The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies

Chistiakov, Dimitry A.; Voronova, Natalia V.; Chistiakov, Pavel A.

doi:10.1016/j.imlet.2008.03.002

Cited by 38 publications

(22 citation statements)

References 52 publications

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“…Other T1D–associated SNPs in the IL-2/IL-2R pathway occur in the IL-2 and CD25 genes (6,7,36–38). Others have recently shown that a protective haplotype of markers at the CD25 gene correlates with increased expression of CD25 (11,26,39).…”

Section: Discussionmentioning

confidence: 99%

An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells

et al. 2010

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The IL-2/IL-2R signaling pathway plays an important role in autoimmunity. Several genes identified in GWA studies encode proteins in the IL-2/IL-2R signaling cascade that are associated with autoimmune diseases. One of these, PTPN2, encodes a protein tyrosine phosphatase that is highly expressed in T cells and regulates cytokine signaling. An intronic risk allele in PTPN2, rs1893217(C), correlated with decreased IL-2R signaling in CD4+ T cells as measured by phosphorylation of STAT5 (pSTAT5). We modeled an additive SNP genotype, in which each copy of the risk allele conferred a decrease in IL-2R signaling (p=4.4×10−8). Decreased pSTAT5 impacted IL-2Rβ chain signaling resulting in reduced FOXP3 expression in activated cells. This phenotype was not due to overt differences in expression of the IL-2R, molecules in the IL-2R signaling cascade or defects in STAT5. However, the rs1893217(C) risk variant did correlate with decreased PTPN2 expression in CD4+CD45RO T cells (p=0.0002). Thus, the PTPN2rs1893217(C) risk allele associated with reduced pSTAT5 in response to IL-2 and reduced PTPN2 expression. Together, these data suggest that decreased expression of PTPN2 may indirectly modulate IL-2 responsiveness. These findings, identified through genotype/phenotype relationships, may lead to identification of novel mechanisms underlying dysregulation of cytokine signaling in autoimmunity.

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Section: Discussionmentioning

confidence: 99%

An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells

et al. 2010

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“…The involvement of IL-2 signaling in chronic inflammatory and autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes) is controversial (Ridderstad et al 1991;Sadlack et al 1993;Parkes et al 1998;Brennan and McInnes 2008;Chistiakov et al 2008). Certain autoimmune conditions, notably those involving inflammation of neurological tissues such as multiple sclerosis (MS) and uveitis, have been shown to be responsive to anti-IL2Ra antibodies (Dunn 2004;Martin 2008;Yeh et al 2008;Kim 2009;Bielekova and Becker 2010).…”

Section: Autoimmune Diseasementioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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“…cells, IL-2 augments cytotoxic activity and activates proliferation of memory CD8? cells [32]. Furthermore, IL-2 contributes to the production of IFN-c by human lymphocytes, suggesting that a cascade of lymphocyte-cell interactions participates in human immune responses [33].…”

Section: Introductionmentioning

confidence: 99%

Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase

Serti

Doumba

Thyphronitis

et al. 2010

Cell. Mol. Life Sci.

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Hepatitis C virus (HCV) has been shown to actively replicate in cells of the immune system, altering both their function and cytokine expression. Naked nucleocapsids have been reported in the serum of infected patients. We investigated interference of recombinant non-enveloped capsid-like particles with signaling pathways in T cells. HCV non-enveloped particles (HCVne) internalization was verified in Jurkat and Hut 78 T cells, as well as primary human peripheral blood and intrahepatic mononuclear cells. HCVne uptake leads to activation of the MAPKs-p38 signaling pathway. Using specific phosphoantibodies, signaling pathways inhibitors, and chemical agents, it was demonstrated that p38 activation in T cells correlated with IL-2 transcriptional activation and was accompanied by a parallel increase of IL-2 cytokine secretion. c-fos and egr-1, two transcription factors, essential for IL-2 promoter activity, were also found to be elevated. We propose that HCVne uptake by T lymphocytes results in increased MAPKs-p38 activity and IL-2 expression, thus altering the host immune response.

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The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies

Cited by 38 publications

References 52 publications

An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells

An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase

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