Interferon regulatory factor 3 as key element of the interferon signature in
plasmacytoid dendritic cells from systemic lupus erythematosus patients: novel
genetic associations in the Mexican mestizo population
#MMPMID25130328
Santana-de Anda K
; Gómez-Martín D
; Monsivais-Urenda AE
; Salgado-Bustamante M
; González-Amaro R
; Alcocer-Varela J
Clin Exp Immunol
2014[Dec]; 178
(3
): 428-37
PMID25130328
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Many genetic studies have found an association between interferon regulatory
factors (IRF) single nucleotide polymorphisms (SNPs) and systemic lupus
erythematosus (SLE); however, specific dendritic cell (DC) alterations have not
been assessed. The aim of the present study was to address the expression of IRF3
and IRF5 on different DC subsets from SLE patients, as well as their association
with interferon (IFN)-? production and novel SNPs. For the genetic association
analyses, 156 SLE patients and 272 healthy controls from the Mexican mestizo
population were included. From these, 36 patients and 36 controls were included
for functional analysis. Two IRF3 SNPs?-?rs2304206 and rs2304204 - were
determined. We found an increased percentage of circulating pDC in SLE patients
in comparison to controls (8.04 ± 1.48 versus 3.35 ± 0.8, P = 0.032). We also
observed enhanced expression of IRF3 (64 ± 6.36 versus 36.1 ± 5.57, P = 0.004)
and IRF5 (40 ± 5.25 versus 22.5 ± 2.6%, P = 0.010) restricted to this circulating
pDC subset from SLE patients versus healthy controls. This finding was associated
with higher IFN-? serum levels in SLE (160.2 ± 21 versus 106.1 ± 14 pg/ml, P =
0.036). Moreover, the IRF3 rs2304206 polymorphism was associated with increased
susceptibility to SLE [odds ratio (OR), 95% confidence interval (CI)?= 2.401
(1.187-4.858), P = 0.021] as well as enhanced levels of serum type I IFN in SLE
patients who were positive for dsDNA autoantibodies. The IRF3 rs2304204 GG and AG
genotypes conferred decreased risk for SLE. Our findings suggest that the
predominant IRF3 expression on circulating pDC is a key element for the increased
IFN-? activation based on the interplay between the rs2304206 gene variant and
the presence of dsDNA autoantibodies in Mexican mestizo SLE patients.
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