Up-to-date information on polymyxin B-immobilized fiber column direct hemoperfusion for septic shock

Endotoxin adsorption therapy by polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) has been used for the treatment of septic shock patients. Endotoxin, an outer membrane component of Gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin triggers a signaling cascade for leukocytes, macrophage, and endothelial cells to secrete various mediators including cytokines and nitric oxide, leading to septic shock and multiple organ dysfunction syndrome. PMX-DHP directly adsorbed not only endotoxin but also monocytes and anandamide. It reduced blood levels of inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha and IL-17A, adhesion molecules, plasminogen activator inhibitor 1, and high mobility group box-1. As a result, PMX-DHP increased blood pressure and reduced the dose of vasoactive-inotropic agents. PMX-DHP improved monocyte human leukocyte antigen-DR expression in patients with severe sepsis and septic shock. A post hoc analysis of EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) trial has shown that PMX-DHP significantly reduced 28-day mortality compared with the control group in septic shock patients with endotoxin activity assay level between 0.60 and 0.89. Longer duration of PMX-DHP may be another strategy to bring out the beneficial effects of PMX-DHP. Further studies are needed to confirm the efficacy of PMX-DHP treatment for septic shock

Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study

INTRODUCTION: TNFAIP3 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. METHODS: A 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. RESULTS: Association 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. CONCLUSIONS: Association 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

TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study

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\u27 untranslated region (3\u27 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\u27 UTR SNP remained significant after we adjusted them for each other. When only the patients and controls carrying the risk genotypes at the 3\u27 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\u27 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\u27 UTR SNP rs3853839 in Japanese women. Our findings support a role of TLR7 in predisposition for SLE in Asian populations

Critical role of lectin pathway mediated by MBL-associated serine proteases in complement activation for the pathogenesis in systemic lupus erythematosus

In complement activation system, although the classical pathway has shown to play a critical role for the pathogenesis of SLE, the role of lectin pathway has remained unknown in the pathogenesis of SLE. As Mannose-binding lectin-associated serine proteases (MASPs) are associated with activation of the lectin pathway, we conducted this study to clarify MASPs associations in the pathogenesis of SLE. We evaluated the serum level of MASPs (MASP-1 and MASP-2) in total 68 SLE patients consisting of 15 patients with biopsy-confirmed membranous lupus nephritis (M-LN), 35 patients with biopsy-confirmed proliferative lupus nephritis (P-LN), and 18 SLE patients without LN (non-LN). Our data showed that the serum levels of MASPs were reduced in both P-LN and non-LN although those of M-LN were not reduced. Our data show that the lectin pathway mediated by MASPs plays a critical role for the pathogenesis of SLE except for M-LN

Association of HLA-G 3' Untranslated Region Polymorphisms with Systemic Lupus Erythematosus in a Japanese Population: A Case-Control Association Study.

HLA-G plays a role in fetal-maternal tolerance as well as immunoregulation, and has been suggested to be involved in autoimmune diseases and cancers. HLA-G encodes two potentially functional polymorphisms in the 3' untranslated region, 14bp insertion/deletion (14bp indel, rs371194629) and a single nucleotide polymorphism rs1063320, previously reported to affect HLA-G expression level or splicing isoform and to be associated with susceptibility to systemic lupus erythematosus (SLE). However, the results of SLE association studies are inconsistent, probably due to the small sample size of each study and lack of consideration of linkage disequilibrium (LD) with HLA-class II haplotypes in each population. In this study, we performed association studies of these polymorphisms on 843 patients with SLE and 778 healthy controls in a Japanese population, in many of whom HLA-DRB1 alleles have been genotyped at the four-digit level. LD was detected between DRB1*13:02, protective against multiple autoimmune diseases in the Japanese, and the rs1063320 G (D' = 0.86, r2 = 0.02) and with 14bp del (D' = 0.62, r2 = 0.01), but not between SLE-susceptible DRB1*15:01 and HLA-G. Although significant association with overall SLE was not detected, 14bp ins allele was significantly associated with SLE with the age of onset <20 years, when compared with healthy controls (P = 0.0067, PFDR = 0.039, OR 1.44, additive model) or with SLE patients with the age of onset ≥20 (P = 0.033, PFDR = 0.0495, OR 2.09, additive model). This association remained significant after conditioning on DRB1*13:02 or DRB1*15:01. On the other hand, significant association was detected between rs1063320 C and anti-RNP antibody and anti-Sm antibody positive SLE, which was dependent on negative LD with DRB1*13:02. eQTL analysis showed reduced HLA-G mRNA level in 14bp ins/ins individuals. In conclusion, our observations showed that HLA-G 14bp ins allele represents a genetic contribution on early-onset SLE independent of DRB1

Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03.

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