A <i>cis</i>-Acting Regulatory Variant in the <i>IL2RA</i> Locus

Qu, Hui; Verlaan, Dominique J.; Ge, Bing; Lü, Yang; Lam, Kevin C. L.; Grabs, Rosemarie; Harmsen, Eef; Hudson, Thomas J.; Hákonarson, Hákon; Pastinen, Tomi; Polychronakos, Constantin

doi:10.4049/jimmunol.0901337

Cited by 18 publications

(15 citation statements)

References 20 publications

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“…These data contradict previous studies that have suggested that a haplotype, best marked by rs3118470 increases T1D risk through diminished expression of the IL-2R. 19 …”

Section: Discussioncontrasting

confidence: 99%

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Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

et al. 2017

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T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.

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“…These data contradict previous studies that have suggested that a haplotype, best marked by rs3118470 increases T1D risk through diminished expression of the IL-2R. 19 …”

Section: Discussioncontrasting

confidence: 99%

“…The rs3118470 SNP has also been associated with differential allele expression of IL2RA messenger RNA. 19 …”

Section: Introductionmentioning

confidence: 99%

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

et al. 2017

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“…These occur in both CD25 hi T cells and memory Teff cells and include decreased IL2RA RNA and CD25 surface expression in Treg (confirmed in Figure S2) and memory Teff [25], [32], [34], increased frequency of CD25 + naive T cells [25], decreased response to IL-2 [32] and increased serum sIL-2RA [16], [24]. In contrast, the IL2RA rs2104286 risk haplotype, associated with both T1D and MS, only shares a subset of these phenotypes, including increased frequency of CD25 + naïve T cells and increased serum sIL-2RA.…”

Section: Discussionmentioning

confidence: 70%

Multiple Autoimmune-Associated Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 1 Diabetic and Multiple Sclerosis Patients

Cerosaletti¹,

Schneider²,

Schwedhelm³

et al. 2013

PLoS ONE

103

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IL-2 receptor (IL-2R) signaling is essential for optimal stability and function of CD4+CD25hiFOXP3+ regulatory T cells (Treg); a cell type that plays an integral role in maintaining tolerance. Thus, we hypothesized that decreased response to IL-2 may be a common phenotype of subjects who have autoimmune diseases associated with variants in the IL2RA locus, including T1D and MS, particularly in cells expressing the high affinity IL-2R alpha chain (IL-2RA or CD25). To examine this question we used phosphorylation of STAT5 (pSTAT5) as a downstream measure of IL-2R signaling, and found a decreased response to IL-2 in CD4+CD25hi T cells of T1D and MS, but not SLE patients. Since the IL2RArs2104286 haplotype is associated with T1D and MS, we measured pSTAT5 in controls carrying the rs2104286 risk haplotype to test whether this variant contributed to reduced IL-2 responsiveness. Consistent with this, we found decreased pSTAT5 in subjects carrying the rs2104286 risk haplotype. Reduced IL-2R signaling did not result from lower CD25 expression on CD25hi cells; instead we detected increased CD25 expression on naive Treg from controls carrying the rs2104286 risk haplotype, and subjects with T1D and MS. However the rs2104286 risk haplotype correlated with increased soluble IL-2RA levels, suggesting that shedding of the IL-2R may account in part for the reduced IL-2R signaling associated with the rs2104286 risk haplotype. In addition to risk variants in IL2RA, we found that the T1D-associated risk variant of PTPN2rs1893217 independently contributed to diminished IL-2R signaling. However, even when holding genotype constant at IL2RA and PTPN2, we still observed a significant signaling defect in T1D and MS patients. Together, these data suggest that multiple mechanisms converge in disease leading to decreased response to IL-2, a phenotype that may eventually lead to loss of tolerance and autoimmunity.

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“…This could indicate a defect in the cellular subset that is the source of cleaved IL2R␣. An alternative explanation may be that, even in the presence of normal Treg frequencies in T1D (70), IL2RA polymorphisms account for functional defects in the Treg compartment (72,346). In conclusion, it seems that although genetic variability in the IL2RA gene is associated with several autoimmune diseases including T1D, the mechanisms and extent to which sIL2R␣ levels mediate these conditions differs significantly.…”

Section: E Il2ramentioning

confidence: 74%

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Belle

Coppieters

Herrath

2011

Physiological Reviews

854

695

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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A cis-Acting Regulatory Variant in the IL2RA Locus

Cited by 18 publications

References 20 publications

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

Multiple Autoimmune-Associated Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 1 Diabetic and Multiple Sclerosis Patients

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

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