人类1号染色体上狼疮易感基因位点的研究及进展

系统性红斑狼疮 (ｓｙｓｔｅｍｉｃｌｕｐｕｓｅｒｙｔｈｅｍａｔｏｓｕｓ,ＳＬＥ)是典型的非器官特异性自身免疫病 ,其自身免疫异常表型特别丰富 ,几乎覆盖整个免疫系统的紊乱 ,被公认为是自身免疫病的原型。ＳＬＥ的病因和发病机制至今未明。但遗传流行病学调查发现 :ＳＬＥ在某些人群中的发病率明显高于其他人群 ;发病有家族聚集倾向 ,一级亲属的发病率明显高于正常人群 ;同卵双生子的患病率 (近 2 4 %～ 6 5 % )明显高于异卵双生子 (2 %～ 9% )。此外自发性ＳＬＥ小鼠模型的遗传背景研究也表明其多种自身免疫表型与特定的基因位点相关联…     

新西兰白鼠狼疮性肾炎易感基因的染色体定位

目的 :探讨新西兰白鼠 (NZW)狼疮性肾炎 (LN)的遗传易感基因。　 方法 :建立 (NZBxNZW )F1xNZB回交小鼠模型 ,采用覆盖小鼠除性染色体以外全部 19条染色体的多态性微卫星遗传标记及数量性状位点 (QTL)分析进行基因定位 ,并应用限制性长度多态方法比较LN易感基因的多态性 ,将小鼠的累积蛋白尿定性作为LN的表现型。　结果 :QTL分析结果显示 ,(NZBxNZW)F1xNZB回交小鼠LN易感基因位点分别与NZW小鼠第 11染色体微卫星遗传标记D11Mit2 6 3及 17染色体微卫星遗传标记D17Mit6 1肯定连锁 (Lod值 >3)。D11Mit2 6 3位点附近存在粒细胞集落刺激因子 3基因 ,D17Mit6 1位点附近存在 (TNF)α和H 2基因。同时携有D17Mit6 1基因B/W型和D11Mit2 6 3基因B/W型两个易感基因位点组的蛋白尿的阳性率比单基因组增高。　 结论 :NZW来源的Csf3基因及TNFα(或H 2 )基因是新西兰小鼠LN重要的易感基因。易感基因之间有相互促进作用     

系统性红斑狼疮

系统性红斑狼疮(systemic lupus erythematosus，SLE)虽然不是本届年会的主题疾病，然而有关SLE易感基因的定位、免疫发病机制的研究以及治疗新方法包括治疗新药的探索等依然是本届年会中最引人注目的焦点之一。     

第38例:临床表现水肿、蛋白尿

<正>患者男性,22岁,因"下肢、眼睑水肿3个月,泡沫尿2个月"于2010年7月16日入院。患者入院前3个月开始出现双侧眼睑及双下肢的可凹性水肿,晨重暮轻。2个月前开始出现尿中泡沫增多。无皮疹、光过敏、关节肿痛、口腔溃疡等。于我院门诊诊断肾病综合征,予泼尼松60 mg/d治疗。既往高血压病史2年,未随诊血压、未治疗,无不适。个人史、家族史无特殊。入院查体:血压159/103 mm Hg,颈静脉     

LRRK2基因多态性与帕金森病相关性的研究进展

LRRK2基因被认为是引起帕金森病易感性最常见的突变基因,也是最常见的家族和散发性帕金森病的原因,其主要为常染色体显性遗传。帕金森病在目前尚不能被治愈,只能在一定程度上控制其进展。为此,从该病易感基因常见突变位点的角度出发进行了一定程度的探索,期待为该病的治疗提供新思路。     

在中国人群中鉴定发现PBX1基因为1q 23-24区域新的狼疮易感基因

目的用连锁不平衡(linkage disequilibrium)的方法对1号染色体狼疮易感区域进行进一步的精细定位,并由此定位新的系统性红斑狼疮(SLE)候选基因.方法用9对高密度的微卫星标记对1q23-24易感区域进行连锁不平衡分析;用延伸型传递不平衡试验(ETDT)、Gene Hunter和家系为基础的相关分析(FBAT)软件分析连锁不平衡的结果;用TaqMan荧光实时定量聚合酶链反应(PCR)检测候选基因mRNA的表达量;用等位基因分型PCR对候选基因内的4个SNP分型.结果①发现微卫星标记D1S2628 (P＝0.000 987,Pc＝0.001 2)和D1S2673 (P＝0.007 082,Pc＝0.010 4)的等位基因存在整体的显著传递不平衡);②发现D1S2628-119 bp (Pc＝0.001 2;传递∶不传递＝91∶45,P＝0.000 1)和D1S2673-103 bp (Pc＝0.010 4,传递∶不传递＝109∶67,P＝0.0016)等位基因从杂合子父母优势传递给受累后代;③在中国汉族红斑狼疮核心家系中单倍型D1S2628 (119 bp)-D1S2673 (103 bp) (传递∶不传递＝43∶18,P＝0.001 4)和单倍型D1S2628 (119 bp)-D1S2673 (107 bp) (传递∶不传递＝29∶12,P＝0.007 9)存在传递不平衡.在中国汉族SLE患者中PBX1的mRNA的表达量显著下降(P＜0.000 1).PBX1基因中的单倍型SNP1(G)-SNP2(C)优势传递给受累后代.结论在中国汉族人群的1q23区存在与微卫星标记D1S2628和D1S2673物理距离相近的SLE易感基因;PBX1基因表达较低,其SNP单倍型与SLE易感显著相关.这提示PBX1基因可能是一个新的候选基因.     

FCGR2A基因多态性与系统性红斑狼疮相关性研究

目的 明确FCGR2A基因H131／R131多态性在中国人群中的分布，探讨该位点是否与系统性红斑狼疮(SLE)的发病有关。方法 应用Taqman MGB方法对340例SLE病人，300例患者父母和183名正常人的H131／R131多态性位点进行大规模等位基因分型，病例对照研究应用χ^2检验，家系为基础的传递不平衡检验应用ETDT22软件。结果 病例对照研究提示SLE组和正常组之间的等位基因频率无明显差异(P=0．413)，传递不平衡检验证实该位点在中国人群SLE家系中无优势传递(P=0．6049)。结论 在中国汉族人群中FCGR2A H131／R131多态性位点与SLE的发病不存在相关性。     

系统性红斑狼疮与CDl9基因多态性的相关性研究

目的研究CDl9基因第4外显子705位点（以下简称CDl9基因705位点）多态性在中国南方地区汉族人群中的分布及其与系统性红斑狼疮（SLE）和狼疮肾炎（LN）的相关性。方法103例患者诊断均符合1982年美国风湿病学会修订的SLE分类标准，男13例，女90例，其中62例伴有LN。正常对照组110例，男2l例，女89例。全部研究对象均为无血缘关系的中国南方地区汉族人群。应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法，对所有SLE患者和正常对照者进行CDl9基因705位点多态性检测。结果CDl9基因705位点多态性在中国南方地区汉族人群中普遍存在。SLE患者CDl9基因705位点基因型和等位基因频率分布与正常对照组比较差异无统计学意义（P〉0．05）；CDl9基因705位点基因型和等位基因频率分布，按性别分层后，男性和女性SLE患者分别与正常对照组比较及LN患者和正常对照组比较以及伴有LN患者与未伴有LN的SLE患者间比较，差异均无统计学意义（P〉0．05）。结论CDl9基因705位点多态性与SLE及LN无相关性。     

雌激素受体及其基因多态性与系统性红斑狼疮相关性的研究进展

大量研究证明人体内雌激素靶器官和一些非雌激素靶器官及恶性肿瘤细胞中均存在雌激素受体（estrogen receptor，ER），雌激素必须与靶组织细胞浆或核内ER结合才能发挥作用。系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种自身免疫性疾病，研究表明该病的发生发展受多基因控制，有家族聚集性、易感性，多个基因表达综合作用导致个体出现SLE。近年来ER在SLE发病中的作用逐渐被人们所重视，本文就ER及其基因多态性与SLE相关性的研究进展做一综述。     

人系统性红斑狼疮遗传易感性研究进展

系统性红斑狼疮(SLE)是一种多因素疾病,其发病机制至今尚未明确.但越来越多的研究证据表明,遗传易感性在疾病发生中起重要作用.人类基因组研究显示约50多个基因座(loci)与SLE有关,独立队列研究证实至少有9个区域有明显相关性,包括lq23、lq31-32、lq41-42、2q35-37、4p16-15.2、6p21-11、11p13、12q24及16q12-13.对具体患者,多个不同位点的基因组合可引起疾病表型的多样性.近期研究进一步证实,遗传因素在决定疾病易感性及临床表型时起作用,不同种族、地域人群中所涉及的相关基因有所差异.     

Ethnicity and lupus nephritis: an Australian single centre study

Background: The clinical impression of Australian physicians is that systemic lupus erythematosus (SLE) is more prevalent and more severe in Asian patients than in their Caucasian counterparts. The presence and severity of lupus nephritis is a major determinant of prognosis in SLE, and largely determines disease impact. Aim: To analyse the relationships between ethnicity and the prevalence and severity of lupus nephritis (LN) in patients attending a tertiary referral centre (The Royal Melbourne Hospital (RMH)). Methods: The ethnicity of all known patients with biopsy‐proven LN was determined according to three definitions of ethnicity – ancestry, country of origin and primary language spoken. The prevalence of Asian ethnicity in the LN cohort was analysed across severity class, and was compared with the prevalences of Asian ethnicity in the general population within the hospital's geographic area, and with that in the relevant RMH cohorts of inpatients and outpatients, over the same time period. Results: Within this single tertiary centre, Asian patients were disproportionately represented in both the systemic lupus erythematosus (SLE) and the LN patient groups, although the distribution of histological severity of LN was not significantly different from Caucasian patients. Conclusion: This study supports the common clinical impression that SLE is more common and more severe in the Asian‐Australian population. Asian patients with SLE were more commonly diagnosed with LN. However, the spectrum of histological severity of LN was similar in Asian and Caucasian patients.     

Renal haemodynamic characteristics in patients with lupus nephritis

OBJECTIVE—To clarify the characteristics of renal haemodynamics in patients with lupus nephritis (LN).
METHODS—The glomerular filtration rate (GFR) and renal plasma flow (RPF) of 37 patients with active LN were studied longitudinally over an interval of 8 to 144 weeks during treatment with corticosteroids or cytotoxic drugs, or both. All patients had clinical renal disorders and underwent renal biopsies.
RESULTS—Analysis of renal biopsy specimens showed that 31 patients had class IV LN. Class II, III, and V LN were present in two patients each. The average GFR increased significantly from 65.4 (SD 33.0) in the pretreatment stage to 86.6 (31.6) ml/min in the post-treatment stage, accompanied by an improvement in urinary or immunological abnormalities, or both. On the other hand, RPF decreased significantly from 625.2 (243.0) to 519.8 (179.0) ml/min. Therefore, the filtration fraction (FF) increased significantly from 10.7 (4.3)% to 16.8 (3.7)%. Low FF was recognised predominantly in patients with class IV LN, but was also observed in patients with other classes. The FF returned towards normal irrespective of the degree of GFR recovery. No significant changes were observed in the levels of blood pressure.
CONCLUSION—A reduction in GFR out of proportion to the reduction in RPF as demonstrated by the low FF values was related to the severity of LN or disease activity, or both. Therefore, relative evaluation of GFR and RPF, namely the determination of FF, may be a useful clinical parameter to determine the status of LN.

     

Estimation of monocyte‐chemoattractantprotein‐1 (Mcp‐1) level in patients with lupus nephritis

Aim: To evaluate the use of non‐invasive estimation of CP‐1 in urine as a good indicator for lupus nephritis activity. Methods: The study was conducted on 30 patients with systemic lupus erythematosus (SLE) (group I): 15 of these patients were selected without renal involvement (group I [A]), and the other 15 were selected with evidence of renal involvement (group I [B]). Further 10 age‐ and sex‐matched healthy subjects were taken as a control group (group II). The SLE disease activity index (SLEDAI) was applied. Laboratory investigations done for the studied group of patients included: renal function tests (antinuclear antibody) titer, (anti‐double‐stranded DNA) titer, and monocyte chemotactic protein 1 (MCP‐1) level in serum and urine samples. Results: Serum MCP‐1 was significantly higher in SLE patients with nephritis than in the control group, while no significant difference was found between SLE patients without nephritis and the control group. Urinary MCP‐1 in patients with active lupus nephritis (LN) were significantly higher than both patients with inactive LN and control the group. Urinary MCP‐1 in SLE patients with nephritis was significantly higher than both group I (A) and group II. Urinary MCP‐1 correlated positively with proteinuria, and negatively with creatinine clearance and hemoglobin; thus, urinary MCP‐1 correlates with the severity of nephritis. Conclusion: Urinary and not serum MCP‐1 is a useful invasive technique for the assessment of renal disease activity in patients with LN.     

Low dose cyclosporine A in the treatment of resistant proliferative lupus nephritis

Objective: This study aimed to evaluate long-term efficacy of low dose cyclosporine A (CsA) in the treatment of resistant proliferative lupus nephritis.

Methods: In this retrospective study, patients with biopsy proven proliferative lupus nephritis who were unresponsive to combination therapy with steroid plus mycophenolate mofetil (MMF) or cyclophosphamide (CYC) and had been treated with CsA were included. Efficacy monitoring was based on the systemic lupus erythematosus (SLE) disease activity index, dose of prednisolone, serum complement, anti–double stranded DNA (anti-dsDNA) titration, urine analysis, proteinuria, creatinine clearance, remission of the renal disease, renal survival and involvement of other organs.

Results: This study included 27 consecutive patients (22 females, 5 males) with resistant proliferative lupus nephritis. Mean duration of follow up and treatment with CsA were 40.7?±?24.9 and 35.2?±?19.1 months, respectively. Complete and partial renal remission occurred in 66.9% and 25.7% patients, respectively. Creatinine clearance was stable, proteinuria and anti-dsDNA titer decreased, and C3 and C4 increased significantly during the treatment with CsA. Severe complications such as death, dialysis, kidney transplantation and severe infection did not occur in the studied patients during the follow-up period.

Conclusions: Low-dose CsA could induce renal remission and ameliorate the SLE disease activity in patients with resistant proliferative lupus nephritis and it would be a safe drug for treatment of these patients.