells; and significantly increased levels of CD11 T cells. Serum immunoglobulin levels are normal or raised. Although serum immunoglobulin (Ig) A levels are often increased, there is a significant decrease in secretory IgA concentration. Raised levels of serum IgE have been reported; however, involvement of parasitic infestation has not been excluded. The numbers of CD201 B cells are reduced and the affinity of antibodies, especially for Tdependent antigens, is impaired. Antibodies to pneumococcal polysaccharide are normal. Type 1 T-helper (TH) cell cytokine (especially interferon g; IFNg) production is reduced. Macrophage-derived and lipopolysaccharidestimulated interleukin (IL)-1 production is reduced, but recovers after nutritional supplementation. Similarly, tumour necrosis factor a (TNFa) production increases after nutritional rehabilitation. Polymorphonuclear leucocyte (PMN) functional defects in protein–calorie malnutrition include impaired phagocytosis and intracellular killing, and altered mobility and chemotaxis. In experimental animals, protein deprivation is associated with decreased production of myeloid cells in the bone marrow and the mobilization of PMNs into inflammatory sites. This could be due to decreased production of granulocyte colony-stimulating factor. Natural killer (NK) cell activity is reduced even in the presence of exogenous IFNg. Following nutritional repletion, NK cell activity is normalized in the presence of IFNg. Therefore, in protein–calorie malnutrition, abnormalities of T cells, B cells, monocytes–macrophages and PMNs are present; however, T-cell deficiency is usually predominant. ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net 1 Immunodeficiency: Secondary Malignancy Although some form of immunodeficiency can be observed in the advanced stages of all types of malignancy, secondary immunodeficiency is commonly observed in lymphoid malignancies (leukaemia, lymphomas and plasma cell dyscrasias). Infections are common in lymphoid malignancies and the most common cause of death in lymphoid malignancy is infection. Lymphoma Antibody deficiency is observed in the advanced stages of nonHodgkin lymphoma; however, significant immune deficiency is a characteristic of Hodgkin disease. Hodgkin disease was the first lymphoma to be associated with abnormalities of the immune system. Immunological defects may be related to the clinical stage of the disease and the histological type (most severe defects are observed in stages III and IV, and in lymphocyte depletion histology). However, immune deficiency is observed even in asymptomatic subjects. Hodgkin disease is a classic example of T-cell deficiency in lymphoreticular malignancies. Lymphocyte depletion of lymphoid tissues, especially of T-cell areas, is well recognized and may be associated with peripheral blood lymphopenia. Both the proportion and absolute number of T cells are reduced. There appears to be an abnormal distribution of T-cell subsets between peripheral blood and the spleen. Lymphocyte locomotion is also abnormal, and this may be responsible for the abnormal distribution of T-cell subsets in the blood and spleen. Functional cell-mediated immune deficiency is characterized by impaired or absent DTH to recall antigens, and depressed proliferative response to mitogens, antigens and alloantigens. Prolonged allograft survival is observed in more than 50% of patients with Hodgkin disease. Impaired synthesis of cytokines has also been observed. Although the precise mechanism of immunosuppression in Hodgkin disease is not known, monocyte-mediated suppression appears to be one of the important mechanisms. In addition, certain plasma factors have been suggested to suppress the immune response. Levels of serum immunoglobulins are usually normal; however, in approximately 10% of patients either hyperimmunoglobulinaemia or hypogammaglobulinaemia may be observed. Secondary (IgG) antibody responses to specific antigens are usually normal, but in some patients primary antibody response (IgM) may be impaired. Specific antibody response to pneumococcal polysaccharide is normal. Total serum complement concentration is normal or raised. Phagocytic functions are usually intact, even in the late stages of the disease. Phagocytosis, chemotaxis and PMN mobilization are normal. 2 In summary, Hodgkin disease is associated with T-cell deficiency without significant changes in other components of the immune system. Leukaemia In contrast to patients with lymphoma, patients with acute leukaemia generally have normal T cell- and B cellmediated immunity until they have advanced to the terminal stage of the disease or have received chemotherapy. However, immune deficiency is commonly observed in patients with chronic lymphocytic leukaemia (CLL). Infections are the leading cause of death in CLL and in multiple myeloma (see below). There appears to be a block in the differentiation of B cells to plasma cells, resulting in hypogammaglobulinaemia and specific antibody defects. The incidence of hypogammaglobulinaemia in CLL varies among various reports, ranging from 34% to 70%. The levels of immunoglobulins vary with the duration of disease. Patients with CLL also have a generalized defect in specific antibody response to both protein and polysaccharide antigens (typhoid, diphtheria, tetanus, mumps, influenza, pneumococcal polysaccharide, Vibrio vaccine). There appears to be a correlation between levels of serum IgG and increased infection rate in CLL; no such correlation is observed with serum IgM levels. The frequency of infection is markedly reduced with intravenous immune globulin treatment. The malignant B cells express CD5 antigens on their surface. Although the proportion of T cells is reduced, absolute numbers are normal. When T cells are purified, on a cell per cell basis, Tcell functions in CLL are normal. Therefore, CLL represents a classical example of secondary immunodeficiency of B cells with essentially normal T-cell functions. Plasma cell dyscrasias Multiple myeloma and Waldenström macroglobulinaemia are the two most common plasma cell dyscrasias associated with immunodeficiency. Both disorders are associated with an increased incidence of infection. Immune deficiency is more common and more severe in multiple myeloma than in Waldenström macroglobulinaemia. Normal immunoglobulins appear to be decreased. There appears to be an inverse correlation between the levels of monoclonal immunoglobulin and normal immunoglobulins. Hypogammaglobulinaemia associated with multiple myeloma appears to be due to increased catabolism (which correlates with the levels of monoclonal immunoglobulin) and increased suppressor activity of monocytes. Specific antibody response to antigens is also impaired. T cell-mediated immunity is generally intact; however, decreased numbers of CD41 T cells and increased CD81 T cells have been observed in patients with multiple myeloma. Immunodeficiency: Secondary Infections A variety of infectious agents are known to induce immunosuppression. Therefore, immune deficiency is observed in a variety of bacterial, fungal, protozoal and viral infections, the latter being the most common clinical condition associated with secondary immunodeficiency. Some of the immunodeficiencies depend on the stage of infection and are transient; others are permanent (e.g. human immunodeficiency virus (HIV) infection). (e.g. pneumococcal and meningococcal vaccine). This abnormality of B-cell function appears to be due to dysregulation of T-cell function. The CD41 /CD81 Tcell ratio is decreased and levels of gd T cells are significantly increased. Although the mechanism of malaria-induced immunosuppression is unclear, deficiency of both IL-2 production and IL-2 receptor expression has been observed. In addition, patients with acute malaria have circulating IL-2 receptors, thereby potentially downregulating the response by binding secreted IL-2. Bacterial infections Viral infection The most common bacterium associated with immunodeficiency is Mycobacterium leprae. Tuberculoid leprosy displays pronounced T-cell immunity with low levels of antibodies, whereas lepromatous leprosy is characterized by severe T-cell deficiency with high antibody levels to M. leprae. T-cell deficiency in lepromatous leprosy is demonstrable by cutaneous anergy and in vitro failure to induce lymphocyte proliferation to soluble extract from M. leprae. CD41 T cells predominate in tuberculoid lesions, whereas CD81 T cells predominate in lepromatous lesions. However, no such alterations are observed in peripheral blood. T lymphocytes in lepromatous lesions are deficient in IL-2 production but express IL-2 receptor (CD25) and respond to IL-2. CD81 T cells from lepromatous lesions, but not from tuberculoid lesions, show suppressor activity, suggesting involvement of suppressor T cells in cutaneous anergy in lepromatous leprosy. Interestingly, the DTH response to other antigens may be intact, suggesting an antigen-specific suppression of T-cell response. A number of viruses can induce immunosuppression, including measles, influenza, adenoviruses, herpesviruses and HIV. Significant immunosuppression is observed with measles, herpesvirus and HIV infection, and therefore these are discussed in some detail. Measles Historically, measles provides the first evidence of viralinduced suppression of immune function. Measles virus can infect both T and B cells; however, for its replication, T and B cells have to be activated. Following a phase of viraemia, virus is present in both lymphocytes and macrophages, and is associated with lymphopenia and suppression of T-cell responses both in vitro and in vivo. Measles virus can suppress T-cell, NK-cell and B-cell functions. Suppression associated with measles infection is usually transient, although it can persist in some individuals. Herpes infections Fungal infections Certain fungal infections have been implicated in the pathogenesis of immune suppression. In vitro, Candida albicans is known to suppress the lymphocyte proliferative response to mitogens. Patients with chronic mucocutaneous candidiasis appear to have impaired DTH, lymphocyte proliferative response to mitogens and antigens, and defective PMN chemotaxis. Immunosuppression has also been observed in disseminated histoplasmosis. It is unclear whether the immunosuppression in severe fungal infection is due to general phenomena of immunological tolerance secondary to high antigen load or to certain fungal antigens that are truly immunosuppressive. Protozoal infections Acute malaria (Plasmodium falciparum infection) is associated with polyclonal hyperimmunoglobulinaemia, multiple autoantibodies and suppression of specific antibody response to both protein antigens (e.g. tetanus toxoid, Salmonella typhi) and polysaccharide antigens Infections by a group of herpes virus (e.g. Epstein–Barr virus, cytomegalovirus (CMV) and herpes simplex virus (HSV)) can be associated with immune suppression. Generally, immunosuppression occurs during the acute stage of infection and is transient. However, in some cases persistence of infection may be associated with clinical sequelae. Epstein–Barr virus The most common syndrome associated with acute Epstein–Barr virus infection is infectious mononucleosis. Immunological changes are characterized by T-cell immunosuppression, which could be due to T-cell receptorspecific impairment. Acute infectious mononucleosis is associated with impaired DTH, decreased proliferative response to mitogens and antigens, decreased NK cell activity, increased IL-10 production, and increased B-cell proliferation and differentiation to produce polyclonal immunoglobulin. Atypical T cells in infectious mononucleosis are CD81 cytotoxic T cells. These immune alterations are transient, but they can lead to long-term immune dysregulation and clinical complications such as 3 Immunodeficiency: Secondary X-linked lymphoproliferative syndrome, Burkitt lymphoma and nasopharyngeal carcinoma. Cytomegalovirus CMV is one of the most powerful immunosuppressive viruses in the herpesvirus family. Immunosuppression appears to be mediated by infected macrophages. CMVinfected macrophages are impaired in their capacity to present antigens to autologous lymphocytes. The macrophage defect may be due to production of IL-1 inhibitor by CMV. Carriers of CMV have an increased number of NK cells with suppressive activity. Prolonged impairment of lymphocyte proliferation to mitogens is observed in children with congenital CMV infection. Herpes simplex virus Acute HSV-1 or HSV-2 infection is associated with immune suppression resulting in depressed lymphocyte transformation and production of specific antibodies. It has been suggested that this is due to increased suppressor T-cell activity; however, HSV glycoprotein can bind to Fc receptor and inhibit phagocytosis, and can also inhibit complement-mediated cytotoxicity. Patients with recurrent HSV infections also have immunological abnormalities characterized by lymphopenia and impaired phagocytosis. Influenza virus Acute influenza infection is associated with T lymphopenia and decreased lymphocyte proliferation to mitogens, increased NK-cell activity, and production of IL-1 and TNFa. In contrast to T-cell lymphopenia, acute influenza is associated with expansion of gd T cells. Immunosuppression appears to be due to increased suppressor T-cell activity and decreased IL-2 production. Increased NK-cell activity appears to be secondary to increased interferon production. Human immunodeficiency virus HIV infection is associated with almost every immunological abnormality, and it is not possible to discuss these in detail here. There is a generalized lymphopenia, shared by all subsets of lymphocytes, that is dependent upon the stage of infection. During the acute stage of infection, there is an expansion of CD81 cytotoxic T cells; however, as the diseases progresses, several T-cell abnormalities are observed, including selective depletion of CD41 T cells resulting in an abnormally low ratio of CD41 /CD81 T cells; decreased proliferative response to mitogens, soluble antigens, autoantigens and alloantigens; decreased production of TH1 cytokines, and increased production of TH2 cytokines; and impaired cytotoxic T-cell function. Blymphocyte abnormalities include impaired specific antibody response to neoantigens; poor primary specific (IgM) antibody response; polyclonal hyperimmunoglobulinae4 mia; increased proportion of circulating B cells; and increased circulating immune complexes. NK-cell activity is markedly impaired. Macrophages are defective in presenting antigens and in the production of various cytokines. Levels of complement components are normal or increased (as acute-phase reactants). In HIV infection, almost every component of the immune system is involved; however, impaired T-cell abnormalities are mostly predominant. Drugs and Other Treatments The recognition and discovery of diseases associated with abnormal immune response have resulted in the discovery of drugs or agents that are capable of inhibiting undesirable immune responses. This group of agents, which are nonspecific inhibitors of immune response (immunosuppressive agents), can be classified as physical, chemical or biological agents. Physical agents Irradiation and depletion of lymphocytes by thoracic duct drainage are two physical means of immunosuppression. Because thoracic duct drainage is no longer used in clinical settings, the immunosuppressive effects of irradiation are discussed. Specific immune responses are predominantly affected. Although phagocytosis is relatively resistant to irradiation, low-dose irradiation suppresses antigen processing by macrophages. The effect on antibody response is dependent on the dose of radiation. In contrast, T cellmediated immunity is significantly suppressed by irradiation. Studies of fractionated total lymphoid irradiation in intractable rheumatoid arthritis and craniospinal radiation in children with acute lymphocytic leukaemia demonstrated that radiation produces a significant effect on T cell-mediated immunity, evident by pronounced lymphocytopenia (predominantly of CD41 T cells), impaired lymphocyte proliferation to mitogens and antigens, and decreased IgM and IgG production in response to pokeweed mitogen (a T cell-dependent function). Levels of CD81 T cells and NK cells are relatively normal or increased. Chemical agents Immunosuppressive drugs can be divided into corticosteroids, cytotoxic drugs, and cyclosporin and allied drugs. Corticosteroids Corticosteroids are widely used as antiinflammatory and immunosuppressive agents. Glucocorticoids are the most effective steroids used for immunosuppression. The effects of steroids are mediated by binding to specific receptors in Immunodeficiency: Secondary the cytoplasm. These translocate to the nucleus when coupled with steroids and interact with chromatin to regulate gene expression. More recently, it has been shown that the major mechanism of corticosteroid-mediated immunosuppression is its inhibition of the activation of nuclear transcription factor NF-kB. The immunosuppressive effects of corticosteroids can be grouped into two categories: effect on leucocyte traffic and effect on leucocyte functions. After a single injection of glucocorticoid there is a rapid decrease in the total number of lymphocytes (that is predominantly shared by CD41 T cells) due to sequestration of T lymphocytes in the lymphoid compartment. The total number of lymphocytes as well as CD41 T cells returns to normal levels 48 h after administration of glucocorticoid. The B cell number is slightly reduced and the NK cell number is unaffected, but the monocytopenia remains significant. In general, corticosteroids preferentially inhibit T-cell functions. They inhibit the entry of cells into the G1 phase and arrest the progression of activated lymphocytes from the G1 to the S phase of the cell cycle. Corticosteroids inhibit the lymphocyte proliferative response to mitogens, antigens, alloantigens and autoantigens. Prolonged treatment also results in impaired DTH. Corticosteroids inhibit production of IL-1, IL-2, TNFa, IL-4 and IL-6. Prolonged treatment with corticosteroids may result in a modest decrease in the serum level of IgG and possibly of IgA, but not IgM. Specific antibody response is generally unaffected. Steroids have no effect on NK cells and antibodydependent cellular cytotoxicity (ADCC). Steroids have a striking effect on monocyte–macrophage functions. They suppress bactericidal activity, interfere with antigen presentation, impair chemotaxis, decrease response to migration inhibition factor, and suppress expression of Fc and complement receptor. Corticosteroids do not alter PMN chemotaxis or lysosomal enzymes; however, steroids decrease the release of nonlysosomal enzymes (e.g. collagenase and plasminogen activator). Cytotoxic agents Cytotoxic agents are a group of chemicals with the pharmacological property of killing self-replicating cells, including lymphocytes. Immunosuppressive activity of these agents is not limited to any single lymphocyte subset; rather, they affect, to a varying extent, all immunocompetent cells, thereby producing generalized immunosuppression. These agents can produce differential cytotoxicity for T and B cells. They are also cytotoxic to nonlymphoid proliferating cells, resulting in their toxicity. Cytotoxic agents can be classified into three major groups. Group I agents exert their maximum immunosuppressive effect when administered just before antigen challenge (e.g. nitrogen mustards). Group II agents suppress immune response if administered following antigenic challenge (e.g. azathioprine and methotrexate). Group III drugs show inhibitory effects if administered either before or after antigenic stimulation (e.g. cyclophosphamide). Azathioprine Azathioprine is a purine analogue that is rapidly converted in vivo to 6-mercaptopurine. Azathioprine is cytostatic for cells when they enter the S phase (deoxyribonucleic acid (DNA) synthesis) of the cell cycle. 6-Mercaptopurine exerts its effect after metabolism to thioinosinic acid, by competitive inhibition of purine metabolism and by incorporation into DNA as fraudulent base. Therefore, the major effect of azathioprine is to inhibit DNA synthesis, resulting in a decreased rate of cell replication. It preferentially inhibits T-cell responses (response to pokeweed mitogen is greater than that to phytohaemagglutinin) as compared to B-cell responses. However, both T- and B-cell responses are inhibited. Primary antibody response (IgM) is inhibited more easily than secondary (IgG) antibody response. Azathioprine significantly reduces the numbers of NK cells and both NK and ADCC activity. Azathioprine has no effect on monocyte chemotaxis, phagocytosis or microbial killing. Cyclophosphamide Cyclophosphamide is an alkylating agent that is toxic for cells at all stages of the mitotic cycle, including the intermitotic (G0) phase. However, it is more toxic for cycling than for resting cells (G0). The cytotoxic effects are due to azathioprine’s ability to crosslink DNA chains and interfere with DNA replication. Although both T and B cells are susceptible to the immunosuppressive effects of cyclophosphamide, it is more cytotoxic for B cells than for T cells. Suppressor T cells are more susceptible than helper T cells to the inhibitory effect of azathioprine. Administration of azathioprine is associated with lymphopenia (CD41 4 CD81 ), depressed DTH response to mumps and Candida, impaired lymphocyte transformation to mitogens (phytohaemagglutinin, pokeweed mitogen), decreased levels of immunoglobulins, and suppressed primary antibody response. Cyclosporin A and related drugs The immunosuppressive property of cyclosporin A (CsA) was discovered in 1976; since then, FK-506 and rapamycin have been shown to have similar properties and analogous mechanisms of action. CsA has been used extensively in a variety of disorders; FK-506 has just started to be used in clinical research trials; and rapamycin has not yet been used in clinical trials. Therefore, CsA alone will be discussed. Cyclosporin is a noncytotoxic immunosuppressive agent, which has a powerful inhibitory effect on T cells, on antigen presentation by macrophages, and on baso5 Immunodeficiency: Secondary phils. It has a preferential effect on CD41 T cells. CsA inhibits lymphocyte proliferation in response to mitogens, antigens, alloantigens and autoantigens. It inhibits IL-2 messenger ribonucleic acid (mRNA) and protein synthesis but not IL-2 receptor expression or the proliferative response of T cells to exogenous IL-2. CsA also inhibits IL-3, IL-4, IFNg, TNFa and granulocyte–macrophage colony-stimulating factor mRNA. B cells are relatively resistant to CsA; however, specific antibody response to Tdependent antigens is inhibited by CsA. CsA inhibits major histocompatibility complex II expression on monocytes and the antigen-presenting property of monocytes–macrophages and Langerhans cells. The molecular mechanisms involved in CsA-mediated immunosuppression include binding of CsA to intracellular cyclophilin; the CsA– cyclophilin complex then binds to calcineurin (a calcium– calmodulin-dependent phosphatase B), and finally inhibition of calcineurin results in inhibition of nuclear transcription factor, NF-AT, and gene expression of certain cytokines, including IL-2. FK-506 has the same mechanism, except that it binds to a different immunophilin, FK-binding protein (FKBP). However, the effects of rapamycin are different, even though it binds to FKBP. Rapamycin does not inhibit early genes by activated T cells. In contrast, it inhibits the effect of IL-2 binding to IL2 receptor. Biological agents Antilymphocyte globulin Antilymphocyte globulin (ALG) is used to prevent allograft rejection and in the treatment of aplastic anaemia. Administration of ALG leads to lymphoid depletion from both the peripheral blood and lymphoid tissues. DTH and lymphocyte transformation to mitogens and antigens are impaired. Primary antibody response to neoantigens is impaired, but secondary antibody response is unaffected. ALG poses a slight risk of lymphoproliferative malignancy in posttransplant patients. Nephrotic Syndrome Serum electrophoresis from patients with idiopathic nephrotic syndrome shows decreased albumin and gglobulin levels but an increased a2-globulin concentration. Of the immunoglobulins, the greatest depletion occurs in IgG. Serum IgG and IgA levels may remain low during remission, although IgM concentration is increased. In idiopathic nephrotic syndrome the antibody response to bacterial antigen (pneumococcus polysaccharide) is impaired, whereas response to viral antigen (influenza vaccine) is normal. T-cell number and functions are generally normal except during uraemia. Complement levels are increased. Neutrophil chemotaxis is impaired. Protein-losing Enteropathy Although a number of disease conditions are associated with protein loss via the gut, protein loss occurs most commonly in patients with gastrointestinal surface abnormalities (e.g. regional enteritis, ulcerative colitis, sprue and coeliac disease). Reduction in the levels of all immunoglobulins is associated with a normal or increased synthetic rate and increased fractional catabolic rates. Albumin and IgG concentrations are markedly decreased, IgM level is mildly depressed, and a2-macroglobulin level is normal. However, the specific antibody response is normal and increased susceptibility to infection is unusual. In addition, lymphopenia is observed in protein-losing enteropathy associated with regional enteritis and intestinal lymphangiectasia. DTH is impaired, as is lymphocyte response to mitogens. The CD41 /CD81 T-cell ratio is decreased. In summary, a number of external factors and certain chemical and biological agents induce a wide spectrum of secondary immunodeficiencies; many of them are transient, but others have long-lasting effects on the immune system. Anti-T cell monoclonal antibodies A number of monoclonal antibodies against T-cell surface antigens have been used in allogeneic organ transplantation, to deplete T cells from the donor marrow before allogeneic bone marrow transplantation, and for the treatment of acute graft-versus-host disease in patients undergoing allogeneic bone marrow transplantation. The most common monoclonal antibody used is against CD3 antigen. This antibody causes marked lymphocytopenia associated with severe impairment of T-cell functions. It should be noted that treatment with anti-CD3 monoclonal antibody is associated with an increased incidence of malignancy. 6 Further Reading Craig L and Hecker AL (eds) (1996) Nutritional Immunomodulation in Disease and Health Promotion. Ohio: Ross Production Division Columbus. Fernandes G (1991) Nutrition and immunity. Encyclopedia of Human Biology, vol. 5, pp. 503–516. New York: Academic Press. Gupta S (1992) Malnutrition and lymphocyte response in humans. In: Cunningham-Rundles S (ed.) Nutritional Modulation of Immune Responses, pp. 441–454. New York: Marcel Dekker. Lachmann PJ, Peters DK, Rosen FS and Walport MJ (eds) (1993) Clinical Aspects of Immunology. Oxford: Blackwell Scientific. Steihm ER (ed). (1996) Immunologic Disorders in Infants and Children, 4th edn. Philadelphia, Pennsylvania: WB Saunders.