Identification of a novel G245R polymorphism in the IL-2 receptor β membrane proximal domain associated with human visceral leishmaniasis

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 b chain (IL-2Rb). Present at a frequency of 7.2%, the IL-2-Rb 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 ¼ 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 þ 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.

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

“…We previously identified variants of the IL2RB gene predisposing individuals infected with L. donovani to KA (14). This prompted us to evaluate the expression profiles of the genes of the IL-2 pathway in Leishmania-infected tissue.…”

“…However, the SNP associated with KA in Sudan (14) was not associated with CL in Brazilians. Further studies are therefore required to determine whether disease dissimilarities and/or different linkage disequilibrium structures between these two populations could account for such results.…”

“…Further studies are therefore required to determine whether disease dissimilarities and/or different linkage disequilibrium structures between these two populations could account for such results. Nevertheless, this work on L. braziliensis and L. tropica and our previous study in a L. donovani-infected population (14) show that polymorphisms of genes of the IL-2R alter human susceptibility to the leishmaniasis caused by various Leishmania species.…”

“…Certain polymorphisms in genes of the immune system have been shown to alter the risk of leishmaniasis, but only a few of the associations identified have been validated in genetically different populations and replicated in individuals infected with different Leishmania strains (11,12). We have shown that susceptibility to KA caused by Leishmania donovani in Sudan is linked to Chr22q12 (13) and that a mutation of the IL2RB gene, which encodes the b-chain of the IL-2R, may partly account for this linkage (14). The IL-2R is composed of three subunits: IL-2Ra (CD25, encoded by IL2RA), which is specific for IL-2 and confers high affinity to the receptor; IL-2Rb (CD122, encoded by IL2RB); and g c (CD132, encoded by IL2RG) (15).…”

Primed Antigen-Specific CD4+ T Cells Are Required for NK Cell Activation In Vivo upon Leishmania major Infection

“…We would then expect that deficiencies in IL-2 signaling pathways would have an impact on the outcome of the response. Interestingly, human genetic studies revealed an association of functional polymorphisms in the b-chain CD122 with visceral Leishmaniasis triggered by Leishmania donovani (60). Further work will be needed to demonstrate such a link.…”