Severe Combined Immunodeficiency Scid

The family of disorders termed SCID stems from defects in lymphoid development that affect either T cells or both T and B cells. All forms of SCID have common features despite differences in the underlying genetic defects. Clinically, SCID is characterized by a very low number of circulating lymphocytes. There is a failure to mount immune responses mediated by T cells. The thymus does not develop, and the few circulating T cells in the SCID patient do not respond to stimulation by mitogens, indicating that they cannot proliferate in response to antigens. Myeloid and erythroid (red-blood-cell precursors) cells appear normal in number and function, indicating that only lymphoid cells are depleted in SCID.

SCID results in severe recurrent infections and is usually fatal in the early years of life. Although both the T and B lineages may be affected, the initial manifestation of SCID in infants is almost always infection by agents, such as fungi or viruses, that are normally dealt with by T-cell immunity. The B-cell defect is not evident in the first few months of the affected infant's life because antibodies are passively obtained from transplacental circulation or from mother's milk. SCID infants suffer from chronic diarrhea, pneumonia, and skin, mouth, and throat lesions as well as a host of other opportunistic infections. The immune system is so compromised that even live attenuated vaccines (such as the Sabin polio vaccine) can cause infection and disease. The life span of a SCID patient can be prolonged by preventing contact with all potentially harmful microorganisms, for example by confinement in a sterile atmosphere. However, extraordinary effort is required to prevent direct contact with other persons and with unfiltered air; any object, including food, that comes in contact with the sequestered SCID patient must first be sterilized. Such isolation is feasible only as a temporary measure, pending treatment.

The search for defects that underlie SCID has revealed several different causes for this general failure of immunity. A survey of 141 patients by Rebecca Buckley indicated that the most common cause (64 cases) was deficiency of the common gamma chain of the IL-2 receptor (IL-2R^; see Figure 12-7). Defects in this chain impede signaling through receptors for IL-4, -7, -9, and -15 as well as the IL-2 receptor, because the chain is present in receptors for all of these cy-tokines. Deficiency in the kinase JAK-3, which has a similar

Deficiency in JAK-3

Defect in y chain of receptors for IL-2, 4, 7, 9, 15

T cell

Defect in recombination-activating genes (RAG-1/2)

FIGURE 19-3

Defects in cell interaction and signaling can lead to severe immunodeficiency. The interaction of T cell and B cell is shown here with a number of the components important to the intra-and extracellular signaling pathways. A number of primary immunodeficiencies are rooted in defects in these interactions. SCID may result from defects in (1) the recombination-activating genes (RAG-1 and -2) required for synthesis of the functional immunoglobulins and T-cell receptors that characterize mature B and T cells; (2) the y chain expression of Class II MHC (bare lymphocyte syndrome)

Defect in Bruton's tyrosine kinase (XLA)

Deficiency in JAK-3

Defect in y chain of receptors for IL-2, 4, 7, 9, 15

Defect in Bruton's tyrosine kinase (XLA)

Jak3 Deficiency Chain Il2

T cell

Defect in recombination-activating genes (RAG-1/2)

expression of Class II MHC (bare lymphocyte syndrome)

of receptors for IL-2, 4, 7, 9, and 15 (IL-Ry); (3) JAK-3, which transduces signals from the gamma chain of the cytokine receptor; or (4) expression of the class II MHC molecule (bare lymphocyte syndrome). XLA results from defective transduction of activating signals from the cell-surface IgM by Bruton's tyrosine kinase (Btk). XHM results from defects in CD40L that preclude normal maturation of B cells. [Adapted from B. A. Smart and H. D. Ochs, 1997, Curr. Opin. Pediatr. 9:570]

phenotype because the IL receptors signal through this molecule, accounted for 9 of the cases (see Figure 12-10). A rare defect found in only 2 of the patients involved the IL-7 receptor; these patients have impaired T and B cells but normal NK cells. Another common defect is the adenosine deami-nase or ADA deficiency found in 22 patients. Adenosine deaminase catalyzes conversion of adenosine to inosine, and its deficiency results in accumulation of adenosine, which interferes with purine metabolism and DNA synthesis. The remaining cases included single instances of reticular dysge-nesis and cartilage hair dysplasia or were classified as autosomal recessive defects not related to known IL-2R^ or JAK-3 mutations. Thirteen of the 141 cases were of unknown origin, with no apparent genetic defect or family history of immunodeficiency.

There are other known defects that give rise to SCID. There is a defect characterized by depletion of CD8+ T cells that involves the tyrosine kinase ZAP-70, an important element in T-cell signal transduction (see Figures 10-11 and 10-12). Infants with defects in ZAP-70 may have normal levels of immunoglobulin and CD4+ lymphocytes, but their CD4+ T cells are nonfunctional. A deficiency in the enzyme purine nucleoside phosphorylase (PNP) causes immunodeficiency by a mechanism similar to the ADA defect. As described in Chapters 5 and 9, both immunoglobulin and T-cell receptor genes undergo rearrangement to express the active forms of these molecules. A defect in the genes that encode mediators of the rearrangement processes (recombination-activating proteins RAG-1 and RAG-2) precludes development of B and T cells with functional receptors and leads to SCID.

A defect leading to general failure of immunity similar to SCID is failure to transcribe the genes that encode class II MHC molecules. Without these molecules, the patient's lymphocytes cannot participate in cellular interactions with T helper cells. This type of immunodeficiency is also called the bare-lymphocyte syndrome. Molecular studies of a class II MHC deficiency revealed a defective interaction between a 5' promoter sequence of the gene for the class II MHC molecule and a DNA-binding protein necessary for gene transcription. Other patients with SCID-like symptoms lack class I MHC molecules. This rare variant of immunodeficiency was ascribed to mutation in the TAP genes that are vital to antigen processing by class I MHC molecules (see Clinical Focus Chapter 8). This defect causes a deficit in CD8-mediated immunity, characterized by susceptibility to viral infection. A recent case of SCID uncovered a defect in the gene for the cell-surface phosphatase CD45. Interestingly, this defect caused lack of ap T-cells but spared the 78 lineage.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Responses

  • Fulgenzio
    Does bare lymphocyte syndrome affect t cells?
    7 years ago

Post a comment