Severe Combined Immunodeficiency ?>

Severe Combined Immunodeficiency

Severe Combined Immunodeficiency


Introduction
Background

Severe combined immunodeficiency (SCID) is a disorder that results from any of a heterogenous group of genetic conditions affecting the immune system. SCID leads to severe T- and B-cell dysfunction. Without intervention, the severe T- and B-cell dysfunction results in severe infection and death in children by age 2 years.

The most common genetic condition responsible for SCID is a mutation of the common gamma chain of the interleukin (IL) receptors shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. This protein is encoded on the X chromosome, and this variant of SCID is, therefore, X-linked (and sometimes referred to as X-linked SCID). These patients account for approximately 50% of all patients with SCIDs.

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes Janus-associated kinase 3 (JAK3) deficiency, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase (PNP) deficiency, bare lymphocyte syndrome, IL-2 deficiency, ZAP-70 protein tyrosine kinase (PTK) deficiency, reticular dysgenesis, and Omenn syndrome.

These are the most common and best characterized forms of SCID, but not all of the genetic conditions leading to SCID are well characterized. Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis carinii pneumonia [PCP], systemic candidiasis, generalized herpetic infections).
Pathophysiology

The pathophysiology and molecular biology vary; however, the lack of T- and B-cell function is the common endpoint in all forms of SCID.

Cellular hallmarks that help differentiate between various forms of SCID are as follows:
X-linked SCID: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3+) and natural killer (NK) cells. Variable levels of B cells occur, which do not make functional antibodies.
JAK3 deficiency: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3+) and NK cells. Normal or high levels of B cells occur, which do not make functional antibodies.
ADA deficiency: Lymphopenia occurs from the death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. Functional antibodies are decreased or absent.
PNP deficiency: Lymphopenia occurs from the death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. This deficiency differs from ADA deficiency because circulating B cells are normal in number. However, B-cell function is poor, as evidenced by the lack of antibody formation.
Bare lymphocyte syndrome: The lymphocyte count is normal or mildly reduced, the CD4+ T cells are decreased, and the CD8+ T cell numbers are normal or mildly increased. The B-cell numbers are normal or mildly decreased, but the ability to make antibodies is decreased.
IL-2 deficiency: Normal, or near normal, numbers of T cells exist (both CD4+ and CD8+). The T cells fail to proliferate in vitro when stimulated with mitogens, unless IL-2 is added to the culture medium. The production of functional antibody is decreased.
ZAP-70 PTK deficiency: Lymphopenia occurs because of the absence of CD8+ T cells. As in all types of SCID, no antibody formation is present.
Reticular dysgenesis: Lymphopenia occurs from the absence of myeloid cells in the bone marrow. Red blood cells and platelets are present and functioning.
Omenn syndrome: Normal or elevated T-cell numbers are present, but these are of maternal not fetal origin. The B cells are usually undetectable, NK cells are present, and the total immunoglobulin level is markedly low with poor antibody production. Eosinophils are elevated, and the total serum immunoglobulin E (IgE) level is elevated.

Molecular abnormalities in various forms of SCID are as follows:
X-linked SCID: Mutation of the common gamma chain (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) of the IL receptors occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK cell development.
JAK3 deficiency: JAK3 is a PTK that associates with the common gamma chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of X-linked SCID.
IL-2 production deficiency: The exact molecular defect is unknown, but it is often associated with other cytokine production defects.
Bare lymphocyte syndrome: This is a deficiency of major histocompatability complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased, or MHC type I may be absent. The defect occurs in a gene regulating expression of MHC type II.
ZAP-70 PTK deficiency: A mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus.
Omenn syndrome: A mutation that impairs the function of immunoglobulin and TCR recombinase genes (ie, Rag1, Rag2 genes) is now believed to be responsible for this syndrome.
Frequency
United States

SCID occurs in approximately 1 in 100,000 births. Some groups report a higher incidence, 1 in 50,000-75,000 births, probably because of better identification of affected subjects. Approximately 50% of all SCID cases are X-linked (ie, mutation of the common gamma chain). The remaining 50% are various forms of autosomal recessive SCID. Approximately 25% of the patients with an autosomal recessive SCID are JAK3 deficient and 40% are ADA deficient. The other disorders make up the remaining 35% of autosomal recessive patients.
Mortality/Morbidity

Without treatment, death from infection usually occurs within the first 2 years of life. Graft versus host disease (GVHD) from maternal cell engraftment can occur in any SCID case, but it is more prone to occur in cases of Omenn syndrome.
Race

No racial predisposition exists for most forms of SCID, but most patients with ZAP-70 deficiency are Mennonites.
Sex

Approximately 50% of SCID cases are X-linked (ie, occurring only in males). No sexual predisposition is associated with autosomal recessive SCID.
Age

The average age at the onset of symptoms is 2 months.
Clinical
History
Family history of consanguinity
Sibling death in infancy and/or previous miscarriages in mother
Family history of SCID
Poor feeding and poor weight gain
Chronic diarrhea
Previous infections, especially pneumonia
Physical

Abnormal physical findings are primarily due to infection or GVHD and are not directly due to the primary immunodeficiency. The patient may present with the following:
Failure to thrive, manifesting as decreased weight, height, and head circumference
Dehydration from chronic diarrhea
Eczema from GVHD, especially in Omenn syndrome
Increased respiratory rate and effort and crepitations secondary to pneumonia (especially PCP)
Fever from sepsis, systemic fungal infections, or generalized herpes
No lymphadenopathy or increased tonsillar tissue despite serious infections
Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome
Neurological sequelae and developmental regression (loss of developmental milestones), especially in PNP deficiency (the cause of which is genetic, not infectious)
Causes
Genetic (molecular defects)
X-linked SCID: Mutation of the common gamma chain shared by multiple receptors (ie, IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a TCR rearrangement. Loss of IL-15R function leads to the ablation of NK cell development.
JAK3 deficiency: JAK3 is a PTK that associates with the common gamma chain shared by the multiple receptors listed above. This deficiency has the same clinical manifestations as those of X-linked SCID.
ADA and PNP deficiencies: These are associated with enzyme deficiencies in the purine salvage pathway; toxic metabolites are responsible for the destruction of lymphocytes that cause the immune deficiency.
Bare lymphocyte syndrome: This is associated with a molecular defect in the gene regulating MHC type II expression.
IL-2 production defects: These occur secondary to poorly defined defects in IL-2 production.
Omenn syndrome: This is associated with abnormalities in the Rag1 and Rag2 genes that are responsible for TCR and immunoglobulin rearrangement.
X-linked SCID: This is, of course, X-linked, while the other forms of SCID are autosomal recessive.
Usual pathogens
Pneumocystis carinii pneumonia
Atypical mycobacterium
Herpes viruses
Candidiasis and other systemic fungal infections
Cryptosporidium
Pneumococcus and other common bacteria

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