Cargando…
The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE
OBJECTIVES: Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of im...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029643/ https://www.ncbi.nlm.nih.gov/pubmed/29475858 http://dx.doi.org/10.1136/annrheumdis-2017-212794 |
_version_ | 1783337003121639424 |
---|---|
author | Hagberg, Niklas Joelsson, Martin Leonard, Dag Reid, Sarah Eloranta, Maija-Leena Mo, John Nilsson, Magnus K Syvänen, Ann-Christine Bryceson, Yenan T Rönnblom, Lars |
author_facet | Hagberg, Niklas Joelsson, Martin Leonard, Dag Reid, Sarah Eloranta, Maija-Leena Mo, John Nilsson, Magnus K Syvänen, Ann-Christine Bryceson, Yenan T Rönnblom, Lars |
author_sort | Hagberg, Niklas |
collection | PubMed |
description | OBJECTIVES: Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ(+) cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs. RESULTS: In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8(+) T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8(+) and CD4(+) T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively. CONCLUSIONS: T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment. |
format | Online Article Text |
id | pubmed-6029643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-60296432018-07-06 The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE Hagberg, Niklas Joelsson, Martin Leonard, Dag Reid, Sarah Eloranta, Maija-Leena Mo, John Nilsson, Magnus K Syvänen, Ann-Christine Bryceson, Yenan T Rönnblom, Lars Ann Rheum Dis Basic and Translational Research OBJECTIVES: Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ(+) cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs. RESULTS: In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8(+) T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8(+) and CD4(+) T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively. CONCLUSIONS: T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment. BMJ Publishing Group 2018-07 2018-02-23 /pmc/articles/PMC6029643/ /pubmed/29475858 http://dx.doi.org/10.1136/annrheumdis-2017-212794 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Basic and Translational Research Hagberg, Niklas Joelsson, Martin Leonard, Dag Reid, Sarah Eloranta, Maija-Leena Mo, John Nilsson, Magnus K Syvänen, Ann-Christine Bryceson, Yenan T Rönnblom, Lars The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title | The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title_full | The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title_fullStr | The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title_full_unstemmed | The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title_short | The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE |
title_sort | stat4 sle risk allele rs7574865[t] is associated with increased il-12-induced ifn-γ production in t cells from patients with sle |
topic | Basic and Translational Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029643/ https://www.ncbi.nlm.nih.gov/pubmed/29475858 http://dx.doi.org/10.1136/annrheumdis-2017-212794 |
work_keys_str_mv | AT hagbergniklas thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT joelssonmartin thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT leonarddag thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT reidsarah thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT elorantamaijaleena thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT mojohn thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT nilssonmagnusk thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT syvanenannchristine thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT brycesonyenant thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT ronnblomlars thestat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT hagbergniklas stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT joelssonmartin stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT leonarddag stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT reidsarah stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT elorantamaijaleena stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT mojohn stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT nilssonmagnusk stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT syvanenannchristine stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT brycesonyenant stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle AT ronnblomlars stat4sleriskallelers7574865tisassociatedwithincreasedil12inducedifngproductionintcellsfrompatientswithsle |