title: The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.
abstract: Type 1 Diabetes (T1D) is an autoimmune disorder characterized by aberrant T cell responses. Innate immune activation defects may facilitate a T helper 1 (Th1) phenotype. The cytokine IL-18 synergizes with IL-12 to induce IFNγ production and Th1 differentiation. The IL-18R subunit (IL18RAP) SNP rs917997 has been linked to decreased IL18RAP gene expression. Prior reports link rs917997 allele A with protection from T1D, and conversely with susceptibility to Celiac disease. However, few studies have investigated the IL-18 pathway in T1D. In this study, we analyzed responsiveness to IL-18 in T1D, and the effect of rs917997 genotype on IL18RAP gene expression post-activation. Upon IL-12 and IL-18 treatment, peripheral blood mononuclear cells from subjects carrying susceptibility alleles at rs917997 produced higher levels of IFNγ than those with protective genotypes. Additionally, the SNP modified IL18RAP surface protein expression by NK cells and gene expression in activated T cells. Taken together, these data suggest that the disease-associated rs917997 allele G permits hyperresponsiveness to IL-18, providing a novel target for therapeutic intervention in T1D.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Courtney B
authors.initials: CB
authors.lastname: Myhr
authors.forename: Maigan A
authors.initials: MA
authors.lastname: Hulme
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hong
authors.forename: Priya Saikumar
authors.initials: PS
authors.lastname: Lakshmi
authors.forename: Desmond A
authors.initials: DA
authors.lastname: Schatz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haller
authors.forename: Todd M
authors.initials: TM
authors.lastname: Brusko
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C115629:IL18RAP protein, human; D020382:Interleukin-18; D053728:Interleukin-18 Receptor beta Subunit; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Autoimmunity; Celiac disease; Genome wide association; IL-18; NK cells; Type 1 diabetes
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