IgA肾病患者腭扁桃体单个核细胞IgA类别转换基因表达变化

目的 研究脂多糖(LPS)或溶血性链球菌(HS)刺激IgA肾病和非肾脏疾病慢性扁桃体炎患者腭扁桃体单个核细胞Iα-Cα胚系转录本、激活诱导的胞嘧啶脱氨酶(AID)mRNA和蛋白的表达,以探讨IgA肾病腭扁桃体单个核细胞IgA及IgA1产生异常的分子机制.方法 入组2009年1月到2010年2月在我院住院的IgA肾病患者27例,非肾脏疾病慢性扁桃体炎患者27例作为对照.通过单个核细胞分离液和密度梯度离心法分离出腭扁桃体单个核细胞.IgA肾病组及非肾脏疾病慢性扁桃体炎组腭扁桃体单个核细胞分别分为3组:LPS刺激组,HS刺激组和未刺激组.ELISA法检测培养上清中IgA和IgA1的浓度.实时PCR检测Iα-Cα胚系转录本和AID mRNA的表达;Western印迹检测AID蛋白的表达.结果 IgA肾病组腭扁桃体单个核细胞IgA和IgA1的分泌,特别是IgA1/IgA较慢性扁桃体炎组显著增加(P＜0.05),Iα-Cα和AID mRNA和AID蛋白的表达较慢性扁桃体炎组显著增加(均P＜0.05).IgA肾病组腭扁桃体单个核细胞IgA和IgA1的水平在刺激后明显增加(P＜0.05);Iα-Cα和AID mRNA的表达明显上调(均P＜0.05);AID蛋白表达明显增加(LPS刺激组P＜0.05,HS刺激组P＜0.01).结论 LPS和HS均能够诱导IgA肾病患者腭扁桃体单个核细胞IgA和IgA1的分泌、AID和Iα-Cα的表达增加,提示IgA肾病患者腭扁桃体IgA和IgA1的分泌增加可能与IgA类别转换相关基因AID和Iα-Cα高表达有关.     

IgA肾病与慢性扁桃体炎患者腭扁桃体病理形态学对比研究

据统计，约40％的IgA肾病（IgAN）患者表现为上呼吸道感染（包括扁桃体炎）后症状发作或加重^[1]，提示扁桃体免疫可能在IgAN发病机制中起草要作用。本研究旨在探讨IgAN与慢性扁桃体炎（CT）患者腭扁桃体病理形态和免疫组织化学特点     

糖皮质激素治疗IgA肾病的进展

正IgA肾病(IgA nephropathy,IgAN)是目前我国最常见的原发性肾小球疾病,临床主要表现为发作性血尿、蛋白尿、高血压和肾功能受损等。其发病率高,除部分单纯性血尿患者预后尚可,相当一部分患者预后差,肾功能缓慢下降,超过30%的患者在发病10~20年后可进入尿毒症期[1]。在我国IgAN是导致终末期肾脏病(end stage kidney disease,ESKD)的首要原因,严     

黏膜免疫系统在IgA肾病发病机制的作用及中医认识进展

正IgA肾病(immunoglobulin A nephropathy,IgAN)是全世界范围内最常见的原发性肾小球肾炎,病理以系膜区IgA沉积为主要特征,临床上常表现为黏膜感染后出现的血尿、伴或不伴蛋白尿。虽然大部分IgAN预后良好,但仍有15%~40%的患者将于起病后20年内进展至终末期肾脏病(end-stage renal diseases,ESRD)~[1]。IgAN的发病机制目前仍尚未明确。     

IgA肾病患者扁桃体CD4+CD25+T细胞及J链mRNA阳性IgA细胞与临床病理的关系

不少学者认为IgA肾病(IgAN)与扁桃体自身免疫反应有一定联系.IgAN患者扁桃体CD4+CD25+T细胞减少和分泌J链mRNA阳性IgA细胞增多,且CD4+CD25+T细胞数与J链mRNA阳性IgA细胞数呈负相关[1].我们分析其与临床病理的关系.     

IgA1分子异常糖基化在IgA肾病发病机制中的研究进展

自1968年IgA肾病(IgAN)首次报道,已40余年,其发病机制目前尚不清楚.Andre等[1]首次报道IgAN患者血清IgA1分子铰链区糖链结构异常,随后,在IgAN患者血清、扁桃体及肾脏组织中均检测到IgA1分子糖链结构异常.很多研究对参与IgA1糖基化过程的各种酶及分子伴侣的表达、活性及基因水平进行了分析,同时利用体外培养的细胞或动物模型进行研究,以寻找IgA1分子糖基化异常在IgAN发病及疾病进展中的可能作用.本文综述近年来IgAN中有关IgA1分子糖基化异常的研究进展,并介绍本研究所的相关研究.     

IgA肾病无创性诊断:异常糖基化IgA1及其相关生物标志物的研究进展

<正>IgA肾病(IgA nephrophathy,IgAN)由法国病理学家Berger[1]首次描述,是世界范围内最常见的原发性肾小球疾病,以IgA或以IgA为主的免疫复合物在肾小球系膜区沉积为特征。临床主要表现为蛋白尿和(或)血尿,病情变化轻重不一,大多数患者病情呈进展性,在确诊后10~20年内有约25%~50%的患者发展为终末期肾脏疾病(end-stage renal disease,ESRD)[2],需行肾脏替代治疗维持生命,给患者及社会带来了     

成人单纯性血尿IgA肾病临床病理及相关危险因素分析

<正>IgA肾病(IgA nephropathy,IgAN)是常见的原发性肾小球疾病,预后不容乐观[1],临床以反复发作的肉眼血尿或镜下血尿为主要表现,可伴有少量蛋白尿,也可出现肾病综合征。目前关于不伴蛋白尿的单纯性血尿成人IgAN患者临床病理特点及血压、尿酸、血脂等相关危险因素对其的影响报道较少。了解这部分患者的病例特点,有助于更好地指导临床治疗,改善预后。     

补体系统参与IgA肾病发病机制的研究进展

IgA肾病(IgA nephropathy,IgAN)病理表现为肾小球系膜区IgA或IgA沉积为主,其主要临床表现为反复发作的镜下或肉眼血尿,伴或不伴蛋白尿。目前认为IgA肾病是一个缓慢进展的疾病,有研究表明,15%~20%的IgA肾病患者在10年内、30%~40%的患者则在20年内进展为ESRD[1]。因此,充分认识该病的特征和发展规律,有利于对该病的发生发展进行     

家族性IgA肾病诊断依据并一个家系资料分析

IgA肾病(IgAN)可以表现为不同程度的血尿、蛋白尿及进行性的肾功能受损.相关的统计资料显示,IgAN可以占到原发性肾小球疾病的25%～50%,并且大约有40%的患者在发病后15年内出现肾衰竭[1-2].由于迄今对家族遗传性IgA肾病(FIgAN)的发病率及临床特征认识不足,临床诊断的IgAN中可能包含了许多FIgAN.自20世纪70年代后期首次报道了2个FIgAN的家系后,多个FIgAN家系陆续报道[3-4],使人们逐渐关注到了IgAN的家族易感性.2007年12月我们发现一中国汉族人家族遗传性肾病家系,对该家系资料进行了深入的分析,同时复习国内外相关文献,明确FIgAN的诊断标准,为今后的临床诊断提供相应的指导.     

IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy

Circulating immune complexes containing aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). A portion of IgA1 secreted by IgA1-producing cells in patients with IgAN is galactose-deficient and consequently recognized by anti-glycan IgG or IgA1 antibodies. Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and mechanisms of biosynthesis have provided new insight into the autoimmune nature of the pathogenesis of this common renal disease. An imbalance in the activities of the pertinent glycosyltransferases in the IgA1-producing cells favors production of molecules with galactose-deficient O-linked glycans at specific sites in the hinge region of the alpha heavy chains. By using sophisticated analytic methods, it may be possible to define biomarkers for diagnostic purposes and identify new therapeutic targets for a future disease-specific therapy.     

Charge and size of mesangial IgA in IgA nephropathy

To characterize the physicochemical properties of the mesangial IgA in primary IgA nephropathy, acid-eluates from percutaneous renal biopsies of 20 patients were examined. The acid-eluates were obtained from 1287 +/- 498 glomerular sections. The IgA content (mean 15 +/- 10 ng) represented 0.4% of the total eluted proteins. To analyze the molecular weight and the charge of eluted IgA, 11 eluates were subjected to high pressure liquid chromatography (at pH 6.8 and/or pH 3.5) and five eluates to isoelectric focusing on agarose. IgA was detected in the fractions by an IgA-RIA. Comparison of the elution profiles at different pH showed a statistically significant decrease of the excluded IgA peak (greater than or equal to 1,000,000 daltons), and a significant increase of polymeric IgA peaks (1,000,000-320,000 and 320,000 daltons) in acidic chromatography, as compared to non-dissociating conditions. Under acidic conditions, polymeric IgA represent 64% of total eluted IgA. Secretory component binding to polymeric IgA was demonstrated in four out of eight eluates tested. The isoelectric point (pI) of eluted IgA ranged from 4.5 to 5.6, contrasting with the broader and more neutral pI of normal serum IgA (4.5 to 6.8). This study shows that the multimeric nature of IgA, the formation of IgA complexes, and the anionic charge of IgA are likely to be involved in the mesangial IgA deposition in idiopathic IgA nephropathy.     

O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis

Structural aberrations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, but their contribution to its pathogenesis remains incompletely understood. In this study, mice implanted with hybridoma secreting 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA rheumatoid factor bearing the same IgA allotype, developed mesangial deposits consisting of IgA, IgG2a, and C3. Studies in immunoglobulin- and C3-deficient mice revealed that the development of these glomerular lesions required the formation of IgA-IgG2a immune complexes and subsequent activation of complement. The proportion of polymeric and monomeric forms, the IgG2a-binding affinity, and the serum levels of IgA-IgG2a immune complexes were similar between 6-19 IgA- and 46-42 IgA-injected mice. In contrast, the analysis of oligosaccharide structures revealed highly galactosylated O-linked glycans in the hinge region of 6-19 IgA and poorly O-glycosylated in the hinge region of 46-42 IgA. Furthermore, the structure of N-linked glycans in the CH1 domain was the complex type in 6-19 IgA and the hybrid type in 46-42 IgA. In summary, this study demonstrates the presence of O-linked glycans in the hinge region of mouse IgA and suggests that 6-19 IgA rheumatoid factor-induced GN could serve as an experimental model for IgA nephropathy.     

Integrin expression and IgA nephropathy: in vitro modulation by IgA with altered glycosylation and macromolecular IgA

BACKGROUND: Signal transduction by mesangial cell (MC) integrins regulates cell growth and survival, extracellular matrix production, and organization. The aim of the study was to investigate human MC integrin modulation by differently glycosylated IgA and macromolecular IgA, which are thought to play a pathogenetic role in IgA nephropathy (IgAN). METHODS: MCs were incubated with purified human polymeric IgA, heat-aggregated IgA, IgA glycoforms generated by enzymatic hydrolysis of saccharide residues and serum fractions from IgAN patients, and controls isolated by lectin affinity and containing IgA with peculiar glycan patterns. Integrins were quantitated by flow cytometry. RESULTS: Cultured MCs highly expressed alphavbeta3 and some alpha3beta1; alphavbeta3 was up-regulated by matrix components (P < 0.02). In vitro desialylated and degalactosylated polymeric human IgA enhanced alphavbeta3 expression on cultured MCs (P < 0.001). Serum IgA glycoforms isolated from IgAN patients with high exposure of internal sugars, GalNAc, Neu5Ac2,6GalNAc, and Man enhanced alphav expression on cultured MCs more than healthy controls. CONCLUSIONS.: These data support the hypothesis that IgA glycation plays a role in modulating the cell-matrix interaction, and that this mechanism can be operating in IgAN.     

Contribution of macromolecular IgA1 to IgA abnormality in IgA nephropathy

To evaluate the contribution of macromolecular IgA₁ to IgA abnormality in childhood IgA nephropathy, serum samples from 29 healthy children and 26 patients with IgA nephropathy in different age-groups (7–9, 10–12, and 13–15 years) were each separated by sucrose density gradient ultracentrifugation and assayed for IgA₁ using an enzyme-linked immunosorbent assay. IgA₁ in fraction I (sedimentation coefficient >11.4s) was significantly greater in patients 7–15 years of age (median 36.3–57.0 mg/dl) than in the age-matched controls (median 8.8–10.4 mg/dl). IgA₁ in fraction II (11.4–9.3s) was significantly greater in patients 10–15 years of age (median 46.7–52.6 mg/dl) than in the controls (median 27.8–35.5 mg/dl), and IgA₁ in fraction III (<9.3s) was significantly greater in patients 13–15 years of age (median 156.9 mg/dl) than in the controls (median 120.7 mg/dl). The ratio of IgA₁ in fractions I–III was higher in the patients of each age-group (median 0.233–0.314) than in the controls (median 0.067–0.082), while the ratio of IgA₁ in fractions II–III was not significantly high in patients 7–12 years old (median 0.268 to 0.318) compared with the controls (median 0.182–0.264). Thus, IgA abnormality in childhood IgA nephropathy would be better represented by an increase in macromolecular IgA₁ of >11.4s than by an increase in IgA₁ in fractions of 11.4–9.3s or <9.3s. Received: 8 December 1999 / Revised: 2 March 2000 / Accepted: 2 May 2000     

The role of secretory IgA and complement in IgA nephropathy

IgA nephropathy (IgAN) is characterized by glomerular deposition of IgA, often together with complement components. This deposited IgA is mainly polymeric in nature. Although early studies suggested a role for local complement activation in the development of glomerular injury in IgAN, recent attention has focused on the involvement of the lectin pathway of complement activation in the progression of renal disease in IgAN. In addition, we have found that glomerular secretory IgA deposition may be one of the initiators of local complement activation in the kidney. In the present review we discuss recent developments in this area and provide a model of how mucosal immunity and renal inflammation may be interconnected.     

Light-chain composition of serum IgA1 and in vitro IgA1 production in IgA nephropathy.

A predominant expression of IgA1 in mesangial deposits, serum, and bone marrow culture supernatants has been shown in IgA nephropathy (IgAN). Furthermore an excess of lambda light chains in both mesangial deposits and serum IgA has been observed. However, the origin of mesangial IgA remains controversial. In the present study, we have examined the IgA1 light chain type in IgAN. Total IgA1, IgA1 kappa and IgA1 lambda were measured by ELISA in serum and culture supernatants from spontaneous and pokeweed-mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC). We observed an increase in IgA and IgA1 serum concentrations in IgA nephropathy patients, with a ratio of serum IgA1 to total serum IgA identical between patients and controls. The concentration of serum IgA kappa did not differ between patients and controls but patients had a significantly higher concentration of serum IgA lambda. The IgA1 kappa to IgA1 lambda ratio was 1.06 +/- 0.42 in IgAN patients versus 1.55 +/- 0.36 in controls (P less than 0.01). By contrast, the concentrations of IgA1 kappa and IgA1 lambda in PBMC culture supernatants, both spontaneous and PWM-stimulated, were identical in patients and controls. Therefore, there is a specific increase in IgA1 lambda in patients' sera. This contrasts with the normal IgA1 production by PBMC, which are derived from mucosal-associated lymphoid tissues. This suggests that IgA isotypic deregulation is confined to the bone marrow compartment and is not a generalised defect of the IgA system.