ReviewAutoantibodies to complement components
Introduction
The complement system plays an important role in immune defence, and is a major component of innate immunity. Under normal physiologic conditions the contribution of complement is beneficial to the host. Inappropriate activation of the complement system, induced by damaged tissue or deposition of autoantibodies and immune-complexes can cause severe injury. Moreover, under certain conditions an immune reaction may develop against the complement system itself and lead to inflammation and tissue injury. The latter topic is the subject of the present review.
There are three known pathways of complement activation, namely the classical pathway (CP), the alternative pathway (AP) and the more recently discovered Mannan Binding Lectin (MBL) pathway. It is known that the CP can be activated by e.g. antigen–antibody complexes composed of IgG and IgM antibodies, while the AP is mainly activated by activating structures such as bacterial surfaces and dimeric or polymeric IgA. The MBL pathway can also be activated independently of antibodies, by the interaction of MBL with carbohydrate-containing surfaces, such as present on bacteria and viruses.
The CP is initiated upon activation of C1 by its interaction with the Fc portions of antibodies in immune complexes, leading to subsequent recruitment and activation of C4 and C2, formation of the classical pathway C3 convertase C4b2a, activation of C3 and finally assembly of C5b-9, the membrane attack complex (MAC). Generation of C4b2a can also occur independently of C1 activation, via the MBL pathway. Binding of MBL and activation of its associated serum proteases (MASP-1, MASP-2, and MASP-3) induces activation of C4 and C2. It has been proposed that C3 can also be activated directly by MASP-1 associated with MBL. Activation of C4 and C2 thus occurs via two independent routes leading to the activation of C3.
Activation of the AP is thought to occur by the continuous hydrolysis of the labile thioester bond in C3 followed by interaction of this C3 with factors B and D, leading to activation of C3 and generation of the amplification convertase C3bBb. This inherently labile convertase is under physiological conditions stabilized by properdin (factor P).
One of the central functions of complement activation is the generation of the MAC. Furthermore, it is thought that activation and covalent attachment of C3b to complement activators is a major event in linking the innate immune response with the acquired immune response, involving the functional activity of cellular C3 receptors on various cells of the immune system. Since complement activation proceeds in an enzymatic fashion, the consequence could be complete depletion of complement components and a secondary deficiency of complement. Therefore, the function of a large number of fluid phase complement regulators is essential to maintain a sufficient level of complement in the circulation and in various body fluids. Control of complement activation occurs at the level of C1 and the MBL–MASP complex by C1-inhibitor (C1-INH), at the amplification level by factors I and H, and by various regulators at the levels of C4b2a and MAC formation (Table 1). Next to regulation of complement activation in the fluid phase, it is essential to protect autologous cells from complement attack. It has been shown that a large number of membrane bound complement regulatory molecules control tissue and cell integrity.
The purpose of the present summary is to elucidate the dysregulation of the delicate balance of the complement system by autoantibodies against complement and complement-related proteins.
Section snippets
Immunoconglutinins
Immunoconglutinins are probably the first autoantibodies described against autologous C3 and C4 fragments. The autoantibodies seem to react only with particle-bound C3 and C4 fragments and not with the corresponding soluble fragments (Lachmann, 1967). Immunoconglutinins are generated in response to acute or chronic inflammation involving complement activation, such as involved in infections and in a number of autoimmune diseases like Crohn's disease (Potter et al., 1980), rheumatoid arthritis (
Anti-C1q autoantibodies
The first suggestion for the occurrence of anti-C1q antibodies is based on the observation that serum from patients with SLE and other hypocomplementaemic states is capable of precipitating C1q in agarose gel (Agnello et al., 1971). First it was found that this activity was associated with high molecular weight IgG presumably in immune complexes. Later it was demonstrated that reactivity with C1q was also present in the 7S region as monomeric IgG (Uwatoko et al., 1984). The detection of
C3 nephritic factor
Initial studies suggested an association between decreased serum concentrations of C3 and chronic proliferative glomerulonephritis (West et al., 1965, Gotoff et al., 1969), later defined as membranoproliferative glomerulonephritis (MPGN). Activation of C3 via the alternative pathway in some patients with MPGN was inferred from the marked depression of serum C3 in the presence of normal levels of C1, C4 and C2 (Gewurz et al., 1968). The observation that coincubation of serum from patients with
Anti-CR1 autoantibodies
Complement receptor-1 (CR1, CD35), a receptor for C3b, is present on a number of nucleated cells and on erythrocytes. It has extensive biologic and immunomodulatory functions, such as the facilitation of the clearance of immunecomplexes in the circulation, the enhancement of phagocytosis and the inhibition of the classical and alternative pathway of complement activation. It has been suggested that the number of CR1 molecules per erythrocyte is inherited (Wilson et al., 1982). In SLE patients
Concluding remarks
All the autoantibodies described in the present review dysregulate the balance between activation and inhibition of the complement system. For only some of the autoantibodies described here, a clear relationship between the autoantibody and pathology has been identified. For most autoantibodies there are only correlations with a certain disease or specific organ manifestation of disease, which enables the detection of such autoantibodies to be used as markers of disease activity or predictors
Acknowledgements
Part of this work was supported by a grant from the Dutch Kidney Foundation, C98.1763.
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Circulating C1q levels in health and disease, more than just a biomarker
2021, Molecular ImmunologyCitation Excerpt :In line with that, C1q regulates cellular functions by autocrine and paracrine signaling, indicating the involvement of C1q receptors in the non-traditional functions of C1q, as reviewed elsewhere (Ghebrehiwet et al., 2017). Autoantibodies against many complement components have been described, including antibodies against C1q (reviewed in (Beurskens et al., 2015; Dragon-Durey et al., 2013; Norsworthy and Davies, 2003; Trouw et al., 2001). Detection of anti-C1q autoantibodies has to be performed using high salt buffers to prevent false positive signals from immune complexes binding to C1q (reviewed in (Beurskens et al., 2015)).
C1q, antibodies and anti-C1q autoantibodies
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2015, Progress in Retinal and Eye ResearchCitation Excerpt :Complement is an arm of the innate immune response, providing a rapid defense against a variety of immunological stimuli. Complement ‘activation’ describes a cascade of proteolytic cleavages that generate chemotactic anaphylatoxins and phagocytosis-enhancing opsonins that ‘complement’ the host's adaptive defense against infectious pathogens (Frank and Fries, 1991), and mediates removal of extracellular debris (Gasque, 2004; Paidassi et al., 2008; Sim et al., 2007), immune complexes (Botto, 1998; Davies et al., 1994; Navratil et al., 1999), and apoptotic cells (Korb and Ahearn, 1997; Taylor et al., 2000; Trouw et al., 2001). There are three distinct complement-activating pathways – ‘classical’, ‘lectin’, and ‘alternative’ – which mediate the complement cascade.
Autoantibodies against complement components and functional consequences
2013, Molecular ImmunologyCitation Excerpt :Next to all the good the complement system does to keep the host clear of pathogens and maintaining tissue integrity, complement activation is also involved in a wide array of diseases, either because of too much activation, too little regulation or both (Ricklin et al., 2010). At the far end of this spectrum complement components themselves are targeted by an immune response of the host resulting in an autoantibody response against complement components (Norsworthy and Davies, 2003; Trouw et al., 2001). The first reports on antibody responses against complement components describe the immunoconglutinins, autoantibodies that target autologous C3 and C4 solid-phase fragments (Lachmann, 1967).
Anti-C1q antibodies and systemic lupus erythematosus in the Tunisian population
2013, Pathologie BiologieCitation Excerpt :Autoantibodies recognise a heterogeneous group of antigens, mainly nuclear or cell surface antigens. However, soluble antigens such as complement components are also targeted [2]. The classical pathway of complement is activated by the binding of C1q to complexed immunoglobulins or C-reactive protein and it was demonstrated that antibodies against C1q are present during SLE [3,4].
Complement activation by (auto-) antibodies
2011, Molecular ImmunologyCitation Excerpt :However, in complement sufficient SLE patients complement activation clearly contributes to damage. Next to the fact that several complement components like MBL, C1q and Properdin can interact with antibodies and result in complement activation, complement itself may be a target of auto-antibodies (Norsworthy and Davies, 2003; Trouw et al., 2001). In this regard the best known auto-antibodies are directed against for instance C1q and the amplification convertase C3bBb.