Abstract
BackgroundType III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis.MethodsTaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-λ3 concentrations of SLE patients.ResultsAll major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, PFDR = 0.0021, OR 1.75, 95% CI 1.24–2.47; rs12979860C, PFDR = 0.0034, OR 1.65, 95% CI 1.18–2.30; rs4803217C, PFDR = 0.0021, OR 1.76, 95% CI 1.25–2.48; and ss469415590TT, PFDR = 0.0021, OR 1.73, 95% CI 1.23–2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis (P = 0.0015, OR 1.68, 95% CI 1.22–2.32). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, PFDR = 0.00177, OR 1.68, 95% CI 1.24–2.28; rs12979860T, PFDR = 0.00299, OR 1.58, 95% CI 1.18–2.32; rs4803217A, PFDR = 0.00176, OR 1.65, 95% CI 1.22–2.23; and ss469415590ΔG, PFDR = 0.00176, OR 1.70, 95% CI 1.26–2.29). Furthermore, the elevated serum levels of IFN-λ3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients.ConclusionsIFN-λ3/4 genetic variants play a unique role in the development of lupus nephritis and SLE.
Highlights
Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys
We demonstrated that IFNL3/4 genetic variants were significantly associated with systemic lupus erythematosus (SLE) susceptibility in lupus nephritis-negative patients
We found that the most common IFNL3/4 Single-nucleotide polymorphism (SNP) haplotype containing the rs4803217C allele was significantly associated with the low risk for SLE in nephritis-negative patients, confirming that a high producer of IFN-λ3 may have a protective role against SLE
Summary
Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. Type III interferons (IFNs) or IFN-λs (IFNLs) are newly discovered cytokines that mediate diverse immune functions [4]. IFN-λs are mainly produced by monocytes, macrophages, DCs, and bronchial epithelial cells in response to viral infections [4]. Accumulating evidence suggests that IFN-λs have a unique role in regulating innate and adaptive immune responses targeting microbial infections of epithelial cells expressing cognate receptor complexes [4, 6]
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