抗内皮细胞抗体及其靶抗原在抗中性粒细胞胞浆抗体相关小血管炎中的意义

目的了解抗内皮细胞抗体(AECA)在抗中性粒细胞胞浆抗体(ANCA)相关小血管炎发病中的作用.方法选取122例原发性ANCA相关小血管炎患者,分为2组显微镜下型多血管炎(MPA)组72例,韦格纳肉芽肿病(WG)组50例.应用体外原代培养的脐带静脉血管内皮细胞制备可溶性抗原,采用Western印迹法检测以上患者疾病活动期血清中的AECA,并分析AECA与临床表现的关系.结果MPA组共有45例(62.5%)血清可检出AECA,共有7种不同的蛋白可以被识别,相对分子质量分别为65 000,72 000,77 000,88 000,97 000,111 000和120 000.AECA阳性组中出现发热及肺脏受累的比例显著高于AECA阴性组(分别为73%比44%;69%比44%,P均＜0.05);其中65 000阳性组中出现发热、关节和眼受累及C反应蛋白(CRP)增高的比例显著高于65 000阴性组(分别为100%比60%;75%比25%;50%比28%;100%比57%,P＜0.05);88 000阳性组中出现血尿的比例显著高于88 000阴性组(98%比70%,P＜0.05).WG组有32例(64%)血清可检出AECA,共有10种不同的蛋白可以被识别,相对分子质量分别为61 000,65 000,69 000,77 000,83 000,88 000,97 000,105 000,113 000和120 000.AECA阳性组中出现血沉增高的比例显著高于AECA阴性组(75%比44%,P＜0.05);77 000阳性组中出现蛋白尿及肾脏病理出现毛细血管袢坏死的比例显著高于77 000阴性患者组(分别为100%比73%;50%比7%,P均＜0.05);105 000阳性组中肌肉受累的比例显著高于105 000阴性组(56%比19%,P＜0.05).结论ANCA相关小血管炎患者血清中含有针对不同靶抗原的AECA,不同的抗体可能具有不同的临床意义,提示AECA在ANCA相关小血管炎的发病中可能起重要的致病作用.     

抗中性粒细胞胞浆抗体特异性靶抗原及其临床应用

抗中性粒细胞胞浆抗体特异性靶抗原及其临床应用赵明辉章友康抗中性粒细胞胞浆抗体（ＡＮＣＡ）是近年来发现的以中性粒细胞胞浆和单核细胞胞浆成分为靶抗原的自身抗体，是原发性小血管炎的特异性血清学诊断工具。间接免疫荧光法（ＩＩＦ）是最先应用的方法，应用酒精固定...     

抗中性粒细胞胞浆抗体相关性小血管炎30例临床诊治分析

目的：探讨抗中性粒细胞胞浆抗体（ANCA）相关性小血管炎的临床特点、诊断和治疗。方法：回顾性分析2002年6月~2009年6月检测并明确诊断的30例ANCA相关性小血管炎患者的临床病理资料。结果：30例患者中胞浆型ANCA（c-ANCA）阳性4例,3例识别蛋白酶3（PR3）,1例识别髓过氧化物酶（MPO）;核周型ANCA（p-ANCA）阳性26例,均识别MPO。临床表现呈多器官受累,以肾、肺受累为主。多数患者有贫血、血沉增快和C反应蛋白增高。糖皮质激素联合免疫抑制剂治疗,诱导缓解的缓解率为83.3%。结论：ANCA相关性小血管炎临床表现为多器官受累,缺乏特异性,其诊断要结合临床表现、ANCA检测和病理活检综合考虑,糖皮质激素联合免疫抑制剂治疗有较好疗效,吗替麦考酚酯和硫唑嘌呤等免疫抑制剂较环磷酰胺毒副作用更小。     

抗中性粒细胞胞浆抗体相关性小血管炎肾损害17例临床分析

目的提高对抗中性粒细胞胞浆抗体（ANCA）相关性小血管炎（AAsV）肾损害的认识。方法对2003年6月至2009年12月在我科住院的17例AASV肾损害患者的临床和病理资料进行回顾性分析。结果（1）本组患者以中老年多见,平均年龄（53．3±21．6）岁。（2）以发热、乏力、纳差、体质量下降等全身非特异性表现为首发症状者17例（占100％）;以肾衰竭为首发症状者8例（占47％）;以咳嗽、咳痰、痰中带血或咯血为首发症状者4例（占23．5％）。（3）76．4%患者血沉（ESR）明显增快,64．7%患者C反应蛋白（CRP）升高。（4）17例患者均有不同程度的肾功能损害,其中需要透析者11例（合并肺出血者4例）,大量蛋白尿者8例,肉眼血尿者3例。（5）本组11例有活动病变者经治疗后,6例血液透析患者中2例脱离透析,其余4例维持血液透析,5例肾功能好转、蛋白尿及血尿明显减轻、病情稳定;其余6例中,3例未接受冲击诱导治疗,只给予血液透析治疗,3例自动出院。结论对中老年肾病患者,临床上表现为多器官损害,ESR增快,CRP升高,尤其是合并咯血的患者,应早期行抗髓过氧化物酶、抗蛋白酶3、抗肾小球基底膜抗体检查,以明确诊断,提高临床治疗的效果。     

血管炎患者抗中性粒细胞胞浆抗体检测的意义

了解血管炎的发病机理、诊断和分类。方法采用间接免疫荧光法（ＩＦ）和酶联免疫吸附试验（ＥＬＩＳＡ）对５０例各类血管炎作血抗中性粒细胞胞浆抗体（ＡＮＣＡ）的定性及定量检测，同时应用ＰＥＧ－紫外分光定量法作循环免疫复合物（ＣＩＣ）水平测定。结果在结节性血管炎和变应性血管炎特别是前者的发病中，ＡＮＣＡ可能起较主要的作用，ＡＮＣＡ水平升高且定性呈阳性尤其是核周型ＡＮＣＡ阳性者，可能代表一组伴肾脏受累的血管炎患者。结论通过ＡＮＣＡ定性、定量及ＣＩＣ水平的检测，有助于血管炎的分类及诊断，并可用于判断器官受累的程度及评价治疗效果。     

丙基硫氧嘧啶致抗中性粒细胞胞浆抗体阳性小血管炎一例报告

近年来,国内外陆续报道甲亢患者服用丙基硫氧嘧啶（PTU）可以引起抗中性粒细胞胞浆抗体（ANCA）阳性小血管炎（MPA）,笔者曾诊治1例,现报告如下。     

抗中性粒细胞胞浆抗体相关性血管炎并发脑梗死1例

血管炎是一种以血管的炎症和损伤为特征的临床病理过程,常有血管病变,伴有受累血管供血组织缺血[1]。抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody,ANCA)相关性血管炎是一组累及全身多系统的自身免疫性疾病。本病病情复杂,临床特征不具有特异性,容易误诊和漏诊。笔者对1例ANCA相关性血管炎患者的诊治经过报道如下,望为提高临床医生对本病的认识略尽绵力。     

儿童抗中性粒细胞胞浆抗体相关性血管炎治疗进展

抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody, ANCA)相关性血管炎(associated vasculitis, AAV)是一组累及中小血管的自身免疫性疾病,以循环中存在ANCA为特征。AAV各分型临床表现多样,但在治疗干预方面基本类似。目前治疗主要分为诱导缓解和维持缓解两个阶段,治疗更趋于个体化。由于缺乏基于儿童AAV的临床试验,其治疗方案通常根据医生的经验和成人研究数据外推。本文将简要描述儿童AAV发病机制、疾病活动度及损伤程度评估,重点介绍近年来儿童AAV在治疗方面的进展。     

Late renal allograft rupture in a patient with small vessel vasculitis following discontinuation of immunosuppression

We report the case of a 21-year-old man with antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis who experienced spontaneous renal allograft rupture 21 months after engraftment. Because of chronic allograft nephropathy, the patient's immunosuppressive regimen had been discontinued approximately 3 weeks prior to his presentation with abdominal pain and evidence of internal hemorrhage. He was emergently taken to the operating room, where a ruptured allograft was found and transplant nephrectomy was performed. Postoperatively, the cause of rupture was determined to have been acute cellular rejection. This case may be the longest interval reported between renal transplant and spontaneous allograft rupture.     

Relationship between ANCA and disease activity in small vessel vasculitis patients with anti-MPO ANCA.

BACKGROUND: We analysed the usefulness of antineutrophil cytoplasmic antibodies (ANCA) as a marker of clinical activity in patients with small vessel vasculitis associated with anti-myeloperoxidase (MPO) ANCA. METHODS: We studied a group of 25 patients, 15 with microscopic polyangitis and 10 with renal limited vasculitis, so-called rapidly progressive glomerulonephritis type III. The clinical and serological follow-up was accomplished quarterly over an average of 2.79 +/- 2.08 years (range 0.25-6 years). ANCA was analysed by indirect immunofluorescence and enzyme-linked immunosorbent assays (ELISAs). RESULTS: At the time of diagnosis, all patients were ANCA positive (P-ANCA and anti-MPO). Following a standardized treatment, all patients except one achieved complete remission of vasculitis in <3 months. One patient suddenly died during the active phase (1 month of follow-up) and with positive ANCA. Seroconversion from positive to negative occurred in 24/25 patients (96%). Eighteen of these 24 patients (75%) achieved the seroconversion within the first 6 months. During the follow-up, two patients had four major relapses, all of them associated with positive ANCA. ANCA seroconversion from negative to positive was observed in one patient with microscopic polyangitis without clinical relapse of vasculitis. CONCLUSION: ANCA should be used in conjunction with other markers of disease activity in the management of microscopic polyangitis and renal limited vasculitis patients with anti-MPO ANCA.     

Does the presence of ANCA in patients with ulcerative colitis necessarily imply renal involvement?

BACKGROUND.: ANCA are thought to play a pathogenic role in renal vasculitis.ANCA may also be detected in patients with diseases not usuallyassociated with renal pathology, such as ulcerative colitis.Our study was conducted to determine if the presence of ANCAin patients with ulcerative colitis is associated with renalpathology. METHODS.: Eight ANCA-positive and five ANCA-negative patients with a histologicaland endoscopic diagnosis of active ulcerative colitis were investigated.Repeated complete urinalyses and determination of microalbuminuriaand creatinine clearance were performed. Serum IgG and IgA ANCAwere evaluated in all patients by indirect immunofluorescenceand ELISA, and when detected the antibodies were further characterizedby alpha granules preparation, myeloperoxidase, lactoferrin,and cathepsin G. RESULTS.: In both ANCA-positive and ANCA-negative patients renal functionwas normal or near normal and urinalyses (including microalbuminuria)failed to disclose any abnormalities. ANCA exhibited a perinuclearpattern in all ANCA-positive patients. Interestingly, none ofthe ANCA-positive patients had antibodies to myeloperoxidaseor to alpha granules which are usually found in the sera ofpatients with ANCA-associated vasculitis, and only one had antibodiesto lactoferrin. The ANCA specificity remained undetermined inthe remaining seven patients. At the end of the 1-year observationperiod, all ANCA-positive patients remained ANCA-positive withoutdeveloping symptoms, signs or laboratory abnormalities consistentwith renal involvement. CONCLUSIONS.: Renal damage was not observed in ANCA-positive patients withulcerative colitis even after 1 year of follow-up, suggestingthat the ANCA found in these patients do not share the antigenictargets with the ANCA commonly found in renal vasculitis. Thereforethe potential of ANCA of inducing renal lesions (if any) isdependent on their own antigenic specificity.     

Molecular analysis of C3 allotypes in patients with systemic vasculitis

The third component of complement (C3) exists in two main allotypicforms, C3S and C3F, distinguished at the DNA level by a singlebase change. An increased frequency of the rarer C3F allelehas been reported in patients with the autoantibody nephriticfactor and in several other autoimmune conditions such as rheumatoidarthritis and IgA nephropathy. Studies of the immunogeneticfactors predisposing to the development of systemic vasculitishave produced conflicting results and no major genetic predisposingfactors have been identified. We have studied the C3S/F polymorphismin 63 patients with systemic vasculitis using DNA allotypingby the amplification refractory mutation system, a modificationof the polymerase chain reaction. The allele frequency in thesepatients was C3S 0.71, C3F 0.29 (expected C3S 0.8, C3F 0.19;chi-squared = 5.1, P<0.025), with the average relative riskfor the development of systemic vasculitis associated with thepresence of a C3F allele being 2.6. Moreover, there was a markedexcess of C3FF homozygotes (11/63, [17.5%], versus 4% expected:chi-squared = 9.5, P<0.01). The average relative risk forthe development of systemic vasculitis in C3F homozygotes was5.1, indicating a gene dosage effect. These data indicate thatthe C3F allele is associated with a predisposition to the developmentof systemic vasculitis and that C3F homozygotes are at particularlyhigh risk. This association is the strongest genetic factorreported so far for this group of diseases.     

Clinicopathologic features of antineutrophil cytoplasm autoantibody (ANCA)-associated acute renal failure in Chinese patients

Summary: The clinical course and renal pathologic features of anti-neutrophil cytoplasm auto-antibody (ANCA)-associated renal disease were studied among Chinese patients from a single centre. Eight ANCA positive patients with acute renal impairment were studied, four of whom required dialysis shortly after presentation. Their mean age at presentation was 61.6 ± 4.2 years. Renal histology, obtained in seven patients, showed paucummune crescentic glomerulonephritis in five patients, interstitial nephritis in two patients, and small vessel vasculitis in one patient. Pulmonary baemorrhage was the other common disease manifestation, present in four of the eight patients, necessitating ventilatory support in three patients. Neurologic, cutaneous, and gastrointestinal involvement were also observed. Seven of the eight patients tested positive for pANCA and anti-myeloperoxidase, while cANCA was detected in one patient of the eight patients, six (75%) responded to therapy, consisting of prednisolone and cyclophosphamide in five patients, and antibacterial therapy alone in one patient, who had interstitial nephritis but no evidence of vasculitis. Two patients died from sepsis and severe debilitation one month after presentation. of the other six patients, five had significant improvement of renal function, while one became dialysis-dependent. the levels of ANCA and C-reactive protein remained normal, and disease reactivation was not observed during follow-up for 32.4 ± 6.1 months. Patient and renal survival rates at one year were 75% and 62.5%, respectively. It was concluded that the clinical and pathologic features of ANCA-associated renal disease in Chinese patients are, in general, similar to those described in Caucasians. Nevertheless, cANCA-positivity is distinctly uncommon. the demonstration of interstitial nephritis in two of the eight patients underlines the importance of renal biopsy for correct histologic diagnosis. Early institution of aggressive immunosuppression and supportive therapies are essential for the achievement of favourable outcome in patients with vasculitis.     

Antineutrophil cytoplasmic autoantibodies (ANCA) and their target antigens in Chinese patients with lupus nephritis

Background: ANCA have been found in patients with systemic lupus erythematosus (SLE); however, the prevalence of ANCA and their target antigens is still not certain. This study is to investigate the prevalence of ANCA and their target antigens in Chinese patients with lupus nephritis. Methods: Ninety-five serum samples were collected from 95 renal-biopsy-proven lupus nephritis patients. Indirect immunofluorescence using ethanol-fixed leukocytes as substrate and ELISA using six highly purified known ANCA antigens as solid-phase ligands were performed. The specific ANCA antigens included proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, human leukocyte elastase, cathepsin G, and lactoferrin. The prevalence of ANCA in patients with (n=65) and without (n=30) active renal pathological lesions was also compared to reveal whether ANCA correlates with disease activity. Results: (i) None of the sera recognized proteinase 3, myeloperoxidase, and human leukocyte elastase, and only one serum recognized bactericidal/permeability-increasing protein. The striking finding was that 59/95 (62.1%) sera recognized cathepsin G and the titres of some sera reached 1/3200. Eight of 95 sera (8.4%) recognized lactoferrin. (ii) The percentage of anticathepsin G antibody positive samples in patients with active renal lesions was significantly higher than in patients without active lesions (73.4 vs 36.7%, P<0.0001), whereas, anti-lactoferrin antibodies had no correlation with active renal lesions. (iii) By indirect immunofluorescence, only 22% of the 95 sera were ANCA positive. Conclusions: Our results suggest that the majority of lupus nephritis patients have ANCA and that the major target antigens is cathepsin G. Anti-cathepsin G antibodies seem to be correlated with renal disease activity. Key words: ANCA; autoantibodies; autoantigen; autoimmune disease; cathepsin G; lupus nephritis; SLE; vasculitis      

中性粒细胞细胞外网络在ANCA相关性小血管炎患者肾组织中的表达及意义

目的:研究中性粒细胞细胞外网络(NETs)在ANCA相关性小血管炎(AASV)患者肾组织中的表达并初步探讨其在AASV中的可能致病机制。方法:采用免疫组织化学技术,分别检测NETs(以瓜氨酸化的组蛋白H3为标志)在8例ANCA相关性小血管炎患者,8例微小病变型肾病综合征患者,3例健康对照的肾小球、肾间质及肾小管的表达,同时检测相应部位B淋巴细胞(CD19做标志)的浸润。结果:(1)AASV患者肾小球中NETs表达较微小病变组患者和健康对照组肾小球中NETs表达明显增多[(0.354±0.347)vs(0±0),P<0.05],在AASV肾脏病理损害严重部位,如中、重度系膜细胞增生的肾小球(0.485±0.721),有炎症细胞浸润的肾间质(2.575±2.99)、肾小管(1.417±2.888)中浸润的NETs明显增多。(2)B淋巴细胞(CD19)的表达:AASV患者肾小球球周B淋巴细胞表达较健康对照组[(3.123±4.411)vs(0±0)]、微小病变组[(3.123±4.411)vs(0±0)]表达明显增多,与微小病变组相比差异有统计学意义(P<0.05)。在AASV患者肾组织中主要分布于硬化的肾小球球周(4.024±7.457)、中重度系膜细胞增生的肾小球球周(2.673±2.948),在肾间质炎细胞浸润的区域常成簇聚集(9.625±8.961),而在肾小球内基本无表达。结论:NETs在AASV患者肾组织广泛表达,肾小球中浸润的NETs可能参与了AASV患者的肾损害。     

C-antineutrophil cytoplasmic antibody positivity in vasculitis patients is associated with the Z allele of alpha-1-antitrypsin, and P-antineutrophil cytoplasmic antibody positivity with the S allele

BACKGROUND.: Antineutrophil cytoplasmic antibodies (ANCA) in vasculitis haveeither cANCA or pANCA patterns as defined by immunofluorescence.The target autoantigen of cANCA is usually proteinase 3 (PR3),whereas that of pANCA is usually myeloperoxidase (MPO). Alpha-1-antitrypsin(1AT) is the major physiological inhibitor of PR3, while MPOis an inhibitor of 1AT. METHODS.: To determine whether there was an association between ANCA positivevasculitis, ANCA pattern, and 1AT deficiency alleles, we studied1AT phenotypes of 99 cANCA and 99 pANCA positive vasculitispatients by isoelectric focusing and immunoblotting, and comparedthem with 2310 controls from the same geographical area. RESULTS.: C-ANCA patients showed an increased frequency of the Z allele(0.055 versus 0.018 in controls), conferring a relative riskof 3. They showed no increase in frequency of the S allele.P-ANCA patients showed an increased frequency of the S allele(0.091 versus 0.046 in controls) conferring a relative riskof 2. The frequency of the Z allele also appeared to be increased(0.030 versus 0.018 in controls), but this was not statisticallysignificant. CONCLUSIONS.: These findings demonstrate an association between ANCA-positivevasculitis and deficiency phenotypes of 1AT, and suggest a rolefor 1AT in the development of systemic vasculitis.     

Clinicopathological characteristics and outcomes of pediatric patients with systemic small blood vessel vasculitis

Background

Systemic small blood vessel vasculitis (SSV) is uncommon among pediatric patients, and the predictive value of the new histopathological classification for SSV in terms of renal outcomes in these patients is unknown.

Methods

The study cohort comprised 38 pediatric patients and 285 adult patients with SSV who were treated in a medical center between 1993 and 2012.

Results

Children accounted for 11.8 % of all patients with SSV diagnosed during the study period. In contrast to the adult patients, the pediatric patients were predominantly female (73.7 vs. 51.9 %; P?P?P?ESRD) among pediatric patients (hazard ratio?2.273, P?ESRD was highest in pediatric patients with the sclerotic glomerulonephritis subtype, followed by the mixed, crescentic and focal glomerulonephritis subtypes (in descending order of probability) (P?Conclusions Estimated histopathological classification has a prognostic value for renal outcome and response to therapy in children with SSV.     

ANCA相关性血管炎肾脏及其他系统损害的临床和病理与预后的相关研究

目的探讨抗中性粒细胞胞浆抗体相关性血管炎(antineutrophil cytoplasmic antibodyassociated vasculitis,AAV)肾损害及其他系统损害患者的临床和病理特征,并对其预后及其相关危险因素进行分析。方法选择1995年9月至2009年9月内蒙古自治区人民医院明确诊断为AVV内蒙古籍患者123例,血清抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody,ANCA)阳性,根据检测结果将患者分为胞质型(C-ANCA)阳性组和核周型(P-ANCA)阳性组,进行临床、实验室、病理及预后相关因素进行分析。随访终点为死亡或终末期肾衰竭进入规律肾脏替代治疗,平均随访时间5年。结果 123例患者中男63例,女60例,男女比例1.05:1,年龄38~82岁,平均年龄(60.0±22.0)岁,50~82岁患者102例(占82.9%)。其中P-ANCA阳性109例,C-ANCA阳性14例。P-ANCA组肾脏、肺脏受累与C-ANCA组相似,消化道、关节、眼损害发生率低于C-ANCA组(P0.05);耳、皮肤、肌肉、神经系统损害2组无统计学差异。123例患者中有62例患者行肾活检,其中细胞性新月体肾炎30例(占48.4%),毛细血管袢坏死12例(占19.4%),细胞伴纤维性新月体形成15例(占24.2%),纤维性新月体伴局灶节段性硬化5例(占8.1%)。对AAV患者进行5年随访,对患者死亡或进入肾脏终末期代替治疗进行相关因素分析:C-ANCA组与P-ANCA组相比,患者死亡与进入终末期替代治疗2组间均无统计学差异(P0.05)。对患者的年龄、性别、ANCA类型、发热、肾衰竭、呼吸衰竭、咯血、脏器受累数目、多脏器衰竭、肺感染因素进行COX回归分析:呼吸衰竭、多脏器衰竭为死亡的相关因素(偏回归分数分别为2.087,1.129,均P0.05)。对患者起病时实验室数据进行回归分析:血肌酐、红细胞沉降率、血浆白蛋白、血红蛋白与终末终点相关。Logistic回归分析,起病的血肌酐及红细胞沉降率是预测患者预后的独立危险因素。结论 AAV以中老年男性多见,PANCA阳性患者较C-ANCA阳性患者,发病率高,受累器官数目多且病程谱广。呼吸衰竭、多脏器衰竭与患者死亡密切相关。患者起病的血肌酐及红细胞沉降率是预测患者预后的独立危险因素。