阿尔茨海默病患者早老素-1基因内含子多态性分布的研究

目的 探讨早老素－１（ＰＳ－１）基因第８外显子３’端内含子等位基因多态性在散发性阿尔茨海默病（ＳＡＤ）发病机制中的作用。方法 应用聚合酶链反应－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）方法检测７５例ＳＡＤ患者（ＳＡＤ组）和７３例正常老年人（对照组）的ＰＳ－１基因第８外显子３’端内含子等位基因多态性分布。结果 ＳＡＤ组１等位基因频率明显高于对照组（Ｐ〈０．０１,ＲＲ＝１．８３）,２等位基因频率明显低于对照组（Ｐ〈０．０１,ＲＲ＝０．５５）;ＳＡＤ组２／２基因型频率低于对照组（Ｐ〈０．０５,ＲＲ＝０．３２）。结论 ＰＳ－１基因多态性与ＳＡＤ发病有关,ＳＡＤ发病与ＰＳ－１基因２等位基因呈明显负关联,与１等位基因呈明显正关联。ＰＳ－１基因２等位基因对ＳＡＤ发病可能有保护作用,１等位基因可能是ＳＡＤ发病的危险因素之一。     

HLA-DQβ遗传多态与重症肌无力的易患性

目的探讨ＨＬＡＤＱβ对重症肌无力（ＭＧ）的遗传易患性。方法采用聚合酶链反应限制片段长度多态性（ＰＣＲＲＦＬＰ）法对３５例ＭＧ患者及５０名健康对照ＨＬＡＤＱβ链对应的ＨＬＡＤＱＢ１基因进行分型，并对患者组和健康对照组的ＤＱＢ１各等位基因频率和ＤＱβ氨基酸序列进行比较分析。结果ＤＱＢ１０２０１和ＤＱＢ１０３０２的频率在患者组中升高，其中两组的ＤＱＢ１０３０２的频率差异具有显著性意义（ＲＲ＝４．４１，Ｐ＜０．０５）；ＨＬＡＤＱβ氨基端５７位的丙氨酸在患者组中显著升高（ＲＲ＝５．１０，Ｐ＜０．００５），在伴有胸腺瘤的ＭＧ患者中差异更显著（ＲＲ＝５７．８８，Ｐ＜０．００１）。结论ＨＬＡＤＱβ５７位的丙氨酸表现对中国人ＭＧ的易患性，特别是在伴有胸腺瘤的ＭＧ患者。这种易患性的遗传基础为非极性的疏水氨基酸丙氨酸替换了带负电荷的极性氨基酸天冬氨酸。     

HLA-DPB_1等位基因对广西汉族重症肌无力的遗传易感性研究

目的探讨ＨＬＡ－ＤＰＢ１等位基因对广西汉族重症肌无力（ＭＧ）的遗传易感性。方法用限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）多酶共同消化法对ＨＬＡ－ＤＰＢ１的３１个等位基因进行分型。结果发现广西汉族ＭＧ患者的ＨＬＡ－ＤＰＢ１０５０１及３６０１的频率明显高于正常人。ＤＰＢ１２７０１在全身型ＭＧ明显增多。ＤＰＢ１易感基因为纯合子时，ＭＧ发病早，并与全身型ＭＧ密切相关。早发病ＭＧ与晚发病ＭＧ、男性ＭＧ与女性ＭＧ、眼肌型ＭＧ与全身型ＭＧ的ＨＬＡ－ＤＰＢ１遗传背景有所不同。结论广西汉族ＭＧ的ＨＬＡ－ＤＰＢ１易感基因为０５０１、３６０１及２７０１，其中前两者对ＭＧ发病最重要，后者见于全身型病人     

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。     

HLA-A、B抗原分型与AIDP易感性

目的 探讨ＡＩＤＰ易感性与ＨＬＡ－Ａ、Ｂ抗原分型的关联性。方法 对３１例ＡＩＤＰ患者和１３２例健康对照采用ＰＣＲ－ＳＳＰ法进行ＨＬＡ－Ａ、Ｂ抗原的基因分型。结果ＨＬＡ－Ａ３３抗原频率在ＡＩＤＰ组升高（Ｐ〈０．０５），相对危险率ＲＲ＝６．１２５。结论 ＨＬＡ－Ａ３３抗原与ＡＩＤＰ易感性相关联。     

家族性重症肌无力患者的临床及遗传学研究

目的研究家族性重症肌无力（ＭＧ）患者的临床和免疫学特征与非家族性患者的异同,并分析家系患者的遗传学特性,试图解释家族发病的机制。方法对诊治１１２例家族性重症肌无力的临床特征、免疫学特征及ＨＬＡ－Ⅱ、Ⅲ类抗原基因分型进行了研究及家系分析。结果本组患者的临床及免疫学特征与散发性病例基本相同,其遗传方式基本符合Ｍｅｎｄｅｌ常染色体遗传,可能为显型或隐性遗传,其中２个家系呈典型显型遗传。ＨＬＡ基因分型发现补体Ｃ４Ａ＊４、补体型Ｓ４２及ＤＲＢ１等位基因中的０９０１和１３０１两对等位基因与ＭＧ相关。结论遗传缺陷与环境因素相互作用导致了重症肌无力。     

MJD1基因单个碱基多态性与CAG重复序列不稳定性的关系

马查多－约瑟夫病患者的ＭＪＤ１基因存在ＣＡＧ三核苷酸不稳定扩展突变，为探讨这种不稳定扩展突变的分子机制。方法对５８名正常人和２０名ＭＪＤ患者的ＭＪＤ１基因内ＣＡＧ／ＣＡＡ、ＣＧＧ／ＧＧＧ两个位点的多态性进行检测。结果正常染色体中，具有ＣＧＧ等位基因的ＣＡＧ重复数目（２７．３２±０．６１，ｎ＝２８）较具有ＧＧＧ等位基因的ＣＡＧ重复数目（１５．９０±０．６９，ｎ＝３０）明显大（Ｐ＜０．０１）。ＣＧＧ等位基因在患者中的分布频率（１００％）明显高于正常人（４８．３％）。结论ＭＪＤ１基因内单个碱基置换影响ＣＡＧ重复序列的稳定性。     

重症肌无力患者红细胞免疫功能的变化

为了探讨重症肌无力（ＭＧ）患者红细胞免疫功能的变化，我们测定了２０１例ＭＧ患者外周血ＲＢＣ－Ｃ３ｂ受体花环率（ＲＢＣ－Ｃ３ｂＲＲ）和ＲＢＣ－ＩＣ花环率（ＲＢＣ－ＩＣＲ）和５０名正常人进行对照。结果为ＭＧ患者的ＲＢＣ－Ｃ３ｂＲＲ（７．５８±３．４％）明显低于正常对照组（１２．８７±５．０７％）（Ｐ＜０．０１），ＲＢＣ－ＩＣＲ（５．８３±４．６２％）稍高于正常对照组（５．０３±３．８４％）（Ｐ＞０．０５），ＭＧ全身型组ＲＢＣ－Ｃ３ｂＲＲ（５．２５±１．８５％）明显低于眼肌型组（８．５９±３．１９％）（Ｐ＜０．０１），强的松治疗前组（７．９８±４．０１％）与治疗后组（１１．６４±４．３５％）有明显差异（Ｐ＜０．０１），强的松治疗前后ＲＢＣ－ＩＣＲ的变化无统计学意义。上述结果表明ＭＧ患者红细胞免疫粘附功能低下与ＭＧ发病有一定的相关性。ＭＧ的发病不仅有体液免疫功能障碍，还可能有红细胞免疫功能障碍，我们的资料为ＭＧ免疫病原学发病机理提供了一项新的实验依据，也可为免疫治疗ＭＧ评定疗效提供客观辅助指标。     

人类白细胞抗原和氯氮平诱发的粒细胞缺乏症

目的探讨氯氮平诱发的粒细胞缺乏症（简称为粒缺）与人类白细胞抗原（ＨＬＡ）的相关关系。方法对２９例精神分裂症患者进行了ＨＬＡ分型研究。结果２９例中７例发生粒缺患者的ＨＬＡ－ＤＲ１２（５）抗原频率显著高于２２例粒缺未发生的患者，Ｐ＜０．０１。在精神分裂症患者与健康对照组之间，未发现该抗原频率差异有显著性。结论提示服用氯氮平发生粒缺的患者可能有特异的遗传素质，遗传基础与ＨＬＡ－ＤＲ１２（５）基因有关，相对危险性（ＲＲ）＝３８．１５６，而与疾病自身因素无关。     

一氧化氮与帕金森病小鼠模型神经损害的研究

目的　研究一氧化氮（ＮＯ） 在帕金森病（ＰＤ）小鼠模型神经损害中的作用。方法　用比色分析、高效液相色谱电化学及免疫组化法检测１甲基４苯基四氢吡啶（ＭＰＴＰ）和７硝基吲唑（７ＮＩ）对Ｃ５７ＢＬ小鼠纹状体一氧化氮合酶（ＮＯＳ） 活性,多巴胺（ＤＡ）、二羟基苯乙酸（ＤＯＰＡＣ）、高香草酸（ＨＶＡ） 水平和酪氨酸羟化酶（ＴＨ） 免疫阳性神经纤维的影响。结果　注射ＭＰＴＰ后Ｃ５７ＢＬ小鼠纹状体ＮＯＳ活性增加,７ＮＩ能明显抑制ＭＰＴＰ引起的ＮＯＳ活性的升高（ 分别为０ ．９３ ±０．２４ 和０．５４ ±０．１６,ｎｍｏｌ·ｍｉｎ－１·ｇ－１ 组织,Ｐ＜０．０１） 。７ＮＩ能明显减轻ＭＰＴＰ引起的Ｃ５７ＢＬ小鼠纹状体ＤＡ（ 分别为０ ．８ ±０ ．２ 和６．８±０．５,μｇ／ｇ 组织,Ｐ＜０．０１） 、ＤＰＯＡＣ（ 分别为０．３ ±０．１ 和０ ．９ ±０ ．３ ,μｇ／ｇ 组织,Ｐ＜ ０ ．０１）、ＨＶＡ（分别为０．４±０．２ 和０．９ ±０ ．２,μｇ／ｇ 湿组织,Ｐ＜ ０．０１） 的降低及ＴＨ 阳性神经纤维损害。结论神经元来源的ＮＯ 参与了ＭＰＴＰ的毒性机制,神经元型ＮＯＳ抑制剂可能有益于ＰＤ的治疗。     

Interleukin-2 production by peripheral blood mononuclear cell from patients with myasthenia gravis--correlation with clinical severity]

Interleukin-2 (IL-2) production by peripheral blood mononuclear cell (PBM) and the frequency of surface IgG+ B cells (%) were studied in 17 patients with myasthenia gravis (MG) and 12 controls. Culture supernatants from phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cell from patients with MG and controls were added to IL-2 dependent proliferative cultures (CTLL-2). Following 24 hr of culture, 3H-Tdr was added and cultured for an additional 6 hr. Cultures were harvested and 3H-Tdr incorporation was determined. In comparison with controls we found significantly increased synthesis of IL-2 in patients with MG (p < 0.05). Highest synthesis was found in severe cases and there were highly significant correlation between IL-2 synthesis and clinical severity score (R = 0.85, p < 0.05). These findings suggest that the ability of IL-2 synthesis by PBM may reflect severity of patients with MG. B cells expressing surface IgG, considered to be differentiated B cells, were less frequent in severe cases (R = -0.67, p < 0.05). It may be that the B cells with further differentiation are transformed into plasma cells expressing other markers such as PCA-1 in severe patients with MG.     

A retrospective review of 15 patients with familial myasthenia gravis over a period of 25?years

We observed, during a 25-year period, 15 patients from 6 families with autoimmune myasthenia gravis (all Chinese Han from Guangdong Province) referred to our department. Their mean onset age was 13.4 years (range 2-25 years) with 10 patients with juvenile onset. The female:male ratio was 3:2. Acetylcholine receptors antibody titers were increased in 11 patients (range 1.62-19.8 nmol/L). Thymectomy was performed in six patients, who received corticosteroids /immune inhibitor plus pyridostigmine treatments after surgery. The other patients were placed on therapy with azathioprine, cyclophosphamide, corticosteroids and acetylcholinesterase inhibitors. All patients responded well to immunosuppressants, and psychiatric symptoms were observed only in one patient who received a high dose of corticosteroids. Patients with generalized type in the same family had different presentations with variable prognosis. HLA-A 0207 was found in 9 patients (9/15), HLA-B 4601 in 11 patients (11/15), and HLA-DRB1 0901 in 12 patients (12/15). When compared to familial autoimmune myasthenia gravis in other countries, we observed peculiar characteristics of Chinese populations, such as the within-family consistency was only found in families with ocular MG type (50% of all MG families), while the pathogenetic conditions and the prognoses of the generalized MG patients may differ greatly within the same family. These findings may shed new light on the genetic predisposition and the origin of immune abnormalities of MG patients.     

重症肌无力患者肺功能改变及其与临床肌无力严重度的相关分析

目的 检测重症肌无力(MG)患者的肺功能改变,探讨其呼吸肌力变化与临床肌无力严重度、肺功能改变的关系. 方法 选取解放军第309医院MG治疗中心自2008年8月至2009年5月收治的Ⅰ型MG患者16例,Ⅱ型50例,选取同期健康体检者30例做为对照,检测并比较呼吸肌力[最大吸气压(PIM)、最大呼气压(PEM)、0.1s口腔闭合压(P0.1)]、和肺功能[肺活量(VC)、最大自主通气量(MVV)、峰流速(PF)、总气道阻力(R5)、中心气道阻力(R20]改变,并对Ⅱ型MG患者的呼吸肌力变化与临床肌无力严重度、MG患者呼吸肌力与肺功能的改变行相关性分析. 结果 与对照组比较,Ⅰ型MG患者MVV、PM降低,R20、R5增高,Ⅱ型MG患者VC、MVV、PF、PIM、PEM降低,R5增高,差异有统计学意义(P<0.05).与Ⅰ型MG患者比较,Ⅱ型MG患者PIM、PEM蹦减少,R5、R20增高,差异有统计学意义(P<0.05);Ⅱ型MG患者的PIM、PEM、MVV、VC与肌无力严重度绝对分数均呈正相关关系(r=0.550,P=0.002;r=0.653,P=0.000;r=0.511,P=0.000;r=0.353,P=0.010);MG患者的PIM、PEM分别与VC、MVV、PF均呈正相关关系(P<0.05),且PEM与PIM之间也呈正相关关系(r=0.650,P=0.000). 结论 Ⅰ型MG患者在疾病早期无明显呼吸肌无力表现时可有呼吸肌力减退和呼吸肌耐受力降低,故MVV、PIM、R20、R5可作为早期诊断MG的敏感指标;Ⅱ型MG患者呼吸阻力的增高和呼吸肌力的受损比Ⅰ型MG更严重.且这种损害伴有肌无力严重度绝对分数的增高;呼吸肌力的减退与肺功能的减退呈一致性.     

Fcγ receptor polymorphisms do not predict response to intravenous immunoglobulin in myasthenia gravis

ABSTRACT: We studied 63 patients with myasthenia gravis (MG) requiring treatment with intravenous immunoglobulin, to determine if polymorphisms within the FCγR2A (rs1801274), FCγR2B (rs1050501), FCγR3A (rs396991), and FCγR3B (NA1/NA2) genes are correlated with response to treatment. There was no significant difference in any of the polymorphisms studied between responders and nonresponders. Patients with the FCγR2B-232I/I polymorphism had higher disease severity measured by the quatitative myasthenia gravis score (QMGS). There was no difference in the distribution of the FCγR2B-232 polymorphisms between the patients and 90 healthy controls. The finding of greater disease severity in patients with the FCγR2B-232I/I polymorphism requires confirmation in a larger population of patients with myasthenia gravis.     

PTPN22 R620W promotes production of anti-AChR autoantibodies and IL-2 in myasthenia gravis

In order to investigate the potential involvement of PTPN22 R620W in the pathogenesis of myasthenia gravis (MG), we performed a case-control study including 409 Swedish MG patients and 1557 normal controls. The W620 variant was significantly overrepresented in patients (odds ratio, 1.52; 95% confidence interval, 1.21-1.90; p=0.00027). Incubation of patient (n=100) derived PBMC cells with the autoantigen, the acetylcholine receptor, resulted in a significantly higher number of cells producing anti-AChR antibodies and IL-2 in W620 carriers, suggesting that PTPN22 W620 may be a loss-of-function variant in MG.     

T suppressor cell function in patients with myasthenia gravis

The activities of Con A-induced Suppressor Cells (Con-ASC) were determined in 50 patients with myasthenia gravis (MG) and 24 healthy controls. The ConA-SC activity of the patients with MG was significantly decreased as compared with that of the controls (10.06%) versus 25.28%, (P less than 0.01). Furthermore, the patients with generalized myasthenia gravis (GMG) had a lower ConA-SC activity than those with extraocular muscle myasthenia gravis (EMMG) (9.37% versus 12.13%, P less than 0.05), but their serum anti-acetylcholine receptor antibody titer was higher than that of patients with EMMG (20.55 x 10(-9) M versus 2.4 x 10(-9) M, P less than 0.01). No correlation found between the ConA-SC activity and the sex or duration of disease of the MG patients. And no effects of prednisone and thymectomy were found on the ConA-SC activity of MG patients. The results of the study suggested that the decreased function of suppressor T lymphocytes might play an important role in the pathogenesis of MG.     

A study of hand preference in myasthenia gravis

A recent study reported an association between left-handedness and some pathologies, such as autoimmune diseases, including myasthenia gravis (MG). We studied hand preference in 102 patients with a generalized autoimmune form of myasthenia gravis and in a control group of 178 subjects. We employed Oldfield's inventory with a few minor modifications. The questionnaire also asked the hand preference of patients' and controls' relatives. For each subject, the laterality quotient (LQ) was calculated and submitted to ANOVA. The frequency of left-handedness in controls was similar to that reported in the literature. Although left-handedness occurred less often in myasthenics, the difference between the two groups was not significant. Also the frequency of left-handedness in relatives of myasthenic patients did not differ from that observed in controls.     

Association between HLA-DRB1 and myasthenia gravis in a northern Han Chinese population

The cause of myasthenia gravis (MG) is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals. The human leukocyte antigen (HLA) region is considered to be the most important genetic region for MG susceptibility genes. To investigate the association between HLA-DRB1 and myasthenia gravis (MG) in a northern Han Chinese population, a polymerase chain reaction with sequence-specific oligonucleotide probe hybridization method was used to determine the HLA-DRB1 genotypes of 91 patients with MG and 171 healthy individuals. We found that the HLA-DRB1^∗09 allele was significantly more prevalent among patients with MG than among healthy controls, especially those who experienced early onset of the disease (?40 years), those who were seronegative for acetylcholine receptor antibody, and those with ocular MG. The prevalence of the HLA-DRB1^∗08 allele was significantly lower among patients with MG than among controls. These results indicate that HLA-DRB1^∗09 might be positively associated and DRB1^∗08 negatively associated with MG in the northern Han Chinese population.     

Effect of clinical status and treatment on the frequency of CD5+ B cells in patients with myasthenia gravis.

CD5+ B cells comprise a subset of B lymphocytes that may play a pathogenetic role in the development of human autoimmune disease. We previously reported a high-frequency phenotype (greater than 30% CD5+ B cells) in the peripheral blood of 57% of myasthenia gravis (MG) patients and 13% of controls. We have now examined additional patients (n = 41) and controls (n = 27) and continue to find that 44% of MG patients have a high-frequency phenotype of CD5+ B cells compared with 7% of controls. Serial studies showed that the frequency of CD5+ B cells in peripheral blood remained fairly stable for controls and that it may decrease with immunosuppressive therapy of MG patients. In patients receiving anticholinesterase only or no therapy (n = 21), the age at onset of MG, presence or absence of detectable serum anti-acetylcholine receptor antibody, clinical extent of MG, and the duration of disease may affect the frequency of CD5+ B cells in the blood.