Severe combined immunodeficiency disease SCID

Severe combined immunodeficiency disease (SCID) affects one in every 80 000 live births. It is the most severe form of primary immunodeficiency with a number of different causes. Affected individuals have abnormalities affecting T, B and NK cells, which prevent the development of normal cell-mediated or humoral responses. One of the features of this disease is lymphopenia (severely reduced numbers of circulating lymphocytes), which is largely due to an extremely low number of T cells that may fail to express MHC gene products (see the section on Bare lymphocyte syndrome). Indeed, the severity of the T cell depletion is reflected in the fact that despite the overall lymphopenia, B cells may be increased in number. In addition, affected individuals generally have very low serum levels of all classes of immunoglobulin and fail to produce specific antibodies following immunisation or infection. At least eight types of SCID can be distinguished according to the clinical signs and symptoms and the inheritance pattern of the disease.

Due to the T cell abnormality, shortly after birth affected babies may develop disseminated yeast infections (usually caused by Monilia spp.), severe pneumonia (caused by Pneumocystis carinii) and recurrent infections caused by other opportunistic pathogens (organisms which, in healthy individuals, are normally prevented from causing disease by the immune system). Since these infections usually affect the skin and the pulmonary and gastrointestinal tracts, their prevalence in patients with SCID suggests that the defect also affects the immune mechanisms normally involved in surface and mucosal immunity. Since both the cell-mediated and humoral systems are affected, patients may die as a result of infection with common viruses such as varicella, herpes and cytomegalovirus. In addition, affected children often have chronic diarrhoea and malabsorption of nutrients from the gut, resulting in a failure to thrive.

The disease is inherited as an autosomal or X-linked, recessive trait. In recent years, clear progress has been made in identifying the genetic lesions leading to the different types of disease. We will consider some of the most common forms of SCID below.

X-LINKED SEVERE COMBINED IMMUNODEFICIENCY DISEASE (XSCID)

The most common form of SCID is X-linked SCID (XSCID), which accounts for 50-60% of all cases of the disease. It is characterised by a severe decrease in the numbers of circulating T and natural killer (NK) cells. B cells are usually normal or increased in number, although their functionality is affected by the lack of T cell help. Histologically, thymic tissue from these patients shows a lack of differentiation between the cortex and medulla, few thymocytes and no Hassal's corpuscles. In addition, the peripheral lymphoid organs are also hypoplastic.

The locus for the genetic defect associated with XSCID was mapped to Xq12-13.1 and this led to the identification in XSCID patients of mutations in the gene encoding the g chain of the IL-2 receptor (IL-2R), which is found in this region. This g chain is common to a number of other cytokine receptors (i.e. IL-4, 7, 9 and 15) and is the signal-transducing molecule for each of these cytokines (gc). Defects in this chain mean that these cytokines are unable to induce the cellular responses seen in normal cells as a result of binding to their respective receptors.

As a result of receptor ligation, a series of downstream molecular interactions occur resulting in the regulation of transcription of certain genes. The downstream interactions (signalling pathway) that occur after gc ligation comprise the Jak-STAT pathway. When IL-2, IL-4, IL-7, IL-9 or IL-15 bind to their respective receptors, the common gamma chain activates an enzyme known as the Janus family tyrosine kinase 3 (Jak-3). In addition, receptor-specific chains (namely IL-2Rb (for IL-2 and IL-15), IL-4Ra, IL-7Ra and IL-9Ra) associate with Jak-1. Thus, since gc-dependent signalling is dependent on Jak-3, mutations in the gene encoding this protein would lead to identical defects to those seen in individuals with mutations in the gc gene. Thus, the defect in XSCID is defined as defective gc-dependent activation of Jak-3 and mutations in those genes encoding either gc or Jak-3 can result in disease.

Upon receptor-ligand interaction, Jak-3 binds to the intracellular tail of gc and is activated resulting in the phosphorylation of the STAT-5 protein. These phosphorylated proteins dimerise and translocate to the nucleus where they induce the transcription of a number of genes involved in cellular replication.

Immunologically, XSCID is characterised by the developmental failure of T and NK cells. IL-7 is known to regulate T cell development in the thymus. In humans, it does not appear to affect B cell development. Evidence has demonstrated that at least one cause of XSCID is abnormal IL-7Ra-dependent signalling. The NK cell abnormalities are probably due to defective IL-15 signalling. The other cytokines affected by the mutations identified in XSCID (namely in gc or Jak-3) do not appear to contribute to the abnormalities observed in the disease. This may be due to the fact that signalling via these receptors does not occur during normal T cell development prior to the key signalling required from IL-7.

SCID WITH ADENOSINE DEAMINASE DEFICIENCY (ADA-SCID)

ADA-SCID is inherited as an autosomal, recessive trait and accounts for 20% of the cases of SCID. The severe immune defect characteristic of this condition is a direct consequence of a deficiency in the enzyme adenosine deaminase (ADA), which is part of the salvage pathway of purine metabolism. ADA catalyses the conversion of adenosine (Ado) to inosine and deoxyadenosine (dAdo) to deoxyinosine. Individuals with ADA-SCID show severe T, B and NK lymphocytopaenia.

In ADA-deficient individuals, adenosine and dAdo accumulate intra-cellularly (as well as extracellularly) and become phosphorylated to deoxyATP (dATP), a compound that is toxic to lymphocytes and is normally not detected at high levels in mammalian cells. Although ADA is normally present in all cells of the body, its absence presents as a defect that characteristically affects the cells of the immune system alone. This is due to the fact that in most tissues, dATP is reversibly degraded into DADO. However, lymphocytes (particularly immature cells) have little ability so to do. dATP inhibits the activity of ribonucleotide reductase, an enzyme required for generation of the other deoxynucleotides. In their absence, DNA synthesis cannot proceed and thus cell division is inhibited.

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