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The STAT4 SLE risk allele rs7574865 T is associated with increased IL-12-induced
IFN-? production in T cells from patients with SLE
#MMPMID29475858
Hagberg N
; Joelsson M
; Leonard D
; Reid S
; Eloranta ML
; Mo J
; Nilsson MK
; Syvänen AC
; Bryceson YT
; Rönnblom L
Ann Rheum Dis
2018[Jul]; 77
(7
): 1070-1077
PMID29475858
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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)-?, IFN-? or interleukin (IL)-12, total levels of
STAT4, STAT1 and T-bet, and frequency of IFN-?(+) 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-?-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-?, and an augmented IL-12-induced IFN-? production in CD8(+) and CD4(+) T
cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-?-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-?. This subset of patients may benefit from
JAKi treatment.
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