Molecular Basis of Severe Combined Immunodeficiency: Lessons from Cytokine Signaling Pathways

2003 ◽  
pp. 279-305
Author(s):  
Roberta Visconti ◽  
Fabio Candotti ◽  
John J. O'Shea
Keyword(s):  
Signaling Pathways ◽  
Molecular Basis ◽  
Severe Combined Immunodeficiency ◽  
Cytokine Signaling ◽  
Combined Immunodeficiency

scholarly journals The molecular basis of IL-21–mediated proliferation

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4135-4142 ◽  
Author(s):  
Rong Zeng ◽  
Rosanne Spolski ◽  
Esther Casas ◽  
Wei Zhu ◽  
David E. Levy ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Severe Combined Immunodeficiency ◽  
Type I ◽  
Combined Immunodeficiency ◽  
Knock Out ◽  
Tyrosine Residues ◽  
The Common ◽  
Knock Out Mice ◽  
Β Chain

AbstractInterleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells. The IL-21 receptor (IL-21R) is closely related to the IL-2 receptor β chain and is capable of transducing signals through its dimerization with the common cytokine receptor γ chain (γc), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency. To clarify the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain. Simultaneous mutation of all 6 tyrosines greatly diminished IL-21–mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation. Y510 efficiently mediated IL-21–induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8+ T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15. In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21–mediated proliferation. Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling.

Defective expression of the interleukin-2/interleukin-15 receptor β subunit leads to a natural killer cell–deficient form of severe combined immunodeficiency

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 877-879 ◽  
Author(s):  
Kimberly C. Gilmour ◽  
Hodaka Fujii ◽  
Treena Cranston ◽  
E. Graham Davies ◽  
Christine Kinnon ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Killer Cell ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Cytokine Signaling ◽  
Receptor Complex ◽  
Combined Immunodeficiency ◽  
Interleukin 15

Abstract Development of T and natural killer (NK) cells is critically dependent on cytokine signaling, and defects in cytokine receptor complex subunits have been shown to result in severe combined immunodeficiency (SCID) syndromes in humans and in murine models. An infant boy had typical clinical features of SCID and was found to lack NK cells in his peripheral circulation. Molecular analysis did not reveal abnormalities in his γc or JAK-3 genes, and he was investigated for defects in the interleukin-15 (IL-15) receptor complex because functional IL-15 signaling is essential for NK cell development. Expression of the IL-2R/IL-15Rβ chain was significantly reduced in the patient's peripheral blood mononuclear cells (PBMCs) by immunoblot, flow cytometry, and Northern blot analysis. Furthermore, IL-2 stimulation of PBMCs showed only minimal tyrosine phosphorylation of JAK-3. These data demonstrate that defects in IL-2R/1L-15Rβ expression can lead to a unique NK-deficient SCID immunophenotype.

The Genetic and Molecular Basis of Severe Combined Immunodeficiency

2014 ◽  
Vol 3 (1) ◽  
pp. 22-33 ◽  
Author(s):  
Capucine Picard ◽  
Despina Moshous ◽  
Alain Fischer
Keyword(s):  
Molecular Basis ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency
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