Specific peripheral B cell tolerance defects in patients with multiple sclerosis

Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood.     

High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.     

严重多发伤患者外周血树突状细胞的变化

目的　探讨严重多发伤后患者早期外周血树突状细胞 (DC)的变化。方法　自严重多发伤患者 (2 4例 ,多发伤组 )和健康人 (13例 ,对照组 )外周血分离出树突状细胞 ;通过流式细胞仪检测各组的DC数量 (CMRF 4 4标记法 )及DC表面HLA DR、CD80、CD86表达水平以及DC诱导的T细胞反应性增殖。结果　多发伤组DC数量〔 (7 3± 3 4 )× 10 6 /L〕明显低于对照组DC数量〔 (14 1± 5 3)× 10 6 /L〕 ,P <0 0 1。多发伤组DC表面HLA DR及CD80、CD86的表达水平与对照组相比明显下调 (P <0 0 1)。DC诱导的T细胞增殖能力多发伤组明显低于对照组 (P <0 0 1)。结论　严重多发伤患者早期外周血DC数量少 ,功能低下 ,与创伤早期免疫功能低下有关。     

多发性硬化患者炎性细胞因子和一氧化氮合酶mRNA表达水平

目的进一步探讨多发性硬化患者外周血淋巴细胞中某些炎性细胞因子的变化与疾病的关系。方法应用逆转录－聚合酶链反应对１５例多发性硬化（ＭＳ）患者外周血单个核细胞ＩＬ－１、ＩＬ－６和诱导型ＮＯ合酶（ｉＮＯＳ）ｍＲＮＡ表达进行了研究。结果患者组（１５例）细胞因子ＩＬ－１、ＩＬ－６和ｉＮＯＳｍＲＮＡ的表达均高于１１名健康对照（１．８１±０．１３／０．５４±０．１５；１．６７±０．５４／０．３９±０．０９；１．２４±０．１８／０．０８±０．０１。Ｐ均＜０．０１）。８例患者经治疗处于稳定期时，细胞因子ＩＬ－１和ＩＬ－６ｍＲＮＡ水平恢复到正常水平，但ｉＮＯＳｍＲＮＡ恢复较慢，仍保持较高水平（１．２３±０．１６／０．７１±０．１５，Ｐ＜０．０５），与正常对照组比较差异有非常显著性（０．７１±０．１５／０．０８±０．０１，Ｐ＜０．０１）。结论该结果从基因水平证明细胞因子（ＩＬ－１、ＩＬ－６）和ｉＮＯＳ参与ＭＳ的病理过程，其水平变化可提示疾病转归     

肺结核患者NO和FOXP3表达水平变化及意义

目的探讨肺结核患者一氧化氮(NO)和叉头蛋白3(FOXP3)表达水平的变化及临床意义。方法选择肺结核患者与健康者各40例,采用Griess比色法检测血清NO水平,采用流式细胞仪检测外周血CD4+CD25+T淋巴细胞百分比;采用实时定量聚合酶链反应检测FOXP3mRNA水平。结果肺结核患者血清NO浓度为(15.71±1.26)μmol/L,高于健康者的(5.45±0.98)μmol/L(P0.05);肺结核患者外周血CD4+CD25+T淋巴细胞约占CD4+T淋巴细胞的(4.57±0.85)%,高于健康者的(1.83±0.49)%(P0.05);肺结核患者外周血CD4+CD25+T淋巴细胞高表达FOXP3。结论肺结核患者NO、FOXP3表达水平均升高,在肺结核免疫调节机制中起着重要作用;动态监测二者表达水平的变化有利于肺结核患者的诊治。     

多发性硬化患者认知功能损害的特点

目的:探讨多发性硬化患者认知功能损害的特点、相关影响因素及认知功能损害对患者生活功能的影响。资料来源:应用计算机检索Medline2000-01/2004-12与多发性硬化患者认知功能相关的文章,检索词“multiplesclerosis,cognitivefunctionorneuropsychology”。限定文章语言种类为English,研究对象为人类。同时计算机检索中国期刊全文数据库2000-01/2004-12期间的相关文章,限定文章语言种类为中文,检索词“多发性硬化,认知功能”。资料选择:对资料进行初审,选取有关多发性硬化患者认知功能损害的特点、相关影响因素及与生活功能相关性方面的文献,筛除关于多发性硬化病因、病理方面的研究及综述文献。对剩余的文献开始查找全文,分析、总结研究内容。f资料提炼:共收集到英文文献259篇,其中研究文章201篇,综述58篇。30篇文献符合纳入标准。收集到的中文文献3篇,纳入0篇。资料综合:多发性硬化不同形式、不同程度认知损害发生率约为45%～65%,其发生及严重程度和躯体残疾状况无明显相关。多发性硬化患者在近记忆、注意力、信息处理速度、视空间能力、执行功能等方面损害明显,而整体智力水平和语言能力相对保存,其认知功能损害和患者的生活能力下降有关。多发性硬化认知损害的检测主要运用神经心理学的方法,常用的有多发性硬化认知损害筛查测验、加利福尼亚词语学习、Rey听觉词语学习测验、符号数字模式测验、言语流畅性测验、威斯康星卡片分类测验,Stroop测验和数字广度测验等。结论:多发性硬化患者认知功能损害以记忆、信息处理速度、执行功能为主,整体认知功能及语言功能相对保存。认知功能损害影响患者的生活功能。     

Management of bladder dysfunction in patients with multiple sclerosis

Multiple sclerosis is a chronic disease of the central nervous system that often has a disabling effect, resulting in reduced quality of life for patients. Bladder dysfunction is a common and distressing symptom. Nurses can have a key role in the management of this symptom by promoting an integrated approach to care, thereby improving bladder control and reducing patient anxiety. This article explores the core elements of a specialist continence assessment in this patient group, and provides a critical overview of treatments used for managing bladder problems.     

多发性硬化患者的听神经损害

多发性硬化(multiplesclerosis,MS)是以中枢神经系统多灶炎症及脱鞘为特征的一种疾病。MS患者中存在听神经的损害的表现,有人观察到3.5%确诊的MS患者在急性期及复发期出现单侧或双侧听力下降。2%～10%MS患者出现脑干诱发电位(brainstemauditoryevokedpotential,BAEP)I波异常,表现为波I潜伏期延长、波幅降低甚至缺失。这些表现随病情的加重明显,随症状的减轻而减轻,甚至恢复正常。MRI显示MS患者听神经病灶,表明听神经周围部分的损害,其原因可能与听神经根的颅外部分出现脱髓鞘有关。     

Tetranectin in cerebrospinal fluid of patients with multiple sclerosis

OBJECTIVE: Tetranectin (TN) is a glycoprotein and C-type lectin thought to play a prominent role in tissue remodelling. The aim of this study was to determine the TN serum and cerebrospinal fluid (CSF) concentration in patients with multiple sclerosis (MS) and controls. MATERIAL AND METHODS: Two-hundred-and-four patients, divided into four diagnostic groups, i.e. definite MS (n = 76), possible onset symptoms of MS (n = 48), other non-inflammatory neurological diseases (n = 61) and other inflammatory neurological diseases (n = 19) and 47 controls with no history of neurological disease were analysed for TN in serum and CSF using a polyclonal sandwich ELISA. RESULTS: All tested groups, e.g. definite MS, possible onset symptoms of MS, other neurological disease, both inflammatory and non-inflammatory, had decreased concentrations of TN in the CSF compared to the concentrations in controls. The quotient of TN in CSF divided by the concentration in serum (QTN) correlated significantly with the same quotient of albumin (QALB), was significantly correlated with the same quotient of albumin QALB. To account for differences in blood brain barrier permeability, we calculated a TN-index defined as: TN-index = QTN/QALB. QTN was significantly decreased in all groups compared to that in controls. However, in definite MS and patients with first attack of MS, the TN-index was not significantly different from that of controls. In contrast, other neurological diseases, both inflammatory and non-inflammatory, were associated with a decreased TN-index. CONCLUSION: These results indicate that TN may play a role in neurological diseases and may serve as a diagnostic aid in MS.