Combined Immunodeficiencies due to defects in signal transduction: Defects of the γ(c)-JAK3 signaling pathway as a model

L. D. Notarangelo, S. Giliani, P. Mella, R. Fabian Schumacher, C. Mazza, G. Savoldi, C. Rodriguez-Perez, R. Badolato, E. Mazzolari, F. Porta, F. Candotti, A. G. Ugazio

Research output: Contribution to journalArticlepeer-review


Combined immune deficiencies comprise a spectrum of genetic disorders characterized 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 form 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 pattern of inheritance (SCIDX1) has been shown to be due to defects of the IL2RG gene, encoding for the common gamma chain (γ(c)), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through γ(c)-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional properties of cytokines that signal through the γ(c)-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the α subunit of the IL-7 receptor (IL7Rα). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity of immunological phenotypes that may associate with defects in the same gene, thus creating a need for detailed immunological and molecular investigations in order to dissect the spectrum of combined immune deficiencies in humans.

Original languageEnglish
Pages (from-to)106-119
Number of pages14
Issue number2
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Immunology


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