Immunodeficiency disorders

ANATOMY OR SYSTEM AFFECTED: Immune system

DEFINITION: Genetic or acquired disorders that result from disturbances in the normal functioning of the immune system

CAUSES: Genetic disorders, infections, damage from drug or radiation treatments, environmental factors

SYMPTOMS: Vary; can include recurrent infections, scaly inflammation of skin, chronic inflammations of internal organs and bones, fever, fatigue

DURATION: Often chronic

TREATMENTS: Typically targeted at source of deficiency; can include antibody injections, antifungal medications, bone marrow transplantation, drug cocktails, alternative medicine (acupuncture, herbal medicine, meditation, homeopathy)

Causes and Symptoms

The defense of the body against foreign invaders is provided by the immune system. In nonspecific immunity, phagocytic cells engulf and destroy invading particles. Specific immunity consists of very specialized cell types that are synthesized in response to a particular type of foreign invader. Self-replicating stem cells within the give rise to lymphocytes, which mediate specific immunity. Lymphocytes establish self-replacing colonies within the thymus, spleen, and lymph nodes. The various categories of T lymphocytes are derived from the colonies, while B lymphocytes develop and mature within the bone marrow. B lymphocytes secrete highly specific antibodies that attack and some viruses.

T lymphocytes do not secrete antibodies. Cytotoxic T cells directly attack body cells that have been infected with a bacterium or virus, while helper T cells regulate the immune response, either by directly interacting with other lymphocytes or by secreting chemicals, called interleukins, that regulate those cells. In immunodeficiency disorders, some or all of these defenses are compromised, which can have life-threatening consequences. Immunodeficiency diseases are generally the result of genetic abnormalities and are present from birth; others may be acquired through infection or exposure to damaging drug or radiation treatments. Depending upon the specific defect, the result may range from limited defects involving a class of cells to an entire shutdown of the immune system; depends on the severity of the defect. Since these defects generally involve recessive traits, expression of immune deficiencies usually results from mutations on the X chromosome; sex-linked traits are generally observed only in males, since males carry a single X chromosome.

The most severe immunodeficiency disorder is attributable to the absence of stem cells, which results in a total lack of both B and T lymphocytes. This rare genetic condition is referred to as Severe combined immunodeficiency syndrome (SCID). Affected infants show a failure to thrive from birth and can easily die from common bacterial or viral infections. The term SCID encompasses a variety of genetic deficiencies. Certain forms are sex-linked, while other types may be autosomal (non-sex-linked). The most common autosomal form is a deficiency in the enzyme adenosine deaminase, resulting in disruption of synthesis in the stem cells.

Major syndromes that involve defects specific to the T population are characterized by recurrent viral and fungal infections. DiGeorge syndrome results from improper development of the thymus, which in turn results in insufficient production of T lymphocytes, often accompanied by other structural abnormalities in the infant. In severe cases, death results in early childhood from overwhelming viral infections.

The most common disorders affecting B lymphocytes are forms of hypogammaglobulinemia. This condition is characterized by insufficient levels of antibody. The cause is generally associated with increased rates of breakdown or loss in the urine secondary to kidney malfunction. Bruton’s agammaglobulinemia is a rare, sex-linked form of the condition, in which B cells fail to mature properly. Severe bacterial infections are the most common symptom. When the disorder is left untreated, infants generally die of severe prior to six months of age.

Several immunodeficiency disorders may be the result of partial defects in the production and/or function of B and T lymphocytes. is a genetically inherited disease manifested by recurrent infections and an itchy, scaly of the skin. Certain classes of antibodies are absent or scarce. Chronic mucocutaneous is characterized by chronic fungal infection of the skin and mucous membranes; reduced levels of T cells are responsible for this disfiguring disorder.

Immunodeficiency disorders may also be the result of defects in phagocytic cells; the underlying cause of most of these disorders is ill-defined but often involves deficiencies in hydrolytic enzymes. In chronic granulomatosis, an inherited enzyme deficiency prevents the from destroying bacteria that have been phagocytized. Infants affected by this disorder develop severe infections and chronic inflammations of internal organs and bones. The bacteria responsible for these infections are generally common that are not considered pathogens in healthy individuals.

Immune disorders may involve defects in antibody production. However, certain forms of inherited disorders involve another group of proteins called complement. Complement actually represents a group of proteins that interact with each other in a series. The pathway may be activated either specifically from antibody-target interactions or nonspecifically by surface components of certain bacteria. Intermediates in the pathway attract or stimulate (opsonins), induce inflammation, and play roles in cell destruction. Some of the intermediates are enzymes that regulate the activation of complement components. The most important intermediate in the pathway is the C3 component. C3 is a protein that acts as an opsonin and at the same time is involved in activating later steps in the sequence. Defects in C3 result in increased susceptibility to infection. Similar immune problems may result from defects in other complement intermediates.

Most of the disorders that affect the immune system are not inherited but develop sometime during the person’s life. They are either the result of an infection or a consequence of another disease or its treatment. The use of corticosteroids to treat inflammations, or the illicit use of them in muscle-building, can interfere with the proper production and function of T lymphocytes. Other immunosuppressive drugs used to diminish the possibilities of graft or transplant rejection, or in the treatment of autoimmune diseases, can severely depress antibody production. Chemotherapeutic agents used in the treatment of cancer can affect DNA and severely compromise the entire immune system. Whole-body radiation can damage or destroy bone marrow stem cells.

Acquired immunodeficiency syndrome (AIDS) is caused by the Human immunodeficiency virus (HIV). HIV is transmitted primarily through unprotected sexual contact, sharing of needles for intravenous drug use, with contaminated blood products, or contact with contaminated body fluids. HIV specifically infects one type of regulatory T lymphocyte, the helper T cell, resulting in severe immune depression. The virus may be harbored in an inapparent form for years. Initial symptoms may be quite mild, but they generally progress so that the affected individual becomes susceptible to a host of opportunistic bacterial and fungal infections. A rare form of cancer called Kaposi’s sarcoma is associated with infection by a particular human herpesvirus, HHV8, in persons with AIDS. AIDS also produces neurological damage in about one-third of infected individuals.

Treatment and Therapy

Most treatment of immunodeficient individuals is palliative. Infections are treated with antibiotics whenever possible. Individuals are counseled to avoid situations in which they may be exposed to contagious agents.

Treatment of immunodeficiency disorders may also target the source of the deficiency. For example, in DiGeorge syndrome, characterized by the congenital absence of the thymus, fetal thymus transplants may correct the problem, with improvement in lymphocyte levels seen within hours after the transplants. The use of thymus extracts has also been beneficial. Syndromes such as hypogammaglobulinemia can be managed by injection with mixtures of antibodies. Drug therapy to substitute for some immune components absent in Wiskott-Aldrich syndrome has been shown to have effects. The most effective treatment for chronic mucocutaneous candidiasis is aggressive antifungal medication to eradicate the causative organism; treatment must continue for several months because are slow to respond to therapy and frequently recur. Chronic granulomatosis is notoriously difficult to treat, and the most effective therapy has been and antifungal agents used aggressively during an overt infection.

Because of the magnitude of the defects, many inherited immunodeficiency disorders are difficult to treat successfully and are commonly fatal early in life. Chronic granulomatosis is usually fatal within the first few years of life, and only about 20 percent of patients reach the age of twenty. SCID is a serious disorder in which affected infants can die before a proper diagnosis is made. For individuals with these and other serious immunodeficiency disorders, maintenance in an environment free of bacteria, viruses, and fungi, such as a sterile “bubble,” has been the best means to prevent life-threatening infections. Such an approach, however, precludes the possibility of a normal life. The most effective treatment for individuals with severely compromised immune systems is bone marrow transplantation. In this procedure, bone marrow from a compatible individual is introduced into the bone marrow of the patient. If the procedure works—and the success rate is high—in approximately one to six months the transplant recipient’s immune system will be reconstituted and functional; full recovery may take up to one year. Bone marrow is a permanent cure for these disorders, since the transplanted marrow will contain stem cells that produce all the cell types of the immune system. The difficulties in transplantation include finding a compatible donor and preventing infections during the period after the transplant.

Drug therapy for AIDS utilizes treatments that interfere with replication of the virus. The first drug to be approved for use was (formerly AZT), a DNA analogue, but its success was somewhat limited, as it was associated with severe side effects and the creation of resistant virus. More recent treatments utilize drug “cocktails,” combinations of drugs that act at different stages of viral replication. Some types of antiretroviral therapy (ART) drugs include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, fusion inhibitors, and pharmacokinetic enhancers. Vaccines and antibiotic therapy are used to prevent or treat the opportunistic illnesses that accompany AIDS. Various drugs may also help to ease symptoms of AIDS such as appetite disturbances, nausea, pain, insomnia, anxiety, depression, fever, and diarrhea. A combination of therapies has been shown to increase life expectancy in AIDS patients. Many patients choose to participate in clinical trials of experimental drugs not approved for general use in the hope that the new drug will be more effective at alleviating the disease. Others seek out alternative or nontraditional medical treatments that have a long history of use in Western cultures. These treatments include acupuncture, herbology, meditation, and homeopathy. An important aspect of therapy for AIDS patients is maintaining mental health through support groups and supportive caregivers.

Illicit use of corticosteroids can seriously compromise the immune system and may lead to permanent damage. The best therapy for this type of acquired immunodeficiency is prevention—that is, to not misuse the drugs. In their supervised use to control inflammation or other disease symptoms, normal immune function will return after treatment has been completed. A huge risk to cancer patients who are being treated with and/or is the of the immune system, which can lead to a host of infections being contracted and not easily fought off by the body’s compromised immune system. These individuals should avoid exposure to infectious agents when possible and be attentive to lifestyle modifications that can strengthen the immune system and encourage its speedy recovery, including a nutritious diet, plenty of rest, and avoidance of stress. Close monitoring for any signs of infection facilitates rapid antibiotic therapy, which can prevent serious complications.

Perspective and Prospects

Prior to the gains in scientific knowledge about the mechanics of the immune system, individuals with genetic immunodeficiency disorders would die of serious infections during their first few years of life. Even when it was finally realized that these individuals suffered from defects of the immune system, little could be done for most of the disorders, except to treat infections as they developed and to avoid contact with potential disease-causing organisms—a near impossibility if one is to lead a normal life. Housing persons with SCID in sterile bubbles was uncommon because of the expense and impracticality. During the 1970s, bone marrow transplants were first developed; by the 1990s they had progressed to a greater than 80 percent success rate. As a result of improved transplant-rejection drugs, transplants from donors with less-than-perfect tissue matches are now possible. Bone marrow transplantation has been a source of cure for many individuals with immune disorders.

Bone marrow transplantation is not suitable or possible in every case of immunodeficiency disorder, and scientists have long sought a means to cure the genetic defects themselves. In 1992, French Anderson of the National Institutes of Health conducted the first gene therapy trial on a young girl suffering from SCID. Some of the girl’s bone marrow cells were removed from her body and exposed to an inactivated virus containing a normal gene for ADA, the defective enzyme. Some of the stem cells in the marrow incorporated the healthy gene, and the engineered cells were returned to her body. The cells lodged in her bone marrow, where they produced healthy immune cells. The procedure was repeated successfully in three other children shortly afterward.

Among the exciting applications of research into the of immunodeficiencies has been the identification of specific genetic defects. Bone marrow stem cells can now be isolated and identified. In the future, such cells may be engineered such that the defective gene associated with the deficiency may be replaced by a normal copy. Since the cells are those from the same individual, transplantation problems can be avoided. However, bone marrow or cord blood transplants remain the only cure for SCID.

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