Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2) is an inhibitory receptor broadly expressed on leukocytes and recognizes HLA-class I and human cytomegalovirus UL18. LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE). In this study, we screened for polymorphisms of LILRB1 and examined their association with SLE and rheumatoid arthritis (RA). In the 5' portion of LILRB1, three haplotypes containing four non-synonymous substitutions within the ligand-binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03. In the 3' portion, two haplotypes (CY01, 02) containing a non-synonymous substitution of the cytoplasmic region were identified. CY01 and 02 did not co-segregate with PE01-03. Significant association with susceptibility to SLE or RA was not observed; however, among the subjects not carrying RA-associated HLA-DRB1 shared epitope (SE), LILRB1.PE01/01 diplotype was significantly associated with RA (odds ratio 2.05, P = 0.019 and Pc = 0.038). Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype. These findings demonstrated that LILRB1 is highly polymorphic and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes. In addition, these observations suggested that the polymorphisms of LILR family members may be substantially involved in the diversity of human immune responses.

Objective. To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population.Methods. A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples.Results. Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P ‫؍‬ 8.3 ؋ 10 ؊5 ). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P ‫؍‬ 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P ‫؍‬ 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role.Conclusion. IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3 -untranslated region polymorphisms, appeared to play a crucial role.Over the last 2 decades, evidence has emerged of the involvement of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE) (1). Elevated serum levels of IFN in SLE patients have been reported (2), and gene expression analyses using microarrays have revealed IFN-inducible genes to be upregulated in peripheral blood cells from SLE patients (3-6).Recently, analyses of single-nucleotide polymorphisms (SNPs) in genes of the type I IFN pathway

IntroductionTNFAIP3 interacting protein 1, TNIP1 (ABIN-1) is involved in inhibition of nuclear factor-κB (NF-κB) activation by interacting with TNF alpha-induced protein 3, A20 (TNFAIP3), an established susceptibility gene to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recent genome-wide association studies revealed association of TNIP1 with SLE in the Caucasian and Chinese populations. In this study, we investigated whether the association of TNIP1 with SLE was replicated in a Japanese population. In addition, association of TNIP1 with RA was also examined.MethodsA case-control association study was conducted on the TNIP1 single nucleotide polymorphism (SNP) rs7708392 in 364 Japanese SLE patients, 553 RA patients and 513 healthy controls.ResultsAssociation of TNIP1 rs7708392C was replicated in Japanese SLE (allele frequency in SLE: 76.5%, control: 69.9%, P = 0.0022, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.13-1.74). Notably, the risk allele frequency in the healthy controls was considerably greater in Japanese (69.9%) than in Caucasians (24.3%). A tendency of stronger association was observed in the SLE patients with renal disorder (P = 0.00065, OR 1.60 [95%CI 1.22-2.10]) than in all SLE patients (P = 0.0022, OR 1.40 [95%CI 1.13-1.74]). Significant association with RA was not observed, regardless of the carriage of human leukocyte antigen DR β1 (HLA-DRB1) shared epitope. Significant gene-gene interaction between TNIP1 and TNFAIP3 was detected neither in SLE nor RA.ConclusionsAssociation of TNIP1 with SLE was confirmed in a Japanese population. TNIP1 is a shared SLE susceptibility gene in the Caucasian and Asian populations, but the genetic contribution appeared to be greater in the Japanese and Chinese populations because of the higher risk allele frequency. Taken together with the association of TNFAIP3, these observations underscore the crucial role of NF-κB regulation in the pathogenesis of SLE.

IntroductionThe Toll-like receptor 7 (TLR7) gene, encoded on human chromosome Xp22.3, is crucial for type I interferon production. A recent multicenter study in East Asian populations, comprising Chinese, Korean and Japanese participants, identified an association of a TLR7 single-nucleotide polymorphism (SNP) located in the 3' untranslated region (3' UTR), rs3853839, with systemic lupus erythematosus (SLE), especially in males, although some difference was observed among the tested populations. To test whether additional polymorphisms contribute to SLE in Japanese, we systematically analyzed the association of TLR7 with SLE in a Japanese female population.MethodsA case-control association study was conducted on eight tag SNPs in the TLR7 region, including rs3853839, in 344 Japanese females with SLE and 274 healthy female controls.ResultsIn addition to rs3853839, two SNPs in intron 2, rs179019 and rs179010, which were in moderate linkage disequilibrium with each other (r2 = 0.53), showed an association with SLE (rs179019: P = 0.016, odds ratio (OR) 2.02, 95% confidence interval (95% CI) 1.15 to 3.54; rs179010: P = 0.018, OR 1.75, 95% CI 1.10 to 2.80 (both under the recessive model)). Conditional logistic regression analysis revealed that the association of the intronic SNPs and the 3' UTR SNP remained significant after we adjusted them for each other. When only the patients and controls carrying the risk genotypes at the 3' UTR SNPpositionwere analyzed, the risk of SLE was significantly increased when the individuals also carried the risk genotypes at both of the intronic SNPs (P = 0.0043, OR 2.45, 95% CI 1.31 to 4.60). Furthermore, the haplotype containing the intronic risk alleles in addition to the 3' UTR risk allele was associated with SLE under the recessive model (P = 0.016, OR 2.37, 95% CI 1.17 to 4.80), but other haplotypes were not associated with SLE.ConclusionsThe TLR7 intronic SNPs rs179019 and rs179010 are associated with SLE independently of the 3' UTR SNP rs3853839 in Japanese women. Our findings support a role of TLR7 in predisposition for SLE in Asian populations.

These results suggest the involvement of MAIT cells in the pathogenesis of AS.

Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10−10, corrected P (Pc) = 1.59×10−8, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69–2.79), decreased DRB1*13:02 (P = 7.17×10−5, Pc = 0.0020, OR 0.46, 95% CI 0.34–0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18–0.63). Additionally, the “*15:01/*13:02 or *14:03” genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10−11, OR 2.39, 95% CI 1.84–3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.

Objectives We examined the effectiveness of plasma exchange (PE) therapy to reduce the mortality of rapidly progressive interstitial lung disease (RP-ILD) in patients positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Methods Among 142 patients newly diagnosed with PM/DM or clinically amyopathic DM from 2008 to 2019 at our hospital, 10 were diagnosed with refractory RP-ILD and were positive for anti-MDA5 antibodies. PE was used as an adjunct to standard therapy and consisted of fresh frozen plasma as replacement solution. The primary outcome was non-disease-specific mortality. Results Anti-MDA5 antibodies were detected in 28 patients, of whom 21 were diagnosed with RP-ILD and 10 were refractory to intensive immunosuppressive therapy. Six patients received PE (PE group) and four did not (non-PE group). The 1-year survival rate of the PE group was higher than that of the non-PE group (100% and 25%, respectively, P = 0.033). Regarding adverse events associated with PE, two patients had anaphylactic shock, one had high fever due to fresh frozen plasma allergy and one had a catheter infection. All adverse events resolved with appropriate treatment. Conclusion We evaluated the association between 1-year survival rate and PE for refractory RP-ILD in patients positive for anti-MDA5 antibodies. Intensive immunosuppressive therapy improved the survival rate in RP-ILD patients with anti-MDA5 antibodies, but 20–30% of cases were still fatal. PE could be administered to patients with active infectious disease who were immunocompromised by intensive immunosuppressive therapy. PE may be considered in refractory RP-ILD patients positive for anti-MDA5 antibodies.

Objective. SPI1, also referred to as PU.1, is an Ets family transcription factor that interacts with IRF2, IRF4, and IRF8. In view of the significance of the type I interferon pathway in systemic lupus erythematosus (SLE), this study was undertaken to investigate a possible association between SPI1 polymorphisms and SLE.Methods. A case-control association study was performed using 6 tag single-nucleotide polymorphisms (SNPs), as well as a SNP located upstream of SPI1 previously found to be associated with acute myelogenous leukemia, in 400 Japanese patients with SLE and 450 healthy controls. Resequencing of all exons and known regulatory regions was performed to identify functional polymorphisms. Association of genotype and SPI1 expression was examined using the GENEVAR database and reporter assays.Results. A significant association was detected in 2 SNPs in intron 2 (rs10769258 and rs4752829) (P ‫؍‬ 0.005 and P ‫؍‬ 0.008, respectively, under the dominant model). The association was stronger in patients with nephropathy. Resequencing identified a potentially functional polymorphism in the 3 -untranslated region (3 -UTR), rs1057233, which was in strong linkage disequilibrium with the SNPs in intron 2. The number of risk alleles at rs1057233 was strongly correlated with SPI1 messenger RNA (mRNA) level in the database analysis (P ‫؍‬ 0.0002), and was confirmed by a reporter assay. Interestingly, rs1057233 alters a target sequence for microRNA hsa-miR-569 (miR-569). Transfection experiments demonstrated that miR-569 inhibits expression of a reporter construct with the 3 -UTR sequence containing the nonrisk allele but not the risk allele.Conclusion. Our findings indicate that a SNP in the 3 -UTR of SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE.