Types and Severity of Immunodeficiency Diseases

Disease severity can range from mild to fatal, depending upon what part of the immune system is affected. Immunodeficiency can originate in normal individuals as a consequence of chemotherapy, viral infections (such as AIDS, which is caused by the HIV virus), or as the result of other processes that prevent immune system function. When immunodeficiency occurs in this manner, it is called acquired.

In contrast, immunodeficiency can also be inherited as a genetic mutation that prevents the normal development and function of the immune system. This is called primary immunodeficiency, of which there are three subtypes: mutations that prevent the function of B-lymphocytes (antibody production), those that prevent the function of T-lymphocytes ("invader"

recognition), and those that affect both B- and T-lymphocyte production. The last group is called severe combined immunodeficiency disease (SCID). These patients make none or very few T-lymphocytes, have nonfunctional B-lymphocytes, and may or may not have a type of immune cell called natural killer cells. This combination results in the absence of a functioning immune system from the moment of birth.

SCID

SCID is a collection of rare diseases, estimated to occur once in every 80,000 live births. If left untreated it always results in fatal infections within the first two years of life. At first, to prolong life, patients were placed in sterile isolators, away from direct human contact. This gave rise to the name "bubble babies." Currently bone marrow transplantation is available with varying degrees of success. Gene therapy to treat SCID is under development.

Although the first known description of SCID was in 1950, very little progress in understanding the genetic basis for the disease was made until the mid-1990s. SCID patients have a wide range of symptoms that make it difficult to define the number of genes involved. The development of strains of mice that exhibited SCID, either naturally or created by a laboratory technique called gene knockout, greatly enhanced the ability to study human SCID genes and permitted the development of strategies for treatment, such as bone marrow transplantation and gene therapy. Many SCID patients were able to live longer through bone marrow transplants. The study of these patients, combined with the advances from the Human Genome Project, has led to a rapid increase in our knowledge about the genetic cause of SCID. The genes involved in five different SCID diseases were confirmed in late 2001 and are described below.

SCID-X1 (XSCID, XL-SCID). This gene is currently the only known X-linked version of SCID (all other SCID forms identified are autosomal and recessive). SCID-X1 accounts for 46 percent of all SCID cases and exhibits a high spontaneous mutation rate. It is caused by mutations in the gene for the y subunit of the interleukin 2 (IL-2) cytokine receptor. This receptor is part of a critical cytokine signal pathway required early in immune system growth and differentiation. The most famous SCID-X1 patient was David Vetter. Known as the "bubble boy," he lived for twelve years in an isolated environment before dying from an Epstein-Barr virus infection.

ADA-SCID. This occurs in 15 percent of SCID patients. It is due to mutation in the ADA gene on chromosome 20. In the absence of ADA enzyme, accumulation of deoxyATP (a DNA nucleotide) occurs within immune cell precursors. This leads to their death through apoptosis within six months of birth. Unlike other forms of SCID, ADA-SCID patients can be treated through enzyme replacement therapy. Weekly injections of ADA enzyme (stabilized with polyethylene glycol) hinders toxic deoxyATP buildup, reducing apoptosis and permitting some B- and T-lymphocytes to mature. However, bone marrow transplantation provides better immunity if it succeeds.

JAK3 Deficiency. This accounts for 7 percent of SCID patients. This form of SCID maps to the Janus kinase 3 gene on chromosome 19. JAK3 enzyme, a tyrosine kinase, is part of the intracellular signaling pathway (JAK-STAT)

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