Abstract
Mixed connective tissue disease (MCTD) is a rare complex autoimmune disease in which autoantigens are recognized by endosomal TLRs. Their activation induces a higher secretion of the type I interferons, IFN-γ and the up-regulation of the INF-inducible genes. The present study aimed to investigate whether SNPs that are located in the IFN-A, IFN-B, and IFN-G genes are associated with MCTD. 145 MCTD patients and 281 healthy subjects were examined for IFN-A, IFN-B, and IFN-G genetic variants by TaqMan SNP genotyping assay. ELISA determined IFN-α/-β/-γ serum levels. Among the seven tested SNPs, four polymorphisms: IFN-A rs10757212, IFN-A rs3758236, IFN-G rs2069705, IFN-G rs2069718, as well as INF-G rs1861493A/rs2069705A/rs2069718G haplotype were significantly associated with a predisposition for MCTD. Raynaud’s phenomenon, erosive arthritis, swollen hands and fingers, and sclerodactyly were significantly more frequently observed in MCTD patients with IFN-G rs2069718 G allele than in patients with IFN-G rs2069718 A allele. We also found that anti-U1-A autoantibodies most frequently occurred in MCTD patients with rs2069718 GA genotype, while the IFN-G rs2069705 AG and rs2069718 GA genotypes might be a marker of anti-Ro60 presence in MCTD patients. Our results indicate that IFN-G genetic variants may be potential genetic biomarkers for MCTD susceptibility and severity.
Highlights
Autoimmune, systemic connective tissue diseases affect a small percentage of the general population
Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (DI), which assesses damage in systemic lupus erythematosus (SLE), we have developed an Mixed connective tissue disease (MCTD) damage scale consisting of clinical symptoms caused by a permanent result of the disease, its treatment or related diseases—Mixed Connective Tissue Disease—Damage Index (MCTD-DI) (Table S2 in Supplementary Files)
All of the MCTD patients had anti-U1-RNP antibodies: anti-70K was detected in 76% of patients, anti-A in 84% of patients, and anti-C in 79% of patients (Table 2)
Summary
Autoimmune, systemic connective tissue diseases affect a small percentage of the general population. The type I interferons, such as IFN-α and IFN-β, as well as IFN-γ (which is the only one type II class of interferons), are a family of pleiotropic cytokines with a wide spectrum of effects on adaptive and innate immune processes [15,16,17] They have a key role in the initiation and progression of autoimmune disease by the promotion of the prolonged survival of activated T lymphocytes, differentiation of the T helper 17 cells (Th17), higher expression of the proinflammatory cytokines and chemokines, as well as by the increase the production of B lymphocyte stimulator and stimulation of B cells proliferation [15,18,19]. The studies highlighted that the overexpression of IFN-inducible genes (IFN signature) is a marker for patients with active and severe CTD [24]
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