Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy

The immune system is responsible for defending the host from a large variety of potential pathogens, while simultaneously avoiding immune reactivity towards self-components. Self-tolerance has to be tightly maintained throughout several central and peripheral processes; immune checkpoints are imperative for regulating the immunity/tolerance balance. Dendritic cells (DCs) are specialized cells that capture antigens, and either activate or inhibit antigen-specific T cells. Therefore, they play a key role at inducing and maintaining immune tolerance. DCs that suppress the immune response have been called tolerogenic dendritic cells (tolDCs). Given their potential as a therapy to prevent transplant rejection and autoimmune damage, several strategies are under development to generate tolDCs, in order to avoid activation and expansion of self-reactive T cells. In this article, we summarize the current knowledge relative to the main features of tolDCs, their mechanisms of action and their therapeutic use for autoimmune diseases. Based on the literature reviewed, autologous antigen-specific tolDCs might constitute a promising strategy to suppress autoreactive T cells and reduce detrimental inflammatory processes.     

Microbe-metabolite-host axis,two-way action in the pathogenesis and treatment of human autoimmunity

The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease.     

Protein biochip array technology for cytokine profiling predicts etanercept responsiveness in rheumatoid arthritis

In rheumatoid arthritis (RA) there are currently no useful indicators to predict a clinical response to tumour necrosis factor-alpha (TNF-alpha) blockade. The purpose of this study was to determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to etanercept in RA. Peripheral blood samples were collected at baseline and at 3 months from 33 patients with active disease who were treated twice weekly by etanercept therapy. Responders are defined by the presence of three of four American College of Rheumatology criteria: > or =20% decrease in C-reactive protein (CRP), visual analogue score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28; four values) by > or =1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array (protein biochip array, Investigator Evidence, Randox France), including interleukin (IL)-6, TNF-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF) and vascular endothelium growth factor. Our results showed that high serum levels of MCP-1 and EGF were associated with a response to etanercept. In addition, the increase of two combined parameters CRP and EGF was predictive of a response to etanercept treatment at 3 months (sensitivity: 87.5% and specificity: 75%, accuracy: 84.4%). These findings suggest that cytokine profiling by proteomic analysis before treatment initiation may help to identify a responder patient to TNF-alpha blocking agents in RA.     

Rheumatoid arthritis complicated by pachy- and leptomeningeal rheumatoid nodule-tike granulomas and systemic vasculitis

Rheumatoid nodule is a frequent and characteristic extra-articular manifestation of rheumatoid arthritis (RA). Its involvement of central nervous system is a rare occurrence with only a few reported cases. A 78-year-old man with severe arthritis showing the formation of rheumatoid nodule-like granulomas in the dura and subarachnoid space along with the spleen is presented. The characteristic morphological finding of the granulomas was the presence of neutrophlls and the absence of definite fibrinoid necrosis, which differed from the typical features of rheumatoid nodules previously described. The diagnosis should be based on the exclusion of diseases that may cause similar granulomatous reactions including infectious diseases. Additionally, there was systemic necrotizing vasculitis in the dura and multiple cerebral Infarcts, although the association between vasculitis and cerebral infarcts was not clear.     

淋巴细胞共刺激信号和凋亡信号异常与RA免疫效应亢进的研究

目的：探究T淋巴细胞表面多种细胞信号分子所介导的细胞活化或凋亡信号在RA患者免疫功能紊乱中的作用。方法：采用流式细胞术检测RA患者外周血T细胞亚群及其表面共刺激分子cD154（cD40L）、CD30和凋亡受体CD95（Fas）的表达。结果：RA患者外周血T细胞亚群偏移，CD4^＋T细胞增加，CD8^＋T细胞减少；共刺激分子CD154在CD4^＋和CD8^＋T细胞上的表达均上调，但CD30分子的表达均降低，并以CD4^＋T细胞降低更为明显。同时，凋亡受体CD95分子在T细胞亚群上的表达均明显增加。结论：RA患者T淋巴细胞表面多种信号分子表达异常，共同导致了RA患者免疫功能紊乱。     

联检多项指标对类风湿关节炎诊断的临床价值

目的:探讨类风湿因子(Rheum atoid factor,RF)、抗角质蛋白抗体(AKA)、C-反应蛋白(C-reactiveprote in,CRP)和血沉(erythrocyte sed im entation rate,ESR)联检对类风湿关节炎(rheum atoid arthritis,RA)的临床诊断价值。方法:对35例类风湿关节炎患者、30例系统性红斑狼疮和30名正常健康体检者的RF、AKA、CRP及ESR检测,应用速率散射比浊法测定RF和CRP;间接免疫荧光法检测AKA;应用魏氏法测定ESR值。结果:35例RA患者血清中,RF灵敏度和特异性分别为71.4%、91.7%,AKA灵敏度和特异性分别为34.3%、96.7%,CRP灵敏度和特异性分别为91.4%、25%,ESR灵敏度和特异性分别为88.6%、83.3%。联检RF和AKA的灵敏度和特异性分别为81.2%、99.7%,联检RF、AKA、CRP及ESR的灵敏度和特异性分别为99.98%、99.97%。结论:RF、AKA、CRP及ESR可作为RA诊断的血清学指标,且四者联检有助于提高RA诊断的灵敏度及特异性。     

Collagenase-like (CL) peptidase activity in synovial fluid from patients with rheumatoid arthritis

We found the presence of collagenase-like (CL) peptidase in synovial fluid by a highly sensitive fluorescence assay using (succinyl-Gly-Pro-Leu-Gly-Pro)-4-methylcoumaryl-7-amide (Suc-GPLGP-MCA) as a substrate. Suc-GPLGP-MCA is hydrolyzed at the Leu-Gly bond by CL-peptidase. The CL-peptidase activity in synovial fluid was significantly higher in patients with rheumatoid arthritis (RA) than in patients with osteoarthritis (OA) and in arthropathy-free controls. No significant difference in CL-peptidase activity in synovial fluid was found between patients with OA and arthropathy-free controls.     

复方丹参注射液对实验性大鼠类风湿关节炎的病理学影响

Rheumatoidarthritis（RA）isakindofautoimmunitydiseases，intheearlyphase，itmainlyaffectssynoviumandthengraduallyextendtojoints．Large－dosedcompoundsagerootinjectioniseffectiveintreatingRAinclinic，therapeuticeffectissatisfying．Inordertostudytheinvolvedmechanism，weestablishedCIAmodelsinducedbycol－lagenIItoinvestigatemechanismspathologically．１Materialsandmethod１．１ExperimentalanimalsNormalWistarratsweighting（１２０±２０）gwereprovidedbyCenterofExperimentalAnimalsofFirstMili－tar…     

类风湿性关节炎和血清阴性脊柱关节病患者血清急性时相反应蛋白的测定及其临床意义

目的：观察活动期类风湿性关节炎（RA）和血清阴性脊柱关节病患者血清4种急性时相反应蛋白α1－酸性糖蛋白（AAG）、α1－扶胰蛋白酶（AAT）、触珠蛋白（HPT）和铜蓝蛋白（CER）浓度的变化及其临床意义。方法采用ARRAY360蛋白质测定系统测定61例RA和血清阴性脊柱关节病患者及31例正常对照组血清AAG、AAT、HPT、CER浓度并进行比较,结果RA、血清阴性脊柱关节病及差了炎综合组患者该4项指标浓度均显著高于正常对照组（P＜0．001）,并与血沉、C－反应蛋白呈正相关。结论动态观察血清4种急性时相反应蛋白浓度的变化对照于关节炎患者病变活动的监测以及及药物疗效的判断等有一定的临床指导意义。     

复方丹参对Ⅱ型胶原蛋白诱导大鼠模型滑膜细胞分泌及肿瘤坏死因子的影响

目的研究复方丹参Ⅱ型胶原蛋白诱导性大鼠关节模型(CIA)关节功能及滑膜细胞分泌前列腺素E2(PGE2)及肿瘤坏死因子(TNF)的影响。方法采用消化分离的方法获得滑膜细胞,放免法检测原代大鼠滑膜细胞培养上清液中PGE2及TNF的水平。结果复方丹参可以明显下调CIA大鼠滑膜细胞分泌PGE2及TNF的水平,改善其关节活动功能。结论复方丹参治疗类风湿性关节炎的机制可能与下调滑膜细胞分泌PGE2及TNF的水平有关。