TheSTAT4SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE

Abstract

ObjectivesGenetic 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.MethodsPeripheral 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.ResultsIn 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.ConclusionsT 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.

Genetics of rheumatoid arthritis: 2018 status

“…Furthermore, eQTL variants can also indicate the direction of gene regulation (figure 3B). For example, upregulation of eQTL risk genes such as STAT4 60 and CCR6 61 has been linked to upregulated production of inflammatory cytokines in patients. As individual effects of eQTL variants are small, examining the overall effects of eQTL variants in the disease was attempted by combining the whole data sets from a GWAS and an eQTL study 62.…”

Interferon pathway in SLE: one key to unlocking the mystery of the disease

“…The intronic SLE-associated STAT4 SNPs are linked to a disease phenotype with an earlier onset and an increased risk for stroke and nephritis with severe renal insufficiency 67–69. We recently showed that activated T cells from STAT4 risk allele carriers with SLE have increased levels of STAT4 protein, resulting in more phosphorylated STAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production 70. In contrast, activated T cells from healthy individuals carrying the STAT4 risk allele displayed a decreased response.…”

Type I interferons in host defence and inflammatory diseases

“…A global transancestral association study of SLE using genomic data from more than 27 000 individuals, including 11 590 patients with SLE, confirmed that SLE risk has both ancestry-dependent and ancestry-independent contributors 50. Hagberg et al demonstrated increased T cell STAT4 responsiveness to interleukin (IL)-12 and IFN-α in patients with SLE carrying the STAT4 risk allele 51. Furthermore, healthy individuals with the risk gene variant have normal STAT4 responsiveness to IL-12, which can become ‘lupus like’ if cells from these individuals are exposed to IFN-α 52.…”