title: The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.
abstract: We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK. Electronic address: pdimegl@nimr.mrc.ac.uk.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Napolitano
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Tosi
authors.affiliation: Department of Twin Research, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Terranova Barberio
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Rose K
authors.initials: RK
authors.lastname: Mak
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK.
authors.forename: Jonathan N W N
authors.initials: JNWN
authors.lastname: Barker
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: St John's Institute of Dermatology, NIHR Biomedical Research Centre, King's College London, London, UK. Electronic address: frank.nestle@kcl.ac.uk.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics* / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin
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