Combined immunodeficiencies due to defects in signal transduction: Defectsof the gamma(c)-JAK3 signaling pathway as a model

Combined immune deficiencies comprise a spectrum of genetic disorders chara cterized by developmental or functional defects of both T and B lymphocytes . Recent progress in cell biology and molecular genetics has unraveled the pathophysiology of most of these defects. In particular, the most common fo rm of severe combined immune deficiency in humans, with lack of circulating T cells, a normal or increased number of B lymphocytes, and an X-linked pa ttern of inheritance (SCIDX1) has been shown to be due to defects of the IL 2RG gene, encoding for the common gamma chain (gamma(c)), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through gam ma(c)-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional propertie s of cytokines that signal through the gamma(c)-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the k ey role of IL-7 in promoting T cell development has been substantiated by t he identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7R alpha). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity o f immunological phenotypes that may associate with defects in the same gene , thus creating a need for detailed immunological and molecular investigati ons in order to dissect the spectrum of combined immune deficiencies in hum ans.