Acquired Secondary Immunodeficiencies

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Deficiencies of the immune system often develop because of abnormalities that are not genetic but acquired during life (Table 20-6). The most prominent of these

TABLE 20-6 Acquired Immunodeficiencies

Cause

Mechanism

HIV infection

Depletion of CD4+ T cells

Protein-calorie malnutrition

Metabolic derangements inhibit lymphocyte maturation and function

Irradiation and chemotherapy for cancer

Decreased bone marrow lymphocyte precursors

Cancer metastases and leukemia involving bone marrow

Reduced site of leukocyte development

Immunosuppression for transplants, autoimmune diseases

Reduced lymphocyte activation

Removal of spleen

Decreased phagocytosis of microbes

abnormalities is HIV infection, and this is described in the next section. Acquired immunodeficiency diseases are caused by two main types of pathogenic mechanisms. First, immunosuppression may occur as a biologic complication of another disease process. Second, so-called iatrogenic immunodeficiencies may develop as complications of therapy for other diseases.

Diseases in which immunodeficiency is a common complicating element include malnutrition, neoplasms, and infections. Protein-calorie malnutrition is common in developing countries and is associated with impaired cellular and humoral immunity to microorganisms. Much of the morbidity and mortality that afflict malnourished people is due to infections. The basis for the immunodeficiency is not well defined, but it is reasonable to assume that the global metabolic disturbances in these individuals, caused by deficient intake of protein, fat, vitamins, and minerals, will adversely affect maturation and function of the cells of the immune system.

Patients with advanced widespread cancer are often susceptible to infection because of impaired cell-mediated and humoral immune responses to a variety of organisms. Bone marrow tumors, including cancers metastatic to marrow and leukemias that arise in the marrow, may interfere with the growth and development of normal lymphocytes and other leukocytes. In addition, tumors may produce substances that interfere with lymphocyte development or function. An example of malignancy-associated immunodeficiency is the impairment in T cell function commonly observed in patients with a type of lymphoma called Hodgkin's disease. This defect was first characterized as an inability to mount a DTH reaction on intradermal injection of various common antigens to which the patients were previously exposed, such as Candida or tetanus toxoid. Other in vitro measures of T cell function, such as proliferative responses to polyclonal activators, are also impaired in patients with Hodgkin's disease. Such a generalized deficiency in DTH responses is called anergy. The cause of these T cell abnormalities is unknown.

Various types of infections lead to immunosuppres-sion. Viruses other than HIV are known to impair immune responses; examples include the measles virus and human T cell lymphotropic virus 1 (HTLV-1). Both viruses can infect lymphocytes, which may be a basis for their immunosuppressive effects. Like HIV, HTLV-1 is a retrovirus with tropism for CD4+ T cells; however, instead of killing helper T cells, it transforms them and produces an aggressive T cell malignant neoplasm called adult T cell leukemia/lymphoma (ATL). Patients with ATL typically have severe immunosuppression with multiple opportunistic infections. Chronic infections with Mycobacterium tuberculosis and various fungi frequently result in anergy to many antigens. Chronic parasitic infections may also lead to immunosuppression. For example, African children with chronic malarial infections have depressed T cell function, and this may be one reason why these children have an increased propensity to develop EBV-associated malignant tumors.

Iatrogenic immunosuppression is most often due to drug therapies that kill or functionally inactivate lymphocytes. Some drugs are given intentionally to immu-nosuppress patients, either for the treatment of inflammatory diseases or to prevent rejection of organ allografts. The most commonly used anti-inflammatory and immunosuppressive drugs are corticosteroids and cyclosporine, respectively. Various chemotherapeutic drugs are administered to patients with cancer, and these drugs are usually cytotoxic to mature and developing lymphocytes as well as to granulocyte and monocyte precursors. Thus, cancer chemotherapy is almost always accompanied by a period of immunosuppression and risk for infection. Iatrogenic immunosuppression and tumors involving the bone marrow are the most common causes of immunodeficiency in developed countries.

One other form of acquired immunosuppression results from the absence of a spleen caused by surgical removal of the organ after trauma and as treatment of certain hematologic diseases or by infarction in sickle cell disease. Patients without spleens are more susceptible to infection by some organisms, particularly encapsulated bacteria such as Streptococcus pneumoniae. This enhanced susceptibility is partly due to defective phagocytic clearance of opsonized blood-borne microbes, an important physiologic function of the spleen, and partly because of defective antibody responses resulting from the absence of marginal zone B cells.

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