多发性硬化研究进展

多发性硬化(MS)因其发病率增高而患病率有增高趋势。近来在研究其病因方面有些进展，认为外因(病毒感染)通过内因起作用，为治疗开拓了新思路。诊断方面引入了MRI并标准化了脑脊液寡克隆(IgG组分)区带。视神经脊髓受累者与经典的MS在其人白细胞抗原(HLA)等方面不同，多数认     

人类白细胞抗原DRB1基因与多发性硬化遗传易患性研究

目的　分析多发性硬化遗传易患的分子免疫遗传背景。方法　采用聚合酶链反应序列特异性引物（ＰＣＲＳＳＰ） 联合技术对４５ 例病例组和１０５ 例正常对照组人类白细胞抗原ＤＲＢ１ 基因（ＨＬＡＤＲＢ１） 进行基因分型。结果　病例组ＨＬＡＤＲ２ 基因频率高于正常对照组,优势比为３．３２１ ,有统计学意义（ Ｐ＜ ０．０１）。结论　ＨＬＡＤＲ２ 基因与多发性硬化遗传易患相关联,提示可能还存在保护性基因。     

多发性硬化与其相关基因

多发性硬化（ＭＳ）是一种多灶性炎性中枢神经系统脱髓鞘性疾病。它的发病年龄多在２０～４０岁之间,是西方青壮年神经系统功能缺损的常见病因之一。ＭＳ的病因尚不清楚,目前普遍认为它是在一定遗传基础上,在某些环境因素作用下发生的自身免疫性疾病［１］。近年随着分子生物学的发展,人们关于基因与该病的知识在快速增长。到目前为止筛选出了多个与ＭＳ相关联,连锁的基因或区域,其中ＨＬＡⅡ类基因结果较恒定,其它区域不同研究结果不尽相同,这主要与ＭＳ的遗传异质性有关。ＭＳ属于多基因遗传病,这一特点使其遗传学研究复杂化,然…     

多发性硬化基因组扫描的研究进展

多发性硬化(MS)是一种由遗传因素与环境因素共同作用引起的中枢神经系统炎性脱髓鞘疾病。目前MS的遗传学研究热点之一是通过结合先进的统计学方法和分子遗传学技术进行人类基因定位,经全基因组筛选以确认易患基因。该文就近年来MS基因组扫描的研究进展进行综述。     

多发性硬化遗传易患基因研究进展

多发性硬化（ｍｕｌｔｉｐｌｅｓｃｌｅｒｏｓｉｓ,ＭＳ）是中枢神经系统（ＣＮＳ）慢性炎性脱髓鞘病,是细胞免疫介导的器官特异性自身免疫病。本病的确切病因至今不明,遗传易患性在本病起重要作用,本文拟就近年来对ＭＳ的候选基因筛查及全基因组扫描的研究情况进行综述。一、候选基因（ｃａｎｄｉｄａｔｅｇｅｎｅ）寻找ＭＳ的易患基因,主要集中在对参与免疫反应产物的各个遗传基因的研究,研究这些基因是否与ＭＳ存在关联和连锁。关联研究（ａｓｓｏｃｉａｔｉｏｎｓｔｕｄｙ）是指某基因在患者和正常人群中同时存在,应是呈随机分布…     

人类白细胞抗原-DQB1等位基因多态性与我国南方汉族人群多发性硬化的相关性研究

目的探讨人类白细胞抗原(HLA)-DQB1基因多态性与我国南方汉族人群多发性硬化(MS)的相关性。方法采用基因测序的方法(SBT)对42例南方汉族MS患者及48名健康对照者进行HLA-DQB1等位基因的检测,并比较MS组与健康对照组之间等位基因型频率的差异。结果共检测到15种HLA-DQB1等位基因片段,其中DQB1*0502等位基因频率MS组(35.7%)显著高于健康对照组(8.9%)(P=0.0018,Pc=0.027,OR=4.29);DQB1*0303等位基因频率MS组(19.0%)低于健康对照组(39.6%)(P=0.04,OR=0.48),但差异经校正后无统计学意义。HLA-DQB1*0601和DQB1*0602等位基因频率在MS组患者与健康对照组之间差异无统计学意义。结论我国南方汉族人群MS与HLA-DQB1*0502等位基因有关,而与HLA-DQB1*0601和DQB1*0602等位基因无关。     

多发性硬化康复治疗

<正>多发性硬化(MS)是一种以中枢神经系统白质脱髓鞘为主要病理改变的自身免疫性疾病,常见病变部位位于脑或脊髓,临床表现为病变多发和反复复发-缓解病程,即空间和时间多发性,以髓鞘脱失、神经胶质增生、不同程度轴索病变和进行性神经功能障碍为主要特点,常累及脑室周围白质、视神经、脊髓、脑干和小脑,尤以侧脑室体部和脊髓前角多     

多发性硬化的磁共振成像诊断及研究进展

多发性硬化（MS）从首例病例报告至今已有近160年历史。然而其病因、病理学机制依然不明。目前,全世界有大批学者从事多发性硬化各方面的研究,仅多发性硬化年会就有4个（美国、欧洲、南美洲和亚洲-大洋洲年会）。     

多发性硬化的磁共振成像诊断及研究进展

多发性硬化(MS)从首例病例报告至今已有近160年历史。然而其病因、病理学机制依然不明。目前,全世界有大批学者从事多发性硬化各方面的研究,仅多发性硬化年会就有4个(美国、欧洲、南美洲和亚洲-大洋洲年会)。1981年,MRI首次应用于多发性硬化的检查,从此极大地帮助了对多发性硬化的理解,在诊断、病理学机制的探索、疗效判断、推测预后等方面发挥了巨大作用。目前公认,多发性硬化是中枢神经系统的一种炎性脱髓鞘     

多发性硬化的免疫研究进展

多发性硬化(multiple sclerosis.MS)是一种病因不明的中枢神经系统(central nervous system,CNS)自身免疫性疾病,以炎性脱髓鞘为主要特征,以髓鞘脱失、神经胶质细胞增生、不同程度的轴索病变为主要病理特点.     

HLA-DRB1基因型与多发性硬化易患性的关系

目的：探讨HLA基因型与多发性硬化（MS）易患者的关系。以及临床表现与基因型的关系。方法：30例MS患者（包括2对双生子患者）、40名健康对照组，应用序列特异性引物聚合酶链反应（PCR－SSP）方法进行HLA－DRB1基因分型，对2个双生子家系进行家系分析。结果：单卵双生子？（经遗传标记确定）同患MS，病变均累及大脑，脑干和脊髓，基因型为HLA－DRB1＊09＊14．1。异卵双生子之一为复发缓解型视神经脊髓炎，基因型为DRB1＊01＊12，其未患病双生子妹妹为DRB1＊17＊12。根据病变部位。30例MS中视神经脊髓炎型和西方型各15个。脊髓（70．0％），和视神经（56．7％）是最常见病变累及部位。DR15的等位基因频率在MS组无显著增高，但DR12等位基因频率在MS中显著升高（10／30vs 4/40,P=0.0157)，分层分析显示视神经脊髓炎患者中DR12等位基因频率升高，差异有极显著意义（8／15vs 4/40,P=0.0019,RR=5.33)。结论：单卵双生子与异卵双生子的患病一致性差异表明，遗传因素在MS发病中起一定作用。DR12可能是部分视神经脊髓炎型MS的易患基因，关联基因的差异可能是东西方MS临床表现和病变部位不同的原因之一。     

HLA and prognosis in multiple sclerosis

The patients of a multiple sclerosis (MS) incidence cohort with 25 years of longitudinal follow-up were typed for HLA-DR and DQ. This type of cohort provides reliable data for gene frequencies and prognostic studies. The influence of sampling bias, mainly due to mortality during the long follow-up, was accounted for. A positive association between MS and DR15,DQ6 was confirmed, but this haplotype did not influence prognosis. There was no difference in haplotype frequency between relapsing-remitting and primary chronic progressive MS. DR17,DQ2 was significantly over-represented in the quartile with the most malignant course. The haplotype DR1,DQ5, which was found rather less frequently in MS patients, also tended to be associated with a poorer prognosis.     

HLA-Dw1 and BfF as protective markers in multiple sclerosis

The frequencies of Properdin factor B allotypes were studied in 54 multiple sclerosis patients and 58 healthy control subjects, and the association of various phenotypes with HLA-Dw1 and Dw2 antigens (found with decreased and increased frequency in MS patients, respectively) was further studied. SS genotype was found in 76% of MS patients and 63% of control subjects (n.s.). F types (FS + FF) were found to be strongly associated with HLA-Dw1 in control subjects (P < 0.0014), whereas neither SS nor F containing types were associated with Dw2. The findings support the concept of a hypothetical MS resistance factor in the HLA gene area.     

Multiple sclerosis in G: genes and geography

Multiple sclerosis (MS) shows uneven geographic distribution globally as well as within countries. In epidemiological studies we have previously demonstrated that there is a high-risk focus for MS in the southern Ostrobothnian region of western Finland. In genetic studies we recently identified haplotypes that associate with MS specifically in patients originating from southern Ostrobothnia suggesting a founder effect. Such haplotypes can be used as molecular tools for tracing common ancestry between patients in different geographic locations. In addition to providing clues to the historical origin, such a genetic archeological approach should help narrow the size of the shared haplotype, thus facilitating the identification of etiological variants and possibly define a superfamily of MS patients with common pathogenetic mechanisms.     

Multiple sclerosis: postlinkage genetics

Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.     

HLA antigens in Italian multiple sclerosis patients

We analyzed HLA-A,-C,-B,-DR and-DQ specificities in 104 Italian multiple sclerosis patients and in 905 healthy controls. The frequencies of HLA-A23, A26, Cw4, DR3 and, especially DR5 antigens were significantly higher in multiple sclerosis patients than in controls. Patients with progressive course were characterized by high frequencies of B7, B8 and DR3 antigens: Cw1 and DRw11 show a negative correlation with the extent of intrathecal IgG production. These data confirm that the HLA system may influence the clinical expression and the immune responses to the disease.

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Sommario Abbiamo analizzato le specificità HLA del locus A, C, B, DR e DQ in 104 pazienti italiani affetti da Sclerosi Multipla e in 905 controlli sani. La frequenza degli antigeni A23, A26, Cw4, DR3 e soprattutto DR5 era aumentata in maniera significativa nei pazienti rispetto ai controlli. I pazienti con decorso progressivo erano caratterizzati da un'alta frequenza degli antigeni B7, B8 e DR3; Cw1 e DRw11 mostravano una correlazione negativa con l'estensione della produzione intratecale di IgG. Questi dati confermano che il sistema HLA può influenzare l'espressione clinica e le risposte immunitarie nella malattia.

     

Multiple sclerosis,sleep latencies and HLA antigens

Summary The role of HLA antigens, and HLA-DR2 in particular, in the determination of mean sleep onset latencies (MSOLs) in multiple sclerosis (MS) was studied. It has been suggested that this antigen may play a part in the reduction of MSOLs, since nearly 100% of patients suffering from narcolepsy are DR2-positive. A multiple sleep latency test was performed in 37 patients suffering from MS without spontaneous complaints of sleep disturbances and who were typed for HLA-A, B, C, DR and DQ. The MSOL was reduced in a total of 21 patients, in only 7 of 15 DR2-positive patients and in 12 of 21 DQw1-positive patients. However, it was reduced in 13 of 16 B8- or B14-positive patients. In contrast with this, in the absence of an early sleep onset (MSOL >30 min), no HLA antigens were found to be over-represented when considered individually; only those patients positive for a group of cross-reacting HLA antigens (B5, B15, B18, B21 or B35) had an MSOL greater than 30min. These results suggest that the genes which code for the DR2 or DQw1 antigens, which are present in nearly 100% of narcoleptics, are not solely responsible for the appearance of an early sleep onset in MS.     

Genetics for understanding and predicting clinical progression in multiple sclerosis

Introduction

Multiple sclerosis (MS) is a dys-immune disease of the central nervous system with highly variable and unpredictable long-term outcome.

State of the art

In the early 1970s association between HLA alleles and MS was established. Very recently, the power of Genome Wide Association Studies (GWAS) enabled the identification of several loci involved in immune functions as genetic risk factors in MS. Recent data suggest that common genetic variations might modulate the clinical phenotype of MS through a regulation of key pathophysiological pathways.

Perspectives

Identification of modifier genes might offer an opportunity to explore new relevant therapeutic targets and early prognostic markers. To date, studies of modifier genes in MS are numerous but results are still unclear. This research field may now benefit from large cohorts of patients available for association studies.

Conclusion

In this context, we propose a review of epidemiological and association studies of genetic modifying effect in MS.     

Multiple sclerosis genetics 2010

Multiple sclerosis (MS) is a complex disease involving interactions among multiple genetic loci with modest effects and environment. The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents by far the strongest MS susceptibility locus genome-wide, with the primary signal arising from the HLA-DRB1gene in the class II segment of the locus. Large, multicenter DNA collections have prospered as the development of new laboratory and analytical approaches has matured at a remarkable pace, allowing the pursuit of comprehensive "agnostic" genome-wide association studies to identify and characterize the non-HLA genetic component of MS. This article summarizes the new knowledge gained from this experimental approach.