Autoantibodies against C1q: view on clinical relevance and pathogenic roles-猫眼课题宝

DOI：

10.1046/j.1365-2249.1999.00867.x

发表时间：

1999-04

期刊：

Clinical & Experimental Immunology

影响因子：

4.6

通讯作者：

中科院分区：

医学3区

文献类型：

作者：

C. Siegert;M. D. Kazatchkine;Anders G. Sjöholm;Reinhard Würzner;Michael Loos;M. R. Daha

C. E. H. SIEGERT， M. D. KAZATCHKINE*， A. SJO¨HOLM§，r . WU¨RZNER†，M. LOOS‡& M. r . daha荷兰莱顿大学医学中心肾内科，*法国巴黎布鲁赛斯医院国立卫生研究所，†奥地利因斯布鲁克利奥波德-弗兰兹大学卫生研究所，德国美因茨j -古登堡大学医学微生物学与卫生研究所，隆德大学医院临床微生物学实验室，对自身抗原的免疫反应是相当普遍的，自身免疫被认为是免疫系统的一个生理部分。自身抗体是许多健康个体抗体库的固有属性，因此被称为天然自身抗体[1,2]。根据涉及的自身抗原是器官特异性的还是非器官特异性的，自身抗体种类繁多，主要分为两大类。非器官特异性抗原大多出现在有核细胞中，如DNA，或存在于循环血浆蛋白中，如凝血蛋白和IgG的Fc部分。天然自身抗体已被提出参与细胞代谢过程中形成的降解产物的清除。在这方面，天然自身抗体也被称为内务抗体。自身抗体也可能与疾病状态有关，但不一定在这类疾病的发病机制中起作用。例如，自身抗体的存在可能继发于组织损伤的产生，或者独立的致病因素可能直接诱导疾病和自身抗体的存在。1984年报道了系统性红斑狼疮患者血清中存在C1q自身抗体（C1qAb）。C1q可能作为一种非器官特异性自身抗原的认识吸引了越来越多的研究者。本研究通过回顾C1qAb的流行病学、疾病关联和病理生理学来讨论C1q作为自身抗原的知识。C1q在免疫复合物清除中的作用激活补体系统是预防免疫复合物损伤的第一步。补体激活的起始通过三种途径发生：经典途径、替代途径和凝集素途径。补体系统的经典途径被认为是免疫复合物清除中最重要的途径。这一途径可能被含有IgM和igg的免疫复合物在结合C1q[5]后激活。C1q是经典通路第一组分（C1）的子组分。它是一个大的高阳离子糖蛋白，分子量为410kD。C1q由3条多肽链A、B和C各6个副本组成。A、B和C链富含羟基化氨基酸，并通过二硫键连接成二聚体[6]这些二聚体形成类似胶原蛋白的三螺旋结构。在C1q的n端，三螺旋相互平行，在c端，它们分散。n端被称为类胶原蛋白区，它由连接链连接到c端，被称为球状头区。据说C1q的大分子结构类似于一束郁金香[5-7]。C1q的功能与其结构直接相关。免疫球蛋白的Fc区域与c1q的球形头部部分结合会引起连接链的扭曲，从而改变胶原样区域的构象[8,9]。C1q与C1、C1r和C1s的其他亚组分之间的动态平衡随后发生变化，并诱导构成经典途径的蛋白质级联进一步激活。这导致防止免疫复合物的晶格形成，并确保它们被单核吞噬细胞系统从循环中清除。尽管凝集素途径的识别蛋白甘露糖结合凝集素在结构上与C1q相关，但尚不清楚它是否参与免疫复合物清除机制[11]。综上所述，免疫复合物结合C1q激活C1是清除免疫复合物的先决条件。由于SLE被认为是人类免疫复合物疾病的原型，各种各样的免疫复合物测定已被用于研究循环免疫复合物可能的致病作用，并将其滴度与疾病表现的存在联系起来。固相C1q结合测定法是两种目的中最常用的测定法之一。这种放射免疫测定是基于免疫复合物与固定在固相上的C1q的结合。70年代早期的研究

C. E. H. SIEGERT, M. D. KAZATCHKINE*, A. SJO¨HOLM§, R. WU¨RZNER†, M. LOOS‡ & M. R. DAHADepartment of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands, *Institut National de la Sante´et de laRecherche Medicale, Hopital Broussais, Paris, France, † Institut fu¨r Hygiene, Leopold-Franzens-Universita¨t, Innsbruck, Austria,‡ Institute for Medical Microbiology and Hygiene, J-Gutenberg University, Mainz, Germany, and§Clinical Microbiology Laboratory,Lund University Hospital, Lund, Sweden(Accepted for publication 6 January 1999)INTRODUCTIONImmune responses to autoantigens are quite common andautoimmunity is considered to be a physiological part of theimmune system. Autoantibodies are an inherent property of theantibody repertoire of many healthy individuals and are thereforereferred to as natural autoantibodies [1,2]. The numerous kinds ofautoantibodies fall into two main categories, depending on whetherorgan-speciﬁc or non-organ-speciﬁc autoantigens are involved.Non-organ-speciﬁc antigens mostly occur in nucleated cells,such as DNA, or are found among circulating plasma proteins,such as coagulant proteins and the Fc portion of IgG.Natural autoantibodies have been proposed to be involved inthe clearance of degradation products that are formed during cellmetabolism. In this respect natural autoantibodies are also referredto as housekeeping antibodies [3]. Autoantibodies may also beassociated with disease states but do not necessarily play a role inthe pathogenesis of such diseases. The presence of autoantibodiesmay for example be secondary to the production of tissue damage,or independent pathogenic factors may directly induce both thedisease and the presence of autoantibodies.In 1984 autoantibodies to C1q (C1qAb) were reported to bepresent in serum of patients with systemic lupus erythematosus(SLE) [4]. The recognition that C1q may serve as a non-organ-speciﬁc autoantigen has attracted a growing number ofinvestigators. This study discusses the knowledge of C1q asautoantigen by reviewing the epidemiology, disease associations,and pathophysiology of C1qAb.ROLE OF C1q IN IMMUNE COMPLEXCLEARANCEActivation of the complement system is the ﬁrst step in theprevention of damage by immune complexes. Initiation of com-plement activation occurs through three pathways: the classical,the alternative, and the lectin pathway. The classical pathway ofthe complement system is considered to be the most importantpathway in immune complex clearance. This pathway may beactivated by IgM- and IgG-containing immune complexes afterbinding of C1q [5]. C1q is a subcomponent of the ﬁrst component(C1) of the classical pathway. It is a large highly cationicglycoprotein with a molecular weight of 410kD. C1q consists ofsix copies each of three polypeptide chains, A, B, and C. The A, B,and C chains are rich in hydroxylated amino acids and are linkedtogether by disulphide bonds into dimers [6] Together these dimersform a triple helix structure which resembles collagen. Towardsthe N-terminal end of C1q the triple helices lay parallel to eachother and towards the C-terminal end they diverge. The N-terminalend is called the collagen-like region which is linked by theconnecting strands to the C-terminal end, which is called theglobular heads region. The macromolecular structure of C1q issaid to resemble a bunch of tulips [5–7].The function of C1q is directly related to its structure. Bindingof Fc regions of immunoglobulins to the globular head portions ofC1q induces distortion of the connecting strand which changes theconformation of the collagen-like region [8,9]. The dynamicequilibrium between C1q and the other subcomponents of C1,C1r and C1s, subsequently shifts and induces further activation ofthe cascade of proteins composing the classical pathway. Thisresults in the prevention of lattice formation of immune complexesand ensures their clearance from the circulation by the mono-nuclear phagocyte system [10]. Although the recognition protein ofthe lectin pathway, mannose-binding lectin, is structurally relatedto C1q, it is not known to be involved in immune complexclearance mechanisms [11]. To summarize, activation of C1 bybinding of immune complexes to C1q is a prerequisite for immunecomplex clearance.HISTORY OF C1qAbSince SLE is considered to be the prototype of immune complexdiseases in man, a large variety of immune complex assays hasbeen employed to investigate possible pathogenic roles of circulat-ing immune complexes and to relate their titres to the presence ofmanifestations of the disease. The solid-phase C1q binding assay isone of the most frequently used assays for both purposes [12]. Thisradioimmunoassay is based on the binding of immune complexesto C1q, which is ﬁxed to a solid phase. Studies in the early 1970s

Autoantibodies against C1q: view on clinical relevance and pathogenic roles

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