Severe combined immunodeficiency
From Wikipedia, the free encyclopedia
| ICD-10 | D81.0-2 |
|---|---|
| ICD-9 | 279.2 |
Severe combined immunodeficiency, or SCID, is a genetic disorder in which both "arms" (B cells and T cells) of the adaptive immune system are crippled, due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency. It is also known as the "bubble boy" disease because its victims are extremely vulnerable to infectious diseases. The most famous case is the boy David Vetter.
SCID affects about 1 in 100,000 live births. These babies, if untreated, usually die within 1 year due to severe, recurrent infections. Chronic diarrhea, ear infections, recurrent Pneumocystis jirovecii pneumonia, and profuse oral candidiasis commonly occur. Treatment options are much improved since David Vetter, and living in a bubble is no longer necessary.
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[edit] Some SCID Types
[edit] Common gamma chain (X-linked severe combined immunodeficiency)
Most cases of SCID are due to mutations in the gene encoding the common gamma chain (γc), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9 and IL-15. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signaling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells.
The common gamma chain is encoded by the gene IL-2 receptor gamma, or IL-2Rγ, which is located on the X-chromosome. Therefore, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an X-linked recessive pattern. All males (who have one X and one Y chromosome) who have an X chromosome with the defective gene will have SCID. Females (who have two X chromosomes) with one defective and normal chromosome will be healthy, as one normal IL-2Rγ gene is sufficient to have a normal immune system. However, these females are carriers. Half of their male children will have X-linked SCID, and their female children have a 50% chance of being carriers.
[edit] JAK3
Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signal. Mutation of its gene also causes SCID.
[edit] V(D)J recombination
The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2. These enzymes are involved in the first stage of V(D)J recombination, the process by which segments of a B cell or T cell's DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies). Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination, causing SCID.
[edit] Adenosine deaminase
Another well-known form of SCID is caused by a defective enzyme, adenosine deaminase (ADA), necessary for the breakdown of purines. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide diphosphate reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. The effectiveness of the immune system depends upon lymphocyte proliferation and hence dNTP synthesis. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised.
[edit] Detection
Standard testing of SCID is not currently available for newborns due to the diversity of the genetic defect. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not detected until about six months of age, usually indicated by recurrent infections. The delay in detection is due to the fact that newborns carry their mother's antibodies for the first few weeks of life and SCID babies look normal.
[edit] Treatment
The most common treatment for SCID is bone marrow transplantation, which requires matched donors (a sibling is generally best). David Vetter, the original "bubble boy", had one of the first transplantations, and finally died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister. Today, transplants done in the first three months of life have a high success rate.
More recently, gene therapy has proved useful. Transduction of the missing gene to hematopoietic stem cells using viral vectors is being tested in ADA SCID and X-linked SCID. The first gene therapy trials were performed in 1990, with peripheral T cells. In 2000, the first gene therapy "success" resulted in SCID patients with a functional immune system. These trials were stopped when it was discovered that three of eleven patients in one trial had developed leukemia resulting from the insertion of the gene-carrying retrovirus near an oncogene. Work is now focusing on correcting the gene without triggering an oncogene. No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when expressed by a retrovirus.
Trial treatments of SCID have been gene therapy's only success; since 1999, gene therapy has restored the immune systems of at least 17 children with two forms (ADA-SCID and X-SCID) of the disorder.
[edit] SCID in animals
SCID mice are used in disease, vaccine, and transplant research, especially as animal models for testing the safety of new vaccines or therapeutic agents in people with weakened immune systems.
[edit] External links
- scid.net SCID self-help support group and resource guide
- Learning About Severe Combined Immunodeficiency (SCID) NIH
- Buckley RH (2004). "Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution". Annu Rev Immunol 22: 625-55. PMID 15032591.
- Chinen J, Puck JM (2004). "Successes and risks of gene therapy in primary immunodeficiencies". J Allergy Clin Immunol 113 (4): 595-603; quiz 604. PMID 15100660.
- Church AC (2002). "X-linked severe combined immunodeficiency". Hosp Med 63 (11): 676-80. PMID 12474613.
- Gennery AR, Cant AJ (2001). "Diagnosis of severe combined immunodeficiency". J Clin Pathol 54 (3): 191-5. PMID 11253129.
