Severe combined immunodeficiency syndrome (SCID)

ALSO KNOWN AS: Bubble boy disease

ANATOMY OR SYSTEM AFFECTED: Immune system

DEFINITION: A syndrome in which the immune system is unable to produce T and B cells, resulting in catastrophic failure of the immune system. The underlying cause is a mutation in one of several key genes, and without specialized treatment, often with cells from a donor, death typically occurs before the age of one.

CAUSES: Various genetic defects

SYMPTOMS: Repeated, persistent infections that are unresponsive to standard treatments; may include meningitis, septic arthritis, opportunistic infections, graft-versus-host disease

DURATION: Chronic

TREATMENTS: Bone marrow transplantation, hormonal therapy, gene therapy

Causes and Symptoms

Severe combined immunodeficiency syndrome (SCID) is a genetic defect in which one of several genes involved in the immune system has a mutation that either prevents gene expression or causes the production of faulty products. The most common cause of SCID, accounting for about half of cases, is mutations in the X-linked gene IL2RG, which codes for the third chain of the interleukin-2 (IL-2) receptor, and also a part of several other interleukin receptors. Interleukin receptors are proteins embedded in the plasma membrane of cells in the immune system that interact with interleukin molecules, which carry important immune system signals. This type of SCID is called X-linked combined immunodeficiency (XCID), and the faulty interleukin receptors prevent the development of Tdf cells and natural killer (NK) cells, both of which are required to prevent infections successfully. Because XCID is an X-linked defect, it is much more common in males.

The remaining cases of SCID are attributable to mutations in many different genes, with new defects being discovered every year. The types of genes involved range from those that code for proteins that interact with interleukin receptors and enzymes involved in purine metabolism, to genes that code for enzymes involved in antigen receptor production. In addition, a variety of lesser known defects and some genetic disorders show some, but not all, of the symptoms of SCID.

The most common of the remaining defects, accounting for about 20 percent of cases, is deficiency in the enzyme adenosine deaminase (ADA), which is involved in purine metabolism. This form of SCID, called ADA SCID, results in the accumulation of a toxic form of adenosine that especially affects lymphatic tissue. No T or B cells are produced. Deficiency in another enzyme, purine nucleoside phosphorylase (PNP), although much rarer, acts in a similar fashion.

Regardless of the underlying causes, symptoms are similar for most types of SCID. The overwhelming clinical symptom is problems with repeated, persistent infections that do not respond to standard treatment. Severe infections such as meningitis or septic arthritis may occur. Infections with opportunistic pathogens such as Pneumocystis carinii also frequently occur. Symptoms of graft-versus-host disease (GVHD) may occur in infants because of lymphocytes received from the mother or in patients following blood transfusion. A chest x-ray typically shows lack of a thymic shadow, indicating that the thymus has not developed properly. There is often also a family history of immunodeficiency and infant deaths caused by serious infection.

Treatment and Therapy

Left untreated, most infants die within the first year, so rapid identification of the symptoms is extremely important. Prenatal diagnosis is possible and is recommended in families with a history of SCID or similar problems. If SCID is detected early enough, then several treatment options are available, even potential prenatal treatment.

For the majority of SCID cases, bone marrow transplantation is the standard treatment. To prevent GVHD, either the marrow must come from an identical twin or it must be depleted of T cells prior to transplantation. Although a close genetic match has the highest success rate, unmatched and T cell–depleted marrow can be used if matched marrow is unavailable. A survival rate of more than 90 percent has been accomplished when the marrow is from a parent or full sibling. It has typically been routine to use chemotherapy to kill the recipient’s bone marrow before transplanting donor marrow, but in the case of SCID patients this has been found unnecessary (and seems to lower the survival rate) because the recipient has no T cells to cause rejection.

When transplantation is successful, donor stem cells present in the marrow populate the recipient’s marrow and establish a functioning immune system. Unfortunately, some residual GVHD may occur, and over time T cell function seems to diminish in many cases, in spite of apparent initial success. The reasons for the latter problem are unknown.

Although transplantation may also work for ADA SCID, an alternative is polyethylene glycol (PEG)-bovine ADA replacement therapy. This treatment must be administered on an ongoing basis by frequent intravenous injections of PEG-ADA to maintain appropriate enzyme levels. Unfortunately, PEG-ADA is not always available and is extremely expensive, leaving transplantation the only option in some cases.

Still in the experimental stage is gene therapy to replace the defective genes. Experiments on this approach began in the early 1990s, and although the first attempts at curing ADA SCID showed partial success, the patients still required continued treatment with PEG-ADA. Since then, efforts have focused on better ways to insert the correct genes into the patient’s own stem cells. Stem cells from the bone marrow must be isolated, treated, and then returned to the patient.

The most promising results came from experiments begun in 1999 involving gene therapy for XCID. Following the procedure, the infants developed apparently normal immune systems. Unfortunately, by the summer of 2002 one of the boys developed leukemia, and another developed it by the end of the same year. Some trials were stopped as a result. The apparent cause of the leukemia was insertion of the gene at an inappropriate location, a concern expressed early in the discussion of gene therapy for this disease. Gene therapy still holds great promise, but more work needs to be done to ensure its long-term safety and effectiveness.

Bibliography:

Blaese, Michael R., et al. “T Lymphocyte-Directed Gene Therapy for ADA SCID: Initial Trial Results After Four Years.” Science 270 (1995): 475–80. Print.

Cohen, Philip. “Fresh Blow for Gene Treatments as Safety of a Second Virus Is Questioned.” New Scientist 178 (2003): 17. Print.

Coico, Richard, and Geoffrey Sunshine. Immunology: A Short Course. 7th ed. Hoboken: Wiley, 2015. Print.

Cooper, Max D., et al. “Immunodeficiency Disorders.” Hematology 2003.1 (2003): 314–30. Print.

Dvorak, Christopher C. et al. "The Diagnosis of Severe Combined Immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions." The Journal of Allergy and Clinical Immunology, vol. 151, no. 2, Feb. 2023, pp. 539-546, doi.org/10.1016/j.jaci.2022.10.022. Accessed 8 Apr. 2024.

 Hawley, Robert G., and Donna A. Sobieski. “Of Mice and Men: The Tale of Two Therapies.” Stem Cells 20 (2002): 275–78. Print.

Schwarz, Klaus, et al. “Human Severe Combined Immune Deficiency and DNA Repair.” Bioessays 25.11 (2003): 1061–070. Print.

Scollay, Roland. “Gene Therapy: A Brief Overview of the Past, Present, and Future.” Annals of the New York Academy of Sciences 953 (2001): 26–30. Print.

"Severe Combined Immunodeficiency (SCID)." National Institute of Allergy and Infectious Diseases, 4 Apr. 2019, www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid. Accessed 9 Apr. 2024.

"Severe Combined Immunodeficiency (SCID)." University of Rochester Medical Center Health Encyclopedia. U of Rochester, 10 Nov. 2015. Web. 9 May 2016.

"X-Linked Severe Combined Immunodeficiency." Genetics Home Reference. Natl. Lib. of Medicine, 3 May 2016. Web. 9 May 2016.