Severe combined immunodeficiency

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.

Recent studies indicate that one in every 2,500 children in the Navajo population inherit Severe combined immunodeficiency (SCID). This condition is a significant cause of illness and death among Navajo children. Ongoing research reveals a similar genetic pattern among the related Apache people. Mortan Cowan, MD, director of the Pediatric Bone Marrow Transplant Program at the University of California-San Fransciso, noted that although researchers have identified about a dozen genes that cause SCID, the Navajo and Apache population has the most severe form of the disorder. This is due to the lack of a gene designated "Artemis." Without the gene, children's bodies are unable to repair DNA or develop disease-fighting cells. (Felicia Fonseca, The Associated Press, Dec.16,2007, reprinted in the Salt Lake Tribune)

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Some SCID Types

Common gamma chain (X-linked severe combined immunodeficiency)

Main article: X-SCID

See also: Common gamma chain

Most cases of SCID are due to mutations in the gene encoding the common gamma chain (γ_c), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. 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 signalling. 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. Their male children have a 50% chance of having X-linked SCID, and their female children have a 50% chance of being carriers.

JAK3

Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γ_c signal. Mutation of its gene also causes SCID.

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.

Adenosine deaminase

The second most common form of SCID after X_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.

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.

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 two of ten patients in one trial had developed leukemia resulting from the insertion of the gene-carrying retrovirus near an oncogene. In 2007, four of the ten patients have developed leukemias ^[1]. 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.

SCID in animals

Main article: Severe combined immunodeficiency (non-human)

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.

An animal variation of the disease, an autosomal recessive gene with clinical signs similar to the human condition, also affects the Arabian horse. In horses, to date, the condition remains a fatal disease, as the animal inevitably succumbs to an opportunistic infection within the first four to six months of life.^[2] However, carriers, who themselves are not affected by the disease, can be detected with a DNA test. Thus careful breeding practices can avoid the risk of an affected foal being produced.^[3]

Another animal with well-characterized SCID pathology is the dog. There are two known forms, an X-linked SCID in Basset Hounds that has similar ontology to X-SCID in humans^[4], and an autosomal recessive form seen in one line of Jack Russell Terriers that is similar to SCID in Arabian horses and mice.^[5]

See also

• Omenn syndrome

References