severe combined immunodeficiency

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Severe Combined Immunodeficiency

 

Definition

Severe combined immunodeficiency (SCID) is the most serious human immunodeficiency disorder(s). It is a group of congenital disorders in which both the humoral part of the patient's immune system and the cells involved in immune responses fail to work properly. Children with SCID are vulnerable to recurrent severe infections, retarded growth, and early death.

Description

SCID is thought to affect between one in every 100,000 persons, and one in every 500,000 infants. Several different immune system disorders are currently grouped under SCID:
  • Swiss-type agammaglobulinemia. This was the first type of SCID discovered, in Switzerland in the 1950s.
  • Adenosine deaminase deficiency (ADA). About 50% of SCID cases are of this type. ADA deficiency leads to low levels of B and T cells in the child's immune system.
  • Autosomal recessive. About 40% of SCID cases are inherited from the parents in an autosomal recessive pattern.
  • Bare lymphocyte syndrome. In this form of SCID, the white blood cells (lymphocytes) in the baby's blood are missing certain proteins. Without these proteins, the lymphocytes cannot activate the T cells in the immune system.
  • SCID with leukopenia. Children with this form of SCID are lacking a type of white blood cell called a granulocyte.
In order to understand why SCID is considered the most severe immunodeficiency disorder, it is helpful to have an outline of the parts of the human immune system. It has three parts: cellular, humoral, and nonspecific. The cellular and humoral parts of the system are both needed to fight infections-they recognize disease agents and attack them. The cellular system is composed of many classes of T-lymphocytes (white blood cells that detect foreign invaders called antigens). The humoral system is made up of B cells, which are the only cells in the body that make antibodies. In SCID, neither the cellular nor the humoral part of the immune system is working properly.

Causes and symptoms

SCID is an inherited disorder. There are two ways in which a developing fetus' immune system can fail to develop normally. In the first type of genetic problem, both B and T cells are defective. In the second type, only the T cells are abnormal, but their defect affects the functioning of the B cells.
For the first few months of life, a child with SCID is protected by antibodies in the mother's blood. As early as three months of age, however, the SCID child begins to suffer from mouth infections (thrush), chronic diarrhea, otitis media and pulmonary infections, including pneumocystis pneumonia. The child loses weight, becomes very weak, and eventually dies from an opportunistic infection.

Diagnosis

SCID is diagnosed by the typing of T and B cells in the child's blood. B cells can be detected by immunofluorescence tests for surface markers (unique proteins)on the cells. T cells can be identified in tissue sections (samples) using enzyme-labeled antibodies.

Treatment

Patients with SCID can be treated with antibiotics and immune serum to protect them from infections, but these treatments cannot cure the disorder. Bone marrow transplants are currently regarded as one of the few effective standard treatments for SCID.

Investigational treatments

In 1990, the Food and Drug Administration (FDA) approved PEG-ADA, an orphan drug (not available in US but available elsewhere), for the treatment of SCID. PEG-ADA, which is also called pegademase bovine, works by replacing the ADA deficiency in children with this form of SCID. Children who receive weekly injections of PEG-ADA appear to have normal immune functions restored. Another treatment that is still in the experimental stage is gene therapy. In gene therapy, the children receive periodic infusions of their own T cells corrected with a gene for ADA that has been implanted in an activated virus.

Prognosis

Currently, there is no cure for SCID. Most untreated patients die before age two.

Prevention

Genetic counseling is recommended for parents of a child with SCID.

Resources

Organizations

Immune Deficiency Foundation. 25 W. Chesapeake Ave., Suite 206, Towson, MD 21204. (800) 296-4433. http://www.primaryimmune.org.
National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673. http://www.rarediseases.org.

Key terms

Adenosine deaminase (ADA) — An enzyme that is lacking in a specific type of SCID. Children with an ADA deficiency have low levels of both B and T cells.
Antigens — A substance that usually causes the formation of an antibody. A foreign invaders in the body.
Autosomal recessive inheritance — A pattern of inheritance of a recessive gene where, among other things, both parents may not show symptoms.
B cell — A type of lymphocyte or white blood cell that is derived from precursor cells in the bone marrow.
Congenital — Present at the time of birth. Most forms of SCID are hereditary as well as congenital.
Gene therapy — An experimental treatment for SCID that consists of implanting a gene for ADA into an activated virus and merging it with some of the patient's own T cells. The corrected T cells are infused back into the patient every few months.
Humoral — Pertaining to or derived from a body fluid. The humoral part of the immune system includes antibodies and immunoglobulins in blood serum.
Lymphocyte — A type of white blood cell that is important in the formation of antibodies.
Orphan drug — A drug that is known to be useful in treatment but lacks sufficient funding for further research and development.
PEG-ADA — An orphan drug that is useful in treating SCID related to ADA deficiency.
T cells — Lymphocytes that originate in the thymus gland. T cells regulate the immune system's response to infections. The thymus gland is small or underdeveloped in children with SCID.
Thrush — A disease of the mouth caused by a yeast, Candida albicans.

immunodeficiency

 [im″u-no-de-fish´en-se]
a deficiency of immune response or a disorder characterized by deficient immune response; classified as antibody (B cell), cellular (T cell), or combined deficiency disorders. Antibody immunodeficiencies are marked by hypo- or dysgammaglobulinemia, recurrent bacterial otitis media, and sinopulmonary infections. Cellular immunodeficiencies are characterized by recurrent low-grade or opportunistic infections, by graft-versus-host disease or reaction after blood transfusions, and by severe disease after immunization with live vaccines. See also acquired immunodeficiency syndrome.
common variable immunodeficiency (CVID) a heterogeneous group of disorders characterized by hypogammaglobulinemia, decreased antibody production in response to antigenic challenge, and recurrent pyogenic infections, often associated with hematologic and autoimmune disorders. Most patients have normal numbers of circulating B cells but lack plasma cells and appear to have an intrinsic defect of B cell differentiation. However, two other forms are also recognized: that due to a disorder of T lymphocyte regulation and that due to production of autoantibodies against T and B lymphocytes.
severe combined immunodeficiency (SCID) any of several rare congenital diseases, some of autosomal recessive and some of X-linked inheritance, in which both humoral and cell-mediated immunity fail to develop normally and T lymphocytes are absent or nearly so. In some forms, B lymphocytes are also absent. Early diagnosis is essential to prevent opportunistic infections. Persistent diarrhea, chronic mucocutaneous candidiasis, and failure to thrive may occur in infancy. Blood transfusions can result in graft-versus-host disease and routine vaccinations in fatal infection. Unless immune function is restored by a matched-donor bone marrow or fetal tissue transplantation or the patient is kept in complete isolation, the prognosis is poor.

se·vere com·bined im·mu·no·de·fi·cien·cy (SCID),

[MIM*202500,MIM*300400, and MIM*312863]
an immunodeficiency in which there is absence of both humoral and cellular immunity with lymphopenia (of both B-type and T-type lymphocytes); characterized by thymus atrophy, lack of delayed hypersensitivity, and marked susceptibility to infections by bacteria, viruses, fungi, protozoa, and live vaccines; although bone marrow transplants have been effective, death may occur in the first year of life. Both autosomal recessive and X-linked forms occur; about half of those affected with autosomal recessive SCID have adenosine deaminase deficiency. The X-linked form is caused by mutation in the interleukin-2 receptor gamma gene (IL2RG) on Xq.

severe combined immunodeficiency

n. Abbr. SCID
A usually fatal congenital disorder of the immune system in which the body is unable to produce enough B cells and T cells to resist infection.

IL2RG

A gene on chromosome Xq13.1 that encodes the gamma subunit of interleukin-2 (IL-2) receptor, which forms a heterotrimer with alpha and gamma subunits resulting in a high-affinity IL-2 receptor. The gamma chain is an important signalling component of many IL receptors, including those of IL-2, IL-4, IL-7 and IL-21, and is thus referred to as the common gamma chain.

Molecular pathology
Defects in IL2RG cause X-linked severe combined immunodeficiency (XSCID), as well as the less severe X-linked combined immunodeficiency (XCID).

severe combined immunodeficiency

A heterogeneous X-linked or less commonly, AR condition, more common in blacks, onset in early infancy, characterized by dysfunctional T and B cells Clinical Morbiliform rash, hyperpigmentation, recurring infections–Candida, Pneumocystis carinii, CMV, EBV, HBV, varicella, FTT, early death Treatment BM transplant; gene therapy–enzyme replacement. See Adenosine deaminase deficiency, 'Bubble boy. ', Gnotobiotic, Purine nucleoside phosphorylase, SCID mice.
Severe combined immunodeficiency
Defining criteria Coma, respiratory distress–pulmonary edema, hypoglycemia, circulatory collapse–clinical shock, repeated convulsions, severe anemia–< 5g/dL and > 10 000 parasites mm3, acidosis–plasma bicarbonate < 15 mmol/L, hemoglobinuria, renal failure, spontaneous bleeding
Supporting criteria Jaundice, prostration, hyperpyrexia, impaired consciousness, hyperparasitemia–> 500 000 parasites mm3 NEJM 1995; 332:1399oa, 1441ed

se·vere com·bined im·mu·no·de·fi·cien·cy

(SCID) (sĕ-vēr kŏm-bīnd imyū-nō-dĕ-fishĕn-sē)
Immunodeficiency with absence of both humoral and cellular immunity with lymphopenia; characterized by thymus atrophy, lack of delayed hypersensitivity, and marked susceptibility to infections by bacteria, viruses, fungi, protozoa, and live vaccines; although bone marrow transplants have been effective, death may occur in the first year of life.

se·vere com·bined im·mu·no·de·fi·cien·cy

(SCID) (sĕ-vēr kŏm-bīnd imyū-nō-dĕ-fishĕn-sē) [MIM*202500,300400, and 312863, MIM*202500, MIM*300400, MIM*312863]
Immunodeficiency with absence of both humoral and cellular immunity with lymphopenia (of both B-type and T-type lymphocytes); characterized by thymus atrophy, lack of delayed hypersensitivity, and markedsusceptibility to infections by bacteria, viruses, fungi, protozoa, and live vaccines.

immunodeficiency

a deficiency in the immune system, either that mediated by antibody or T lymphocytes, or both. See also agammaglobulinemia, hypogammaglobulinemia, feline immunodeficiency virus, bovine immunodeficiency virus.

acquired immunodeficiency
see immune deficiency disease.
cancer-associated immunodeficiency
in general, associated with cachexia and debilitation, and also related to the type of neoplasia. Tumor-related effects on the immune system include impaired function of lymphocytes, altered cytokine production and activation of suppressor cell functions.
combined immunodeficiency
common variable immunodeficiency
a term encompassing a heterogeneous group of syndromes, which may be inherited or acquired, characterized by recurring persistent infections and deficiencies of some of the immunoglobulin classes.
congenital immunodeficiency
see immune deficiency disease.
immunodeficiency disease
iatrogenic immunodeficiency
secondary immune deficiency disease.
severe combined immunodeficiency
X-linked immunodeficiency
an inherited form of severe combined immunodeficiency has been reported in dogs. Puppies fail to grow and die from overwhelming infections at an early age.