Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus

Human toll-like receptors (TLRs) participate in the innate response and signal the activation of adaptive immunity. Therefore, these TLRs may be important in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We investigated, by using a polymerase chain reaction restriction-fragment length polymorphism method, the possible association between the polymorphisms of TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes with the susceptibility or severity of RA and SLE. Our study population consisted of 122 patients with SLE, 224 patients with RA, and a control group of 199 healthy individuals. The TLR2 polymorphisms were very rare in our population; no individual carrying the TLR2-Arg677Trp polymorphism was observed, whereas the TLR2-Arg753Gln polymorphism was present in only 1% of the total population. We found no statistically significant differences in the TLR4-Asp299Gly and the TLR4-Thr399Ile genotype or allele distribution between SLE patients, RA patients, and control individuals. Similarly, no association was found with any of the demographic and clinical parameters tested either in RA or in SLE patients. In conclusion, a case-control study was used to analyze, for the first time, the influence of TLR2 and TLR4 gene polymorphism on the predisposition and clinical characteristics of SLE and RA but provided no evidence for association of TLR2 or TLR4 gene polymorphism with either disease in the population under study.     

Epigenetic dysregulation in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease that affects multiple organs and is characterized by episodic flares and elevated morbidity. The etiology of SLE is only partly known. In this context, recent attention has been paid to the importance of environmentally induced epigenetic modifications as significant contributors to the disease pathogenesis in genetically predisposed individuals. Here we review what is currently known on the role of epigenetics in SLE, and the investigations aimed at possibly targeting epigenetic mechanisms and/or related biomarkers to improve the monitoring, management and, ultimately, the prognosis of SLE.     

Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus

Mammalian Toll-like receptors (TLR) play an important role in both adaptive immunity and innate immunity. Genetic variations within TLR genes are known to be associated with a variety of inflammatory and infectious diseases. TLR9 is potentially associated with autoimmune diseases, because it participates in the production of pro-inflammatory cytokines and the maturation of dendritic cells. We investigated the association of four TLR9 gene polymorphisms (-1486 T>C, -1237 C>T, +1174 A>G and +2848 G>A) with the susceptibility to systemic lupus erythematosus (SLE) and related phenotypes in 680 Korean people (350 SLE patients and 330 controls). TLR9 gene polymorphisms were not significantly associated with the susceptibility to SLE and related phenotypes.     

Genetic dissection of systemic lupus erythematosus

Recent progress towards elucidating the genetic basis for susceptibility to systemic lupus erythematosus (SLE) has provided insights into the manner in which individual susceptibility genes contribute to disease pathogenesis. Studies in animal models of systemic autoimmunity suggest that genes in three separate pathways contribute to the initiation and progression of systemic autoimmunity. Linkage studies in humans suggest that at least some susceptibility genes mediating disease in lupus-prone mice may also contribute to susceptibility in humans.     

Quantitation of autoantibody-secreting B cells in systemic lupus erythematosus

An ELISA spot assay was used to quantitate the number of autoantibody-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Patients with active disease had 20 fold more anti-DNA, 4 fold more anti-actin and 3 fold more anti-myosin secreting lymphocytes than controls but normal numbers of anti-cardiolipin and anti-transferrin secreting B cells. 60% of SLE patients had increased numbers of B cells reactive with multiple autoantigens. These data suggest that B cell activation in SLE may be influenced by both antigen-specific and antigen-independent factors.     

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Double‐stranded (ds) DNA, DNA‐ or RNA‐associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non‐specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol‐residing DNA or RNA viruses. Thus, endosomal Toll‐like receptors (TLR) mediate responses to double‐stranded RNA (TLR‐3), single‐stranded RNA (TLR‐7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)‐DNA (TLR‐9), while DNA‐dependent activator of IRFs/Z‐DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN‐inducible nuclear protein‐200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid‐inducible gene‐I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR‐induced responses are more robust than those induced by cytosolic DNA‐ or RNA‐ sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)‐dependent type I interferon (IFN) induction and nuclear factor (NF)‐κB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA‐ or RNA‐like synthetic inhibitory oligonucleotides (INH‐ODN) have been developed that antagonize TLR‐7‐ and/or TLR‐9‐induced activation in autoimmune B cells and in type I IFN‐producing dendritic cells at low nanomolar concentrations. It is not known whether these INH‐ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH‐ODNs into human therapeutics for treating SLE and bacterial DNA‐induced sepsis.     

雌激素受体与系统性红斑狼疮的关系

系统性红斑狼疮（SLE）发病机理涉及免疫系统自身识别的丧失,较易发生于生育期女性。雌激素对SLE的发病及病情发展有重要影响。雌激素通过与T、B细胞核内表达的雌激素受体ER-α和ER-β结合进而刺激或调节特异性免疫相关基因的转录。受体结构以及与靶基因相互作用的差异造成了雌激素的异常活动,使得对自身抗原耐受起重要作用的一系列调节通路紊乱,从而导致自身免疫病如SLE的发生。多种经典和非经典雌激素信号的传导通路在转录和转录后水平均调控T细胞活化基因的表达,造成SLE患者的T细胞对雌激素应答的敏感性差异。     

Dendritic cells and the immunopathogenesis of systemic lupus erythematosus

Over the last decade, the role of dendritic cells (DCs) in the immunopathogenesis of systemic lupus erythematosus (SLE) has become apparent. As unique mediators of both tolerance and immunity, aberrant myeloid and plasmacytoid DC function can promote autoimmune responses via a number of mechanisms and proinflammatory pathways. This review provides an overview of DC function, the potential role of DCs in promoting autoimmune responses in SLE, and how other abnormalities in lupus can lead to an enhanced engagement of DCs in immune responses. How medications used to treat SLE and other autoimmune conditions may exert effects on DCs is also explored.     

The role of autoantibodies in pediatric neuropsychiatric systemic lupus erythematosus

Neuropsychiatric syndromes are prevalent in pediatric patients with systemic lupus erythematosus (SLE) and often manifest early in disease course and with significant associated morbidity. Postulated pathogenic mechanisms of peripheral and central nervous system events include vasculopathy, autoantibody effects and systemic inflammation. The pathogenic roles of anti-phospholipid, anti-ribosomal-P and anti-neuronal autoantibodies have been examined in both focal and diffuse adult neuropsychiatric syndromes. Few studies have probed associations between these autoantibodies and pediatric neuropsychiatric SLE (NP-SLE). Retrospective review of a large ethnically diverse pediatric SLE cohort revealed anti-phospholipid, anti-ribosomal P, and anti-neuronal antibodies to be more prevalent than in many adult studies. Rates of anti-phospholipid and anti-ribosomal P antibody positivity were similar to those of other pediatric reports. Association between anti-neuronal antibodies and NP-SLE events appeared statistically significant in this cohort. Prospective inception cohort studies will need to be undertaken to investigate the significance and utility of autoantibody testing in pediatric NP-SLE.     

The emerging role of interferon in human systemic lupus erythematosus

Recent studies of patients with systemic lupus erythematosus, together with data from lupus-prone mice, suggest that inappropriate activation of type I interferon might have a role in disease pathogenesis. Serum levels of IFN-alpha are elevated in SLE patients, and gene expression profiling of peripheral blood cells shows that most lupus cases demonstrate an upregulation of IFN-responsive genes. Of interest, the IFN gene 'signature' correlates with more severe disease. The available data support a model whereby chromatin-containing immune complexes circulating in the blood of lupus patients stimulate leukocytes to produce IFN, which perpetuates disease. These emerging insights into the connection between IFN and lupus provide a host of new diagnostic and therapeutic opportunities.     

Endosomal toll-like receptors play a key role in activation of primary human monocytes by cowpea mosaic virus

The plant virus, cowpea mosaic virus (CPMV), has demonstrated a remarkable capacity to induce anti-tumour immune responses following direct administration into solid tumours. The molecular pathways that account for these effects and the capacity of CPMV to activate human cells are not well defined. Here, we examine the ability of CPMV particles to activate human monocytes, dendritic cells (DCs) and macrophages. Monocytes in peripheral blood mononuclear cell cultures and purified CD14+ monocytes were readily activated by CPMV in vitro, leading to induction of HLA-DR, CD86, PD-L1, IL-15R and CXCL10 expression. Monocytes released chemokines, CXCL10, MIP-1α and MIP-1β into cell culture supernatants after incubation with CPMV. DC subsets (pDC and mDC) and monocyte-derived macrophages also demonstrated evidence of activation after incubation with CPMV. Inhibitors of spleen tyrosine kinase (SYK), endocytosis or endocytic acidification impaired the capacity of CPMV to activate monocytes. Furthermore, CPMV activation of monocytes was partially blocked by a TLR7/8 antagonist. These data demonstrate that CPMV activates human monocytes in a manner dependent on SYK signalling, endosomal acidification and with an important contribution from TLR7/8 recognition.     

Phenotype and function of dendritic cells of patients with systemic lupus erythematosus

Dendritic cells (DC) regulate the activation and differentiation of T cells. They are activated by signals of inflammation and tissue damage, and thus could play a role in the amplification and perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE). Here we analyzed the phenotype of circulating DC from patients with SLE and studied their differentiation from monocytes. Peripheral blood DC exhibited increased levels of activation in patients with SLE. Although their in vitro differentiation process occurred normally, their responses to activation stimuli (LPS, TNF-α plus PGE(2), anti-CD40) were abnormal when compared to DC differentiated from healthy monocytes. When incubated in the presence of IL-10, DC from patients with SLE were able to induce tolerance to allogeneic antigens in a normal manner. Our results suggest that DC from patients with SLE are abnormal, in part due to the effect of abundant pro-inflammatory signals, but also because of intrinsic cellular defects that alter their responses to activation stimuli.     

初发系统性红斑狼疮患者调节性T细胞的变化

目的 探讨初发系统性红斑狼疮(SLE)患者CD4 T细胞中FOXP3和CD25的表达及其临床意义.方法 应用流式细胞仪检测CD4 FOXP3 、CD4 CD25 、CD4 CD25high T细胞表达,同时检测CD4 FOXP3 T细胞中CD25及CD4 CD25highT细胞中FOXP3的表达.结果 活动组SLE患者CD4 CD25 T细胞显著低于对照组和低活动组(P＜0.05).活动组患者CD4 CD25highT细胞明显低于低活动组患者(P＜0.01).初发SLE患者CD4 FOXP3 T细胞明显高于对照组(P＜0.01).活动组SLE患者CD4 FOXP3 T细胞中CD25表达显著低于对照组和低活动组(P＜0.05).同时活动组SLE患者CD4 CD25highT细胞中FOXP3表达的平均荧光强度较对照组显著降低(P＜0.05).活动组患者治疗后CD4 CD25highT细胞显著增高(P＜0.05).结论 初发活动期SLE患者CD4 T细胞中CD25high和FOXP3表达不一致可能在SLE患者免疫失衡中发挥作用.