Severe combined immunodeficiency

December 31, 2014January 25, 2020

Synonyms

Overview

Severe combined immunodeficiency, SCID, also known as alymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, and thymic alymphoplasia, is a genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in heterogeneous clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" (B cells and T cells) of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble baby disease and bubble boy disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

SCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive. Ear infections, recurrent Pneumocystis jirovecii (previously carinii) pneumonia, and profuse oral candidiasis commonly occur. These babies, if untreated, usually die within 1 year due to severe, recurrent infections unless they have undergone successful hematopoietic stem cell transplantation.

Symptoms

If a baby exhibits any of the following persistent symptoms within the first year of life, he or she should be evaluated for SCID or other types of immune deficiency syndromes:

Eight or more ear infections
Two or more cases of pneumonia
Infections that do not resolve with antibiotic treatment for two or more months
Failure to gain weight or grow normally
Infections that require intravenous antibiotic treatment
Deep-seated infections, such as pneumonia that affects an entire lung or an abscess in the liver
Persistent thrush in the mouth or throat
A family history of immune deficiency or infant deaths due to infections

Causes

Lymphocytes, a type of white blood cell, are made from blood forming precursors, or "stem", cells in the bone marrow. Some lymphocyte precursors move to the thymus gland, where they become T cells. Others remain in the bone marrow where they mature into B cells and natural killer cells. Each specialized type of cell is responsible for a particular immune response. Normally, T cells encourage other immune cells to respond to foreign substances as well as directly combat certain viral and fungal infections. B cells become antibody-producing cells. The antibodies attack foreign substances, or antigens, that mark invading viruses, bacteria and fungi.

Severe combined immunodeficiency (SCID) is a term applied to a group of inherited disorders characterized by defects in both T and B cell responses, hence the term "combined". Problems in the T-lymphocyte system are generally profound, causing severe combined immunodeficiency syndromes that declare themselves soon after birth. Unless these defects are corrected the child will die of opportunistic infections before the first or second birthday. Current estimates suggest that 1 in every 50,000 to 100,000 births may be affected, indicating SCID may be about as common as some of the inherited illnesses for which states currently screen all newborns.

The most common type of SCID is called XSCID because the mutated gene IL2RG, which normally produces a receptor for activation signals on immune cells, is located on the X chromosome. Another form of SCID is caused by a deficiency of the enzyme adenosine deaminase (ADA), normally produced by a gene on chromosome 20.

XSCID:

X-linked severe combined immunodeficiency (XSCID) is caused by mutations in a gene on the X chromosome called IL2RG. This gene creates a key part of a receptor on the surface of a lymphocyte which, when activated by chemical messengers called cytokines, transmits information that directs lymphocytes to mature, proliferate and mobilize to fight infection. The defective part of the lymphocyte receptor is called the "common" gamma chain (γc), because it is a common component of lymphocyte receptors for several types of cytokines, including the interleukin-2 (IL-2) receptor. Thus, it is a critical component for mobilizing the body's defenses against infection.

Because females have two X chromosomes, if they have a mutation that disrupts the IL2RG gene on one X chromosome, they still have a spare normal gene on the other X chromosome that can compensate for the mutation. Thus, they have normal immune systems. However, since males have only one X chromosome and one Y chromosome, they do not have a spare IL2RG gene. A male with a defect in his only IL2RG gene produces immune cells that are missing the γc part of their receptors. Because the receptors cannot respond to stimulation, immune dysfunction and SCID sets in. XSCID affects only males and is the most common type of SCID. Therefore, the overall incidence of SCID is higher in males than in females.

ADA deficiency SCID:

Adenosine deaminase deficiency SCID, commonly called ADA SCID, is a very rare genetic disorder. It is caused by a mutation in the gene that encodes a protein called adenosine deaminase (ADA). This ADA protein is an essential enzyme needed by all body cells to produce new DNA. This enzyme also breaks down toxic metabolites that otherwise accumulate to harmful levels that kill lymphocytes. People afflicted with this disease often have to take antibiotics and supplemental infusions of antibodies to protect themselves from serious infections. They can also receive adenosine deaminase injections given once or twice a week. ADA SCID is lethal without treatment.

Prevention

Since SCID is caused by mutations in the genome, a prevention of this rare disease is not possible.

Diagnosis

Early diagnosis of SCID is rare because doctors do not routinely count each type of white blood cell in newborns. After an occurrence of symptoms that indicate SCID, blood tests are made that typically reveal significantly lower-than-normal levels of T cells and a lack of germ-fighting antibodies, which are characteristic features of SCID.

If the mutation leading to SCID in a family is known, an at-risk pregnancy can be tested by sequencing DNA from the fetus or from the baby directly after birth.

Another diagnosis method is based on the maturation of T cells. While rearranging the receptor gene, the maturing T cell produces a bit of leftover genetic material that forms a ring structure within the cell (T-cell receptor excision circles (TRECs) ). Because all patients with SCID make few or no T cells, measuring the number of these rings within a dried blood sample allows for a differentiation of normal infants from those with SCID.

Prognosis

Children with untreated SCID rarely live past the age of two, but a successful treatment is possible with bone marrow transplantation.

Treatment

The most common treatment for SCID is bone marrow transplantation, which has been successful using either a matched related or unrelated donor, or a half-matched donor, who would be either parent. The half-matched type of transplant is called haploidentical. Haploidentical bone marrow transplants require the donor marrow to be depleted of all mature T cells to avoid the occurrence of graft-versus-host disease (GVHD). Consequently, a functional immune system takes longer to develop in a patient who receives a haploidentical bone marrow transplant compared to a patient receiving a matched transplant. David Vetter, the original "bubble boy", had one of the first transplantations, but eventually died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister, an unmatched bone marrow donor. Today, transplants done in the first three months of life have a high success rate. Physicians have also had some success with in utero transplants done before the child is born and also by using cord blood which is rich in stem cells. In utero transplants allow for the fetus to develop a functional immune system in the sterile environment of the uterus; however complications such as GVHD would be difficult to detect or treat if they were to occur.

More recently gene therapy has been attempted as an alternative to the bone marrow transplant. Transduction of the missing gene to hematopoietic stem cells using viral vectors is being tested in ADA SCID and X-linked SCID. In 1990, four-year-old Ashanthi DeSilva became the first patient to undergo successful gene therapy. Researchers collected samples of DeSilva's blood, isolated some of her white blood cells, and used a retrovirus to insert a healthy adenosine deaminase (ADA) gene into them. These cells were then injected back into her body, and began to express a normal enzyme. This, augmented by weekly injections of ADA, corrected her deficiency. However, the concurrent treatment of ADA injections may impair the success of gene therapy, since transduced cells will have no selective advantage to proliferate if untransduced cells can survive in the presence of the injected ADA.

In 2000, a 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. Work aimed at improving gene therapy is now focusing on modifying the viral vector to reduce the likelihood of oncogenesis, and using zinc-finger nucleases to more specifically target gene insertion. 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 first 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.

There are also some non-curative methods for treating SCID. Reverse isolation involves the use of laminar air flow and mechanical barriers (to avoid physical contact with others) to isolate the patient from any harmful pathogens present in the external environment. A non-curative treatment for patients with ADA-SCID is enzyme replacement therapy, in which the patient is injected with polyethyleneglycol-coupled adenosine deaminase (PEG-ADA) which metabolizes the toxic substrates of the ADA enzyme and prevents their accumulation. Treatment with PEG-ADA may be used to restore T cell function in the short term, enough to clear any existing infections before proceeding with curative treatment such as a bone marrow transplant.