Autoantibodies against C1q: view on clinical relevance and pathogenic roles (1999)

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