TLR7/8/9 polymorphisms and their associations in systemic lupus erythematosus patients from southern Brazil

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and can affect several organs and systems. It is characterized by high production of autoantibodies against nuclear compounds. TLR7/8/9 are responsible for nucleic acid recognition and they trigger proinflammatory responses through activation of NK-kappaB and Type I IFN production, making a bridge between the innate and the adaptative immune systems. We analyzed the frequency of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and rs352140 in 370 patients with SLE and 415 healthy controls from southern Brazil. All analyses were conducted with regard to gender and ethnicity. Genotypic and allelic frequencies were different for TLR7 rs179008 (0.253 vs. 0.163, p = 0.020 and p = 0.003, OR for T allele: 1.74 CI 95% 1.12-2.70) and TLR9 rs5743836 (0.174 vs. 0.112, p = 0.045 and p = 0.017, OR for C allele: 1.59, CI 95% 0.99-2.57) between European-derived female groups. A higher frequency was observed for the presence of Anti-SSa/Ro for TRL9 rs5743836 C allele carriers (0.228 vs 0.126, Bonferroni corrected p = 0.06). No statistical differences were found for TLR9 haplotypic analyses. We suggest that TLR7 rs179008 and TLR9 rs5743836 can be considered SLE susceptibility factors for women of European descent in our population.     

TLR9 polymorphisms and systemic lupus erythematosus risk: an update meta-analysis study

It has been reported that the Toll-like receptor 9 (TLR9) gene polymorphisms may be associated with systemic lupus erythematosus (SLE) risk. However, some studies yielded conflicting results. Therefore, a comprehensive meta-analysis was performed to assess the precise association between TLR9 polymorphisms and SLE susceptibility. We performed a systematic search in PubMed, Embase (Ovid), China National Knowledge Internet, and Wanfang databases up to July 15, 2015. Odds ratio (OR) and 95 % confidence interval (CI) were used to pool the effect size. Statistical analyses were performed with STATA 11.0 software. In total, 21 studies from nineteen articles with 10,273 subjects were included in this meta-analysis. The overall results suggested that there was a statistically significant association between TLR9 rs187084 polymorphism and SLE risk observed in recessive model (TT vs. TC + CC: OR 1.17, 95 % CI 1.05–1.30, P = 0.005), codominant model (TT vs. CC: OR 1.22, 95 % CI 1.03–1.43, P = 0.019), and allele model (T vs. C: OR 1.15, 95 % CI 1.02–1.30, P = 0.020) in Asians. However, we found that there may be no significant association between the other three TLR9 polymorphisms and SLE risk in either Asians or non-Asians. In conclusion, the meta-analysis results suggested that TLR9 rs187084 polymorphism may increase the risk of SLE in Asians. However, no significant association between TLR9 SNPs (rs352139, rs352140, and rs5743836) and SLE risk was identified.     

Lack of association of Toll-like receptor 9 polymorphisms with susceptibility to systemic lupus erythematosus in an Asian population: a meta-analysis

The association of Toll-like receptor 9 (TLR9) gene polymorphisms with systemic lupus erythematosus (SLE) risk remains controversial and ambiguous. To more precisely estimate the relationship between TLR9 gene polymorphisms and the susceptibility to SLE, a meta-analysis was performed. A total of seven independent studies were involved in this analysis. Meta-analysis was performed for three TLR9 gene polymorphisms (rs187084, rs352139, and rs352140). We have compared allele or genotype frequencies of the polymorphisms in SLE patients and controls. When available studies were pooled into the meta-analysis, there was no evidence showing a significant association between rs187084 and SLE risk in an Asian population (for C vs. T: OR?=?0.81, P?=?0.117; for CC vs. TT: OR?=?0.71, P?=?0.158; for CT vs. TT: OR?=?0.86, P?=?0.085; for CC?+?CT vs. TT: OR?=?0.78, P?=?0.093; for CC vs. CT?+?TT: OR?=?0.81, P?=?0.285). Similar results were found between rs352139 and SLE. No significant association was detected in any genetic model in the Asian population either (for G vs. A: OR?=?1.11, P?=?0.095; for GG vs. AA: OR?=?1.32, P?=?0.238; for GA vs. AA: OR?=?1.17, P?=?0.084; for GG?+?GA vs. AA: OR?=?1.17, P?=?0.073; for GG vs. GA?+?AA: OR?=?1.17, P?=?0.404). We found no association between TLR9 gene rs352140 polymorphism and SLE in the Asian population (for A vs. G: OR?=?1.02, P?=?0.728). In conclusion, there is still not enough evidence to indicate an association between TLR9 gene rs187084, rs352139, and rs352140 polymorphisms and the development of SLE in the Asian population.     

Lack of association of Toll-like receptor 9 polymorphisms with susceptibility to systemic lupus erythematosus in an Asian population: a meta-analysis

Abstract

The association of Toll-like receptor 9 (TLR9) gene polymorphisms with systemic lupus erythematosus (SLE) risk remains controversial and ambiguous. To more precisely estimate the relationship between TLR9 gene polymorphisms and the susceptibility to SLE, a meta-analysis was performed. A total of seven independent studies were involved in this analysis. Meta-analysis was performed for three TLR9 gene polymorphisms (rs187084, rs352139, and rs352140). We have compared allele or genotype frequencies of the polymorphisms in SLE patients and controls. When available studies were pooled into the meta-analysis, there was no evidence showing a significant association between rs187084 and SLE risk in an Asian population (for C vs. T: OR = 0.81, P = 0.117; for CC vs. TT: OR = 0.71, P = 0.158; for CT vs. TT: OR = 0.86, P = 0.085; for CC + CT vs. TT: OR = 0.78, P = 0.093; for CC vs. CT + TT: OR = 0.81, P = 0.285). Similar results were found between rs352139 and SLE. No significant association was detected in any genetic model in the Asian population either (for G vs. A: OR = 1.11, P = 0.095; for GG vs. AA: OR = 1.32, P = 0.238; for GA vs. AA: OR = 1.17, P = 0.084; for GG + GA vs. AA: OR = 1.17, P = 0.073; for GG vs. GA + AA: OR = 1.17, P = 0.404). We found no association between TLR9 gene rs352140 polymorphism and SLE in the Asian population (for A vs. G: OR = 1.02, P = 0.728). In conclusion, there is still not enough evidence to indicate an association between TLR9 gene rs187084, rs352139, and rs352140 polymorphisms and the development of SLE in the Asian population.     

Association of toll-like receptor 9 gene polymorphism in Chinese patients with systemic lupus erythematosus in Taiwan

The purpose of this study was to determine whether toll-like receptor 9 (TLR9) gene polymorphisms were markers of susceptibility to or severity of systemic lupus erythematosus (SLE) in Taiwanese patients. The study included 211 healthy individuals and 167 Chinese patients with SLE. Polymorphisms of TLR9 [rs2066807 and rs187084 (?1486 T/C)] were typed from genomic DNA. The genotypes, allelic frequencies, and carriage rates were compared between patients with SLE and control subjects. The relationship between allelic frequencies and clinical manifestations of 167 patients with SLE was evaluated. There was no statistically significant difference in TLR9 (rs2066807) gene polymorphism, allelic frequency, and carriage rate between the SLE and control groups. However, for the genotype of TLR9 ?1486 T/C (rs187084) polymorphism, there was a statistically significant difference between the SLE and the control groups (P?<?0.001, χ²?=?15.9). Moreover, there was a significant association between the two groups in allelic frequency and carriage rate of the T allele (P?<?0.001, χ²?=?18.5 and P?<?0.01, χ²?=?8.06, respectively). We did not detect any association between the TLR9 genotype and the clinical or laboratory profiles in patients with SLE. The results suggest that the TLR9 ?1486 T/C (rs187084), but not TLR9 (rs2066807), polymorphism is related to SLE in Taiwanese patients.     

Toll-like receptor (TLR9) -1486 T/C (rs187084) gene polymorphism in Egyptian patients with rheumatoid arthritis

Aim of the workThe aim of the study was to assess the role of Toll-like receptor-9 (TLR9) gene polymorphism in rheumatoid arthritis (RA) and to evaluate its association with disease activity and severity in Egyptian patients.Patients and methodsThe study included 100 RA patients and 100 matched controls. Genotyping of TLR9 -1486 T/C (rs187084) gene polymorphism for all participants was performed. Medical Records-Based Index of Severity (RARBIS), modified Health Assessment Questionnaire (mHAQ), disease activity score (DAS28) and clinical and laboratory parameters of disease activity were assesses in RA patients. Anti-cyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) were also determined.ResultsThe patients mean age was 43.7 ± 8.9 years and were 73 females and 27 males with mean disease duration of 13.3 ± 6.2 years. The mean DAS28 was 3.5 ± 1.1, RARBIS was 6.6 ± 2.8 and the mHAQ 1.4 ± 0.8. The frequency of the TLR9 TT genotype carriers were significantly higher in RA patients than in controls (27% and 9% respectively). Similarly, the T allele was significantly more frequent in RA patients in comparison to the controls (56.5% and 42% respectively). No significant association was found between the TLR9 genotypes with the gender or the age at disease onset. The clinical and laboratory parameters reflecting disease activity showed no association with the TLR9 genotype. No significant association was found between the TRL9 genotyping with the RARBIS or presence of RF or anti-CCP antibodies.ConclusionTLR9 gene polymorphism -1486 T/C is associated with the increased RA susceptibility in Egyptian patients.     

Different genetic effects of interferon regulatory factor 5 (IRF5) polymorphisms on systemic lupus erythematosus in a Korean population

OBJECTIVE: .In an effort to replicate additional associations of interferon regulatory factor 5 (IRF5) polymorphisms with systemic lupus erythematosus (SLE) in an Asian population, we examined those genetic effects in a Korean SLE cohort. METHODS: Each IRF5 polymorphism was genotyped in 1565 subjects using the TaqMan method and examined to determine whether it could explain the association with SLE. RESULTS: Three single-nucleotide polymorphisms (IRF5-15-1, rs2070197, and rs10488631), which showed strong and/or independent association in Caucasian populations, were not polymorphic in our Korean population. Association analysis revealed different genetic effects in Koreans compared with Caucasian populations. In addition, conditional analysis suggested independent genetic effects of 3 variant groups in the Korean population. CONCLUSION: We demonstrate different genetic effects of IRF5 polymorphisms on the risk of SLE according to ethnicity.     

Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population

BACKGROUND: Systemic lupus erythematosus (SLE) is characterised by dysregulation of autoreactive lymphocytes and antigen-presenting cells. Signalling through Toll-like receptor 9 (TLR9), a mediator of innate immune responses, has a role in activation of dendritic cells and autoreactive B cells. OBJECTIVE: To investigate whether TLR9 polymorphisms are associated with an increased risk of SLE. METHODS: DNA samples were obtained from 220 Japanese patients with SLE (with >4 American College of Rheumatology criteria for SLE) and 203 controls. The genetic variations of TLR9 were detected by PCR, followed by DNA sequencing. The promoter and enhancer activities of TLR9 were measured by luciferase reporter gene assay. The titres of anti-dsDNA antibodies in sera from control or TLR9-deficient mice were analysed by ELISA. RESULTS: The G allele at position +1174 (located in intron 1 of TLR9) is closely associated with an increased risk of SLE (p = 0.029). Furthermore, patients with SLE tend to have C allele at position -1486 (p = 0.11). Both alleles down regulate TLR9 expression by reporter gene assay. TLR9-deficient mice under a C57BL/6 background possess higher titres of anti-dsDNA serum antibodies than control C57BL/6 mice. CONCLUSIONS: These results indicate that the presence of the G allele at position +1174 of TLR9 predisposes humans to an increased risk of SLE. It is speculated that TLR9 normally prevents the development of human SLE.     

Toll-like Receptor and Hepatitis B Virus Clearance in Chronic Infected Patients: A Long-Term Prospective Cohort Study in Taiwan

Background.We sought to elucidate the impacts of the Toll-like receptors (TLRs) on spontaneous hepatitis B virus (HBV) e antigen (HBeAg) and hepatitis B s antigen (HBsAg) seroconversion in chronic HBV-infected patients. Methods.Human TLR2, TLR4, TLR5, and TLR9 gene polymorphisms were assessed in 278 HBeAg-positive, chronic HBV-infected patients. Additionally, HBV core antigen (HBcAg) in vitro stimulation using peripheral blood mononuclear cells (PBMCs) from 113 patients was done to assess interferon γ (IFN- γ) production. Results.Of the study subjects, 204 (73.4%) developed spontaneous HBeAg seroconversion, 21 (7.6%) developed spontaneous HBsAg clearance, and 10 (3.6%) had spontaneous HBsAg seroconversion during the 19.1?±?9.9 years of follow-up. The T allele at TLR5 rs5744174 (p.Phe616Leu) and the C allele at TLR9 rs5743836 promoter predicted earlier HBeAg seroconversion (hazard ratios [HRs], 2.45 and 3.65; P?=?.04, and .006, respectively). The TLR5 rs5744174 T allele carriers have higher PBMCs IFN-γ secretion to HBcAg stimulation (P=?.0002). The G allele carriers at TLR4 rs4986790 (p.Asp299Gly) predicted spontaneous HBsAg seroclearance (HR, 18.73; P?相似文献   

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms

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 x 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.     

TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort

BACKGROUND AND AIM: Toll-like receptors (TLRs) have been identified as susceptibility genes for Crohn's disease (CD) in some, but not all, studies. Here we examined the association between candidate disease-susceptibility polymorphisms in the TLR2, TLR4 and TLR9 genes and CD in a New Zealand Caucasian population. METHODS: The frequency of gene polymorphisms was examined in 182 CD patients and in 188 ethnically matched controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: We could not detect any significant difference in the allele frequencies of polymorphisms in the TLR2 (R753Q, 0.029 vs 0.016, P = 0.25), TLR4 (D299G and T399I, 0.085 vs 0.071, P = 0.49; and 0.085 vs 0.082, P = 0.90), and TLR9 (-1237T/C, 0.154 vs 0.148, P = 0.82) genes between controls and patients, respectively. There was no evidence that the variant TLR alleles were associated with disease phenotype. However, combination of the datasets of published studies with our dataset confirmed that the TLR4 polymorphism 299G (P = 0.0005; OR of 1.42 [95% CI 1.17-1.74]) and the TLR9 polymorphism -1237C (P = 0.0416; OR of 1.33 [95% CI 1.01-1.75]) are associated with CD. CONCLUSIONS: There was no evidence that the above variants of the TLR2, TLR4 and TLR9 genes are major risk factors for CD or influence disease phenotype in our New Zealand case-control study. Nevertheless, the significance of the TLR4 299G and TLR9-1237C associations with CD worldwide was confirmed by a meta-analysis test using our datasets and datasets from previously published studies.     

Toll-Like Receptor (TLR)-9 rs352140 Polymorphism is an Immunopathology Protective Factor in Parkinson's Disease in the Northern Iranian Population

Background: Neuroinflammation and immunopathology in Parkinson's disease (PD) are believed to be associated with genetic and environmental factors. Objective: We conducted the current study to evaluate the Toll-like receptors (TLR4 and TLR9) genes polymorphism in patients with Parkinson's disease in northern Iran. Methods: We extracted DNA from peripheral blood samples of 100 sporadic cases of Parkinson's disease and 100 healthy-matched controls with the mean age of 69.98 and 71.94 years, respectively. Subsequently, single-nucleotide polymorphisms (SNPs) of TLR4 and TLR9 were genotyped using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Results were confirmed employing Sanger sequencing. For the analysis of our data, we used SNPStats and SPSS 22 software. Results: Our findings indicated that the allele distribution for rs352140 of TLR9 gene was significantly different in the PD group compared with the healthy controls (p=0.02). Moreover, rs352140 T allele was observed to be correlated with PD reduced risk (TT + TC vs. CC). The dominant rs352140 model was approved as the most acceptable inheritance model for fitting the data (OR 0.41, 95% CI 0.23-0.75, p=0.0031). Additionally, haplotype analysis revealed a significant correlation between TLR9 polymorphisms and Parkinson's disease. Conclusion: The results of this study indicated that rs352140T of TLR9 gene was a protective factor in Parkinson's disease. Furthermore, this SNP could be regarded as a prognostic factor. However, this conclusion should be confirmed by further investigations.     

A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis that includes susceptibility gene(s) within the chromosome 1q41-1q42 region. Toll-like receptor 5 (TLR5), the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common stop codon polymorphism that abrogates signaling (allele C1174T) and is associated with an increased risk of infection. By using transmission disequilibrium testing in a cohort containing 199 affected patients and their 75 unaffected siblings and 326 parents, we found that allele 1174C, but not 1174T (with the stop codon), was preferentially transmitted to SLE-affected offspring (a 19:6 transmitted/not transmitted ratio, P = 0.009). In contrast, the alleles of the other three TLR5 SNPs did not exhibit preferential transmission. In addition, we found that allele 1174C was not preferentially transmitted to unaffected offspring (3:6 transmitted/not transmitted ratio, P value not significant). The allele frequency of 1174T in the probands was 3.2% compared with 5.8% in unaffected individuals, which was consistent with a protective association (odds ratio, 0.51; 95% confidence interval, 0.26-0.98; P = 0.041). Subjects with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines in comparison with individuals with the wild-type genotype. Together, these results indicate that the TLR5 stop codon polymorphism is associated with protection from the development of SLE. These data support a role for flagellated bacteria and the innate immune response in the development of SLE with implications for novel immunomodulatory treatment strategies.     

Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population.

AIMS: The toll-like receptor 4 (TLR4) is predominantly known for its role as an important mediator of immune reactions and has been implicated in the initiation, progression, and plaque destabilization stages of atherosclerosis. We investigated whether genotypes and haplotypes of the 896A/G (Asp299Gly; rs4986790) and 1196C/T (Thr399Ile; rs4986791) single nucleotide polymorphisms of the gene encoding the TLR4 were associated with myocardial infarction (MI) in a large Caucasian sample. METHODS AND RESULTS: The case group included 3657 patients with MI and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of MI. Genotypes were determined with the use of TaqMan assays. Genotype distributions of the 896A/G and 1196C/T polymorphisms were not significantly different between the control and patient groups (P> or =0.30). The frequencies of haplotypes defined by the 896A/G and 1196C/T polymorphisms were similar between the control group and the patient group (P> or =0.16). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group (P> or =0.12). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with MI (P> or =0.11). CONCLUSION: The results indicate that the 896A/G and 1196C/T polymorphisms of the TLR4 gene or haplotypes based on these polymorphisms are not associated with MI.     

Toll样受体基因多态性与福建籍非人类免疫缺陷病毒相关隐球菌性脑膜炎易感性的关联分析

目的:探讨Toll样受体(Toll-like receptor,TLR)基因多态性与福建籍非人类免疫缺陷病毒(human immunodeficiency virus,HIV)相关隐球菌性脑膜炎易感性的关联。方法:纳入2016年10月至2019年4月在上海市复旦大学附属华山医院和福建省福州市联勤保障部队第九〇〇医院仓山院区住院治疗的101例福建籍非HIV相关隐球菌性脑膜炎患者为病例组,270名福建籍门诊健康体格检查者为健康对照组。提取患者基因组DNA,采用多重SNaPshot单核苷酸多态性(single nucleotide polymorphism,SNP)分型技术,对既往文献报道的与疾病相关但未得到充分验证的8个TLR SNP位点进行基因分型。分别比较病例组和健康对照组、无易感因素患者组和健康对照组TLR基因多态性的分布差异。统计学分析采用χ²检验或Fisher确切概率法。结果:除TLR1 rs5743563外,TLR1 rs5743604、TLR2 rs3804099、TLR4 rs1927907、TLR6 rs3796508、TLR6 rs5743794、TLR9 rs164637、TLR9 rs3521407个TLR SNP检测位点的等位基因频率分布均符合哈迪-温伯格平衡。病例组与健康对照组比较发现,TLR2 rs3804099位点的T/T基因型[52.5%(53/101)比40.4%(109/270),比值比(odds ratio,OR)=1.63,χ²=4.378,P=0.036]和TLR6 rs5743794位点的G/G基因型[44.6%(45/101)比32.2%(87/270),OR=1.69,χ²=4.877,P=0.027]为隐球菌性脑膜炎的风险基因型;而TLR6 rs3796508的G/G基因型[83.2%(84/101)比92.6%(250/270),OR=0.40,χ²=7.271,P=0.007]和TLR9 rs164637的C/C基因型[96.0%(97/101)比100.0%(270/270),Fisher确切概率法,P=0.005]为隐球菌性脑膜炎的保护性因素。101例患者中有70例无易感因素。无易感因素患者组与健康对照组比较发现,TLR6 rs5743794位点的G/G基因型[52.9%(37/70)比32.2%(87/270),OR=2.36,χ²=10.216,P=0.001]为隐球菌性脑膜炎的风险基因型,TLR6 rs3796508的G/G基因型[81.4%(57/70)比92.6%(250/270),OR=0.35,χ²=7.906,P=0.005]和TLR9 rs164637的C/C基因型[97.1%(68/70)比100.0%(270/270),Fisher确切概率法,P=0.042]为隐球菌性脑膜炎的保护性因素。结论:TLR基因多态性与福建籍非HIV相关隐球菌性脑膜炎的易感性密切关联,提示TLR在隐球菌性脑膜炎的发病过程中可能起到重要作用。     

Toll-like receptor expression in lupus peripheral blood mononuclear cells

OBJECTIVE: To investigate expression of members of the Toll-like receptor (TLR) family in peripheral blood mononuclear cells (PBMC) in patients with systemic lupus erythematosus (SLE). METHODS: We analyzed PBMC from 14 patients with SLE and 15 healthy subjects. The surface expressions of TLR2 and TLR4 and intracellular expression of TLR9 on PBMC were analyzed by flow cytometry. RESULTS: Although TLR4 expressions on CD14+ monocytes were not significantly different between healthy subjects and patients with SLE, TLR2 expressions on monocytes were reduced in patients with SLE compared to healthy subjects. Intracellular TLR9 expression levels of CD19+ B lymphocytes were significantly elevated in patients with SLE. However, the TLR9 expression levels of plasmacytoid dendritic cells were not significantly different between these patients and healthy subjects. CONCLUSION: Our results show that human peripheral blood B cells express TLR9 and that its expression is increased in patients with SLE. This upregulated expression of TLR9 in B cells may be related to the abnormal B cell hyperactivity in patients with SLE.     

Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling

Toll-like receptor 4 (TLR4) and MD-2 recognize lipid A, the active moiety of microbial lipopolysaccharide (LPS). Little is known about mechanisms for LPS recognition by TLR4/MD-2. We here showed, by using in vitro transfectants, ligand-induced TLR4-oligomerization, which required both membrane CD14 and MD-2. We previously reported that lipid IVa, a lipid A precursor, is agonistic on mouse TLR4/MD-2 but antagonistic on human TLR4/MD-2 and chimeric mouse TLR4/human MD-2. Lipid IVa triggered oligomerization of mouse TLR4/MD-2 but not human TLR4/MD-2 or chimeric mouse TLR4/human MD-2. Further, lipid IVa inhibited lipid A-dependent oligomerization of chimeric mouse TLR4/human MD-2. These results demonstrate that ligand-induced TLR4-oligomerization is directly linked with TLR4-signaling and suggest that MD-2 has an important role in regulating TLR4-oligomerization.     

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.