Severe Combined Immune Deficiency
Severe Combined Immune Deficiency
The development of the immune system is a very complicated process. Stem cells in the bone marrow continually give rise to the white blood cells responsible for producing antibodies (B-lymphocytes), recognizing and destroying foreign cells (T-lymphocytes) and performing immune surveillance for cancer and foreign cells. Immunodeficiency results when the normal complex interactions of the immune system required to do this fail, resulting in susceptibility to infections or cancer.
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 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 γ 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.
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.
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) that activates the genes for T-lymphocyte differentiation. To do so, it must bind to the SCID-X1 gene product.
Interleukin-7 receptor α Chain Deficiency.
This is responsible for SCID in a small number of patients. This receptor is part of a larger complex that includes the SCID-X1, JAK3 proteins, and four other interleukin receptors (IL-2, IL-5, IL-9 and IL-15). Thus, at least three of the known SCID genes have been found to disrupt the same receptor complex involved in immune system development.
RAG1 and 2 Deficiencies.
These can also lead to SCID. RAG1 and RAG2 are found side-by-side on chromosome 6. Mutations in either can result in SCID. They are involved in the genetic rearrangement of both the T- and B-lymphocyte receptor genes during differentiation that gives rise to the ability of the immune system to recognize foreign agents. Mutations in RAG1 or 2 also account for 50 percent of those patients with an unusual autoimmunity form of SCID called Omenn syndrome.
The genes involved in two additional rare forms of SCID, reticular dysgenesis and cartilage-hair hypoplasia, remain unknown. In addition, the gene(s) for over 30 percent of those patients diagnosed with SCID also remain unidentified, even though these patients seem to display the same phenotypes as those patients whose genetic defect has been identified.
Understanding the genes responsible for SCID has also led to an increased understanding of the genes involved in the overall development of the immune system. It has also helped to unravel the complicated signaling pathways between the cells of the immune system that control and define the immune response itself. There has also been another major benefit. The study of SCID has, in the past, aided in developing an effective program for bone marrow transplantation.
In 1990 the first gene therapy was attempted in two ADA-SCID patients. ADA-SCID was specifically chosen for the first attempted gene therapy for several reasons: bone marrow transplantation had indicated that replacing the defective gene was possible; mouse SCID models had been effectively treated through gene therapy; and ADA-SCID could be treated with some success with enzyme-replacement therapy, enhancing the opportunity for successful gene therapy.
Unfortunately, the majority of ADA-SCID patients, as well as the 3,000 patients enrolled in gene therapy trials for a broad array of other diseases since the first ADA-SCID gene therapy, have not been significantly helped. One exception is the very first gene therapy patient, four-year-old Ashanti de Silva who, ten years later, had a normal lifestyle, with a level of 20 to 25 percent normal T-lymphocytes. Learning from these gene therapy experiences, French researchers modified the procedure. In 2000 they reported successful gene therapy for two infants with SCID-X1. The patients had left the hospital and its protective isolation after a three-month stay. Ten months after gene therapy, they remained healthy, with normal levels of B- and T-lymphocytes and natural killer cells. Thus SCID continues to define the current state of the art for gene therapy, exposing its limitations while simultaneously pointing to its eventual success.
Diane C. Rein
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