Abstract
Binding of the interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) triggers a series of intracellular events culminating in lymphocyte proliferation and differentiation. We report here the identification of a novel G245R polymorphism in the membrane proximal domain of the IL-2 receptor β chain (IL-2Rβ). Present at a frequency of 7.2%, the IL-2-Rβ G245R was identified in a population of Eastern Sudan exposed to a severe outbreak of visceral leishmaniasis (VL), a disease associated with a marked depression of T-cell antigen-specific responses. The location of the G245R polymorphism next to the box1/box2 proximal cytokine receptor homology segment and suggestive genetic association with the development of disease (P=0.043), suggest that it may affect Janus kinase (JAK) association and impair growth signal transduction. However, additional genetic association with a synonymous single nucleotide polymorphism (IL2RB+8777T) suggests that other variations of IL2RB or nearby genes participate in the highly significant linkage with VL at 22q12 previously reported for this population.
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Lin JX, Leonard WJ . Signaling from the IL-2 receptor to the nucleus. Cytokine Growth Factor Rev 1997; 8: 313–332.
Nelson BH . IL-2, regulatory T cells, and tolerance. J Immunol 2004; 172: 3983–3988.
Dutcher J . Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Williston Park) 2002; 16 (11 Suppl 13): 4–10.
Jacobson EL, Pilaro F, Smith KA . Rational interleukin-2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci USA 1996; 93: 10405–10410.
Waldmann TA, O'Shea J . The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol 1998; 10: 507–512.
Kozanidou VI, Theocharis AD, Georgiadis A, Voulgari PV, Drosos AA, Karamanos NK . Signal transduction by IL-2 and its receptors as target in treatment of rheumatoid arthritis. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 41–50.
Gaffen SL . Signaling domains of the interleukin-2 receptor. Cytokine 2001; 14: 63–77.
Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M et al. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 1994; 266: 1042–1045.
Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 1994; 266: 1045–1047.
Ellery JM, Nicholls PJ . Alternate signalling pathways from the interleukin-2 receptor. Cytokine Growth Factor Rev 2002; 13: 27–40.
Locksley RM, Pingel S, Lacy D, Wakil AE, Bix M, Fowell DJ . Susceptibility to infectious diseases: Leishmania as a paradigm. J Infect Dis 1999; 179 (Suppl 2): S305–S308.
Ho M, Koech DK, Iha DW, Bryceson AD . Immunosuppression in Kenyan visceral leishmaniasis. Clin Exp Immunol 1983; 51: 207–214.
Carvalho EM, Badaro R, Reed SG, Jones TC, Johnson Jr WD . Absence of gamma interferon and interleukin-2 production during active visceral leishmaniasis. J Clin Invest 1985; 76: 2066–2069.
Eslami Z, Olivier M, Tanner CE . Immunotherapy with IL-2-stimulated splenocytes reduces in vitro the level of Leishmania donovani infection in peritoneal macrophages. Int J Parasitol 1995; 25: 975–981.
Carvalho EM, Bacellar O, Brownell C, Regis T, Coffman RL, Reed SG . Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis. J Immunol 1994; 152: 5949–5956.
Barral-Netto M, Barral A, Santos SB, Carvalho EM, Badaro R, Rocha H et al. Soluble IL-2 receptor as an agent of serum-mediated suppression in human visceral leishmaniasis. J Immunol 1991; 147: 281–284.
Bucheton B, Abel L, El-Safi S, Kheir MM, Pavek S, Lemainque A et al. A major susceptibility locus on chromosome 22q12 plays a critical role in the control of kala-azar. Am J Hum Genet 2003; 73: 1052–1060.
Bucheton B, Kheir MM, El-Safi SH, Hammad A, Mergani A, Mary C et al. The interplay between environmental and host factors during an outbreak of visceral leishmaniasis in eastern Sudan. Microbes Infect 2002; 4: 1449–1457.
EL-Safi S, Bucheton B, Kheir MM, Musa HA, M EL-O, Hammad A et al. Epidemiology of visceral leishmaniasis in Atbara River area, eastern Sudan: the outbreak of Barbar El Fugara village (1996–1997). Microbes Infect 2002; 4: 1439–1447.
Howard OM, Kirken RA, Garcia GG, Hackett RH, Farrar WL . Structural domains of interleukin-2 receptor beta critical for signal transduction: kinase association and nuclear complex-formation. Biochem J 1995; 306 (Part 1): 217–224.
Liu KD, Lai SY, Goldsmith MA, Greene WC . Identification of a variable region within the cytoplasmic tail of the IL-2 receptor beta chain that is required for growth signal transduction. J Biol Chem 1995; 270: 22176–22181.
Goldsmith MA, Xu W, Amaral MC, Kuczek ES, Greene WC . The cytoplasmic domain of the interleukin-2 receptor beta chain contains both unique and functionally redundant signal transduction elements. J Biol Chem 1994; 269: 14698–14704.
Kirken RA, Rui H, Malabarba MG, Howard OM, Kawamura M, O'Shea JJ et al. Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain. Cytokine 1995; 7: 689–700.
Zhu MH, Berry JA, Russell SM, Leonard WJ . Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to IL-2Rbeta. J Biol Chem 1998; 273: 10719–10725.
Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O . Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 1995; 13: 369–398.
Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
Lake SL, Blacker D, Laird NM . Family-based tests of association in the presence of linkage. Am J Hum Genet 2000; 67: 1515–1525.
Nishikawa K, Saito S, Morii T, Kato Y, Narita N, Ichijo M et al. Differential expression of the interleukin-2 receptor beta (p75) chain on human peripheral blood natural killer subsets. Int Immunol 1990; 2: 481–486.
Espinoza-Delgado I, Ortaldo JR, Winkler-Pickett R, Sugamura K, Varesio L, Longo DL . Expression and role of p75 interleukin-2 receptor on human monocytes. J Exp Med 1990; 171: 1821–1826.
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This work was supported by a Grant IC 18 CT 98 0373 (European Commission) by the French Research Ministry Programme PRFMMIP/Microbiology and by INSERM.
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Bucheton, B., Argiro, L., Chevillard, C. et al. Identification of a novel G245R polymorphism in the IL-2 receptor β membrane proximal domain associated with human visceral leishmaniasis. Genes Immun 8, 79–83 (2007). https://doi.org/10.1038/sj.gene.6364355
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DOI: https://doi.org/10.1038/sj.gene.6364355
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