Immunodeficiency diseases, genetic causes

The complex workings of the immune system requires the cooperation of various organs, tissues, cells and proteins and thus, it can be compromised in a number of different ways. People who have normal immune function at birth who later acquire some form of immunodeficiency are said to have secondary or acquired immunodeficiency diseases. Examples would include AIDS , age-related immune depression, and other immune deficiencies caused by infections, drug reactions, radiation sickness, or cancer. Individuals who are born with an intrinsically reduced capacity for immunologic activity usually have some genetic alteration present at birth. There are varieties of different genes involved, and they render people susceptible to infection by an assortment of different germs. Some of these diseases are relatively mild with onset in adolescence or adulthood. Others are severely debilitating and severely compromise daily activity. Clinically significant primary immunodeficiencies are relatively rare with 1 in 5,000 to 1 in 10,000 people in developed countries afflicted.

The most common form of primary immunodeficiency, selective IgA deficiency, is a very mild deficiency and may affect as many as 1 in every 300 persons, most of whom will never realize they have an immunodeficiency at all. B-cells are lymphocytes that produce antibodies and this component of the immune system is often called humoral immunity . Defects in humoral immunity predispose the body to viral infections. T-cells are lymphocytes that are processed in the thymus gland. Granulocytes are cells which consume an destroy bacteria .

There are now thought to be around 70 different primary immunodeficiency diseases. Of the more common forms, the vast majority of these conditions are recessive. This means that a single working copy of the gene is generally sufficient to permit normal immune functioning. Some of the genes are found on the X chromosome. Since males receive only a single X chromosome, recessive mutations of these genes will result in disease. Females have two copies of the X chromosome, and so rarely will express X-linked recessive diseases.

The most widely known of the primary immunodeficiencies is severe combined immune deficiency (SCID ) and it conjures pictures of a child who must live his life encased in a plastic bubble to keep out germs. SCID is manifest in early childhood as a severe combined T cell and B cell deficiency, and can be caused by a number of different gene mutations. The most common form is X-linked, and so primarily affects boys. It can also be caused by an enzyme called adenosine deaminase. When ADA is deficient, toxic chemicals kill off the lymphocytes. Until recently, SCID was uniformly lethal. In recent years, the elucidation of the genes responsible has made possible interventions based on gene therapy. SCID often presents in early childhood as persistent diaper rash or thrush . Pneumonia , meningitis , blood poisoning, and many common viral infections are serious threats to children born with SCID. Diagnosis demands immediate medical attention and bone marrow transplants are a common form of treatment for SCID. Children with ADA deficiency may be treated with ADA infusions to correct the enzyme deficiency. Partial combined immune deficiencies are milder conditions in which cellular and humoral immunity are both compromised but not completely shut down. These are generally accompanied by other physical symptoms and so constitute syndromes. Wiskott-Aldrich syndrome, for example, is an X-linked partial combined syndrome in which the repeated infections are combined with eczema and a tendency toward bleeding. Another combined B and T cell deficiency is ataxia telangiectasia (AT). In AT, the combined B and T cell deficiency causes repeated respiratory infections, and is accompanied by a jerky movement disorder and dilated blood vessels in the eyes and skin. The thymus gland where T-cells are processed is underdeveloped.

Deficiency of the B cell population results in decreased antibody production and thus, an increased risk of viral or bacterial infection . X-linked agammaglobulinemia (XLA) is a condition in which boys (because it is X-linked) produce little to no antibodies due to an absence of B cells and plasma cells in circulation. As these children grow, they deplete the antibodies transmitted through the mother, and they become susceptible to repeated infections. Common variable immunodeficiency (CVID) is a group of disorders in which the number of B cells is normal, but the levels of antibody production are reduced.

DiGeorge anomaly is an example of a T cell deficiency produced by an underdeveloped thymus gland. Children with DiGeorge anomaly often have characteristic facial features, developmental delays, and certain kinds of heart defects usually stemming from small deletions on chromosome 22 (or more rarely, chromosome 10). In rare cases, there is an autosomal dominant gene mutation rather than a chromosome deletion.

Phagocytosis , the ability of the granulocytes to ingest and destroy bacteria, can also be the chief problem. One example of this is chronic granulomatous disease (CGD). There are four known genes that cause CGD; all are recessive. One is on the X chromosome, and the other three are on autosomes. These children do well until around age three when they begin to have problems with staphylococcal infections and infections with fungi which are generally benign in other people. Their granulosa cells may aggregate in tissues forming tumor like masses. Similarly, leukocyte adhesion defect (LAD) is a condition in which granulocytes fail to work because they are unable to migrate to the site of infections. In Chediak-Higashi syndrome (CHS), not only granulocytes, but also melanocytes and platelets are diminished. CHS is generally fatal in adolescence unless treated by bone marrow transplantation.

One other class of primary immunodeficiencies, the complement system defects, result from the body's inability to recognize and/or destroy germs that have been bound by antibodies. Complement fixation is a complex multi step process, and thus a number of different gene mutations can potentially corrupt the normal pathway. Complement system defects are rare and often not expressed until later in life.

The prospect of the development of effective and safe gene therapies holds hope for the primary immunodeficiency diseases. As these genes and their genetic pathways are more fully understood, interventions which replace the missing gene product will likely provide effective treatments.

See also Immunity, cell mediated; Immunity, humoral regulation; Microbial genetics; Microbiology, clinical