精神分裂症的人类白细胞抗原病因学研究

目的研究精神分裂症与人类白细胞抗原（ＨＬＡ）的关系方法用国际标准微量淋巴细胞毒实验方法对２３例北京地区的精神分裂症患者进行ＨＬＡ分型研究，并与４９例健康对照者进行比较。结果精神分裂症患者Ｂ２７、Ａ９、ＤＱ２抗原频率高，并且Ｂ２７抗原在两组中差异显著。未发现各亚型之间有不同的相关抗原。结论ＨＬＡ与精神分裂症的发生有关，Ｂ２７、Ａ９抗原表型者患精神分裂症的危险性高（ＲＲＢ２７＝５．６５，ＲＲＡ９＝２４７）。     

HLA-DR抗原在精神分裂症患者脑组织的表达

ＨＬＡ－ＤＲ抗原在精神分裂症患者脑组织的表达吴宜恕，冯方波，王宝珍，张原进，冯萍为探讨精神分裂症患者脑组织的免疫状态和遗传因素，我们应用免疫组化碱性磷酸酶抗碱性磷酸酶桥联酶标方法（ＡＰＡＡＰ法），对精神分裂症患者的脑组织进行了人类白细胞抗原Ａ系统ＤＲ...     

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。     

5-羟色胺2A受体基因多态性与精神分裂症的相关性研究

目的探讨５－羟色胺２Ａ受体基因多态性与精神分裂症的相关性。方法采用Ａｍｐ－ＲＦＬＰ方法对精神分裂症患者和各对照组的５－羟色胺２Ａ受体（简称５－ＨＴ２ＡＲ）基因的相关性进行了研究。结果精神分裂症患者５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子基因型频率及等位基因Ａ２频率均高于对照组（χ２＝８．９９，８３８Ｐ均＜０．０１），对发生精神分裂症的５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子相对危险度是２３６。结论本实验结果提示５－ＨＴ２ＡＲ基因的变异与精神分裂症有密切相关性。     

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。     

精神分裂症d－芬氟拉明激发的神经内分泌反应与临床症状的关系

目的探讨ｄ－芬氟拉明（ｄ－ＦＦ）激发的神经内分泌反应与精神分裂症临床症状的关系。方法把１５例精神分裂症患者在氯氮平治疗前、后行ｄ－ＦＦ激发试验，同时以简明精神病评定量表（ＢＰＲＳ）、阳性症状量表（ＳＡＰＳ）、阴性症状量表（ＳＡＮＳ）评定精神症状。结果混合型患者治疗前基础皮质醇（ＣＯＲ）值、治疗后ｄ－ＦＦ激发的ＣＯＲ值及治疗前、后ｄ－ＦＦ激发的催乳素（ＰＲＬ）值均显著高于阳性型。症状评分与激素反应有一定的相关关系。结论提示精神分裂症的发生可能与中枢５－羟色胺／多巴胺（５－ＨＴ／ＤＡ）功能失平衡有关。     

重症肌无力患者HLA－DRB_1等位基因分析

作者应用ＰＣＲ－ＳＳＰ方法，对３４例重症肌无力（ＭＧ）患者和８６名健康汉人ＨＬＡ－ＤＲＢ１等位基因进行分析、研究，结果发现，ＭＧ病人组ＭＲＢ１区域内０９０１、１３０１两对等位基因的频率明显高于对照组（ＲＲ分别为１６．９４４和５．５１２，Ｐ均＜０．０１）。其中８例伴有胸腺瘤的ＭＧ患者除０９０１、１３０１两对等位基因频率增高外，０４０１基因频率亦明显高于正常对照组（ＲＲ分别为３９．５０３、４．９８０和４．０００．Ｐ均＜０．０１）。作者认为，ＭＧ发病可能与ＨＬＡ－ＤＲＢ１区域内０９０１、１３０１和０４０１三对等住基因相关联。     

氯氮平治疗600例精神分裂症临床观察

氯氮平治疗６００例精神分裂症临床观察曹典永以氯氮平单项用药治疗６００例首次住院的患者，符合ＣＣＭＤ－２精神分裂症的诊断标准。患者均为男性，年龄１６～６０岁，平均２０．８岁；病程３～３３年，平均３．５年。其中未分化型４８０例，偏执型１０８例，青春型１２...     

氯氮平对慢性难治性精神分裂症的疗效与5—羟色胺2A受体基 …

目的 探讨与氯氮平对慢性难治性精神分裂症疗效有关的５－羟色胺２Ａ（５－ＨＴ２Ａ）受体基因的基因型及其他相关因素。方法 抽取１０４例慢性难治性精神分裂症患者,给予氯氮平≥４００ｍｇ／ｄ治疗２个月。治疗前后用阴性和阳性症状量表（ＰＡＮＳＳ）评定氯氮平疗效,按ＰＡＮＳＳ的减分率≥３０％和≤３０％将氯氮平治疗的患者分为有效组和无效组,用聚合酶链反应扩增及限制性片段长度多态性（ＰＣＲ－ＲＦＬＰｓ）技术测定患     

HLA DR2 in narcolepsy with sleep-onset REM periods but not cataplexy.

To determine the association of HLA DR2 in patients with narcolepsy without cataplexy, a case-control study was performed. Patients receiving the diagnosis of narcolepsy without cataplexy had excessive daytime sleepiness (EDS) and polysomnographic findings consistent with narcolepsy but no clinical evidence of cataplexy. Of 28 patients identified, 12 agreed to return for HLA typing. Respondents did not differ from nonrespondents in demographic, clinical, or sleep laboratory data. The comparison group was 503 individuals, those 30 years and older, on the Michigan Kidney Transplant Registry. The odds ratio obtained from logistic regression indicated a strong association between narcolepsy without cataplexy and HLA DR2. To control for potential confounding variables, multivariate models were constructed to explore the joint effects of HLA DR2 and each one of the covariates (age, sex, and race), their possible combinations, and the effect of all three covariates. The odds ratios decreased minimally and the association between the disease and HLA DR2 remained significant.     

Clozapine-induced agranulocytosis in a Native American: HLA typing and further support for an immune-mediated mechanism.

BACKGROUND: Approximately 30% of schizophrenic patients defined as treatment refractory significantly improve with clozapine. However, clozapine produces agranulocytosis in approximately 1% to 2% of patients in the United States. The mechanism of clozapine-induced agranulocytosis has not been established, but evidence suggests an immune-mediated mechanism. METHOD: Human leukocyte antigen (HLA) typing was performed in a native American with clozapine-induced agranulocytosis. RESULTS: Our findings support previous observations of a role of the HLA-B16, DR4, DQw3 haplotype in predicting susceptibility to agranulocytosis in clozapine-treated patients. CONCLUSION: We suggest that HLA typing of clozapine candidates may be useful for predicting the risk for clozapine-induced agranulocytosis.     

Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue

Significantly increased up-regulation of HLA DR (major histocompatibility complex class II antigen) was seen using immunohistochemistry in postmortem brain tissue from demented patients with Alzheimer’s disease (AD) (73 cases, 61 females/12 males, mean age 84 ± 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 ± 9 years). The counts of HLA DR-expressing activated microglia were significantly higher in female AD patients compared to males, significantly higher in AD patients with the age at death greater than 75 years compared to those dying younger and higher, although not statistically significantly, in AD patients with the apolipoprotein E (ApoE) ɛ4 allele compared to those patients not carrying this allele. In contrast to the situation in AD patients, in the control cases the HLA DR expression was higher in males compared to females. Furthermore, in the very old non-demented patients (age at death > 80 years), a decrease in the up-regulation of HLA DR expression was observed. A significant correlation between activated microglia and neurofibrillary tangles was seen in female AD patients compared to males, in AD cases without ApoE ɛ4 allele compared to those with this allele, in sporadic cases compared to familial and in cases with senile rather than presenile onset of the disease. Our results indicate that there is an age- and/or sex-related variability in up-regulation of HLA DR expression of microglia and that the linkage between this up-regulation and AD lesions is significantly influenced by the ApoE ɛ4 allele, gender of subjects, age at onset and familiality of the disease. Received: 20 May 1998 / Revised: 5 August 1998, 4 October 1998 / Accepted: 21 October 1998     

HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia

Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.     

Clozapine-induced concordant agranulocytosis in monozygotic twins

Two monozygotic twin sisters were admitted to a psychiatric hospital and diagnosed as having first-episode schizophrenia. Clozapine treatment led to the complete remission of psychotic symptoms within a short time. In both twins the low leukocyte count was detected after 9 weeks of clozapine. Serological typing of the HLA system was performed and an identical pattern was detected in both twins: HLA-A: 28, 26; HLA-B: 49, 63; DR: 2 (vs 16), 12, 52; DQ:1. It is the first report of concordant manifestation of clozapine-induced agranulocytosis in monozygotic twins. Our case report of twins afflicted synchronously with schizophrenia and later with agranulocytosis after clozapine is of interest because it suggests that genetic factors may participate not only in timing of onset of schizophrenia, but also in the emergence and timing of agranulocytosis in response to clozapine treatment. ( Int J Psych Clin Pract 2001; 5:71-73)     

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.     

Study of HLA as a predisposing factor and its possible influence on the outcome of multiple sclerosis in the sanitary district of Calatayud, northern Spain.

The relationship between multiple sclerosis (MS) and the HLA antigens DR2 and DQ1 is well recognised, but, in Spain, it has not been clearly defined. The aim of our study was to investigate the relationship between MS and HLA antigens in the sanitary district of Calatayud, northern Spain, and to correlate these antigens with the progression of the disease. Thirty-four patients were selected from a long-term (October 1990 to July 1996) prospective survey in the region where there was a prevalence rate of 58 per 100,000 population. The HLA antigens were determined in 31 patients. A control group of 895 people of Caucasian race was recruited from the same population. We performed serologic tests on all participants. Nucleotide typing was carried out in DR2-positive patients. The most frequent antigens in excess in MS were: A19 (odds ratio, OR: 2.29, p = 0.04), B5 (OR: 2.85, p = 0.02), B41 (OR: 7.65, p = 0.04), CW7 (OR: 3.4, p = 0.004), DR6 (OR: 6.18, p = 0.0001) and DR10 (OR: 3.4, p = 0. 004). The DR2 antigen was also more frequent in MS patients (39%) than in controls (19%; OR: 2.69, p = 0.01). All positive DR2 patients showed the DR15(2) split but not the DR16(2) split. The frequency of antigens CW4 and DR1 was lower in MS patients than in controls. The CW4 antigen was detected in 12% of the patients and in 33% of the controls (OR: 0.28, p = 0.04). The DR1 antigen was found in 20% of the controls and in none of the MS patients (OR: undefined, p = 0.01). The DQ1 antigen was observed in 68% of the patients and in 50% of the controls (OR: 2.1, p = 0.07). We did not find any relationship between HLA antigens and progression of the disease. Although we found that DR2 antigen is linked to MS, we also found other antigens related to the disease. This suggests a genetic heterogeneity in our geographic area. We also concluded that the DR1 antigen may play a protective role, as it was detected in 20% of the controls and in none of the MS cases.     

HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population

BACKGROUND: An association between HLA antigens and susceptibility to multiple sclerosis (MS) has been established, especially in Caucasian populations. Such associations have not been as clearly defined in many Arab populations, where even the frequencies of specific HLA antigens remain unclear OBJECTIVE: The study was designed to (i) investigate the frequencies of HLA Class I and II antigens in Kuwaiti Arabs with MS, and; (ii) assess possible inter-relationships between HLA Class II antigens and such clinical phenotypic variables in MS as age at onset, gender, disease subtype and scale of disability. SUBJECTS AND METHODS: HLA Class I (A, B, C) and Class II (DR, DQ) antigens' tissue-typing was performed by the standard complement-dependent microlymphocytotoxicity technique in two groups of age- and sex-matched Kuwaiti subjects: (i) 67 patients with definite MS (48 relapsing remitting, 19 relapsing-progressive) and (ii) 145 unrelated healthy controls. The frequencies of specific HLA types were then compared between patients with controls, and in the former, related to specified clinical parameters. RESULTS: The frequencies for the Class I antigens: A9, A10, A19, A33, B5 and CW4 appeared higher with the presence of MS, although the numbers of positive subjects were rather low. For the Class II antigens, frequencies of DR4, DQ5, DQ6, DQ7 and DQ8 were increased while those for DR6 and DR1 were decreased in the patients with MS. HLA types DR15 and DR4 were present at higher frequencies in patients with a younger age at disease onset; DR15 also appeared more frequent in the female patients. CONCLUSION: There is a trend towards an association between HLA Class II antigens (DR4, DQ6, DQ7 and DQ8) and MS in Kuwaiti subjects. Additionally, it appeared that DR4 and DR15 were more frequent in females and those with an early onset of the disease. These patterns of HLA Class II determinants of susceptibility to MS differ from reports in some other populations, and may reflect the recognized variability in genetic influence on HLA and disease expression.     

Influence of HLA on progression of optic neuritis to multiple sclerosis: results of a four-year follow-up study

BACKGROUND: Genetic predisposition in multiple sclerosis (MS) has always been a critical concern in aetiology and progress of the disease. The present study looks into the relations between human leukocyte antigen (HLA), optic neuritis (ON) and MS in the Iranian population. METHODS: Patients with potential diagnosis of acute ON underwent a standardized clinical examination for confirming the diagnosis. Selected patients were gathered for HLA typing and clinical follow up. RESULTS: Of the 55 patients, 46 (83.6%) were female. The mean age was 25(+/-7.3) with a range of 12-43. Twenty of the 55 (36%) were confirmed for the diagnosis of clinically definite MS (CDMS). Results show that A23, B21, A11 and B51 alleles were present in 4 (20%), 6 (30%), 2 (10%) and 1 (5%) of the CDMS patients, respectively. Ten (50%) and 17 (85%) CDMS patients were positive for HLA class II alleles, DR2 and DQ1, correspondingly. CONCLUSIONS: The study strongly suggests the association among DR2, A23 and B21 allele and the evolution of ON to MS. High prevalence of A23 and DR2 alleles in CDMS patients compared with the normal population may suggest an important role for these alleles in the development of MS. The study suggests B51 as a protective factor against development of ON in the normal population. In addition, results do not confirm previous studies considering A11 as a predisposing factor. The present study finally evokes that different classes of HLA have different roles in susceptibility to MS and confirms disease heterogeneity as an important emerging concept in MS.     

HLA‐DR2 and White Matter Lesion Distribution in MS

Human leukocyte antigen DR2 (HLA‐DR2) is a well‐established genetic risk factor for multiple sclerosis (MS). However, it is still unknown whether this factor is associated with a specific disease phenotype, and in particular, to a regional distribution of white matter (WM) lesion phenotype on magnetic resonance imaging (MRI). On a voxel‐by‐voxel basis, we analyzed the T1 and T2 MRI‐derived lesion maps of 50 patients with MS in order to determine the possible influence of HLA‐DR2 genotype on the lesional MRI pattern at early stages of the disease. HLA‐DR2 was present in 15 (30%) patients of our cohort. They displayed similar WM lesion distribution as the subjects without this factor. Thus, lesion distribution in MS seems to be independent of the DR2 genotype.