Review
Autoantibodies to complement components

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Abstract

The complement system is a major component of innate immunity. Under normal conditions the contribution of the complement system is beneficial, but when inappropriately activated it may cause damage to the host and under certain conditions it may even be the target of an autoantibody response. Autoantibodies directed against individual complement components, convertases, complement regulators and complement receptors have been described. The presence of autoantibodies in individuals may be associated with manifestations of disease, but only for some autoantibodies have clear causal relations been described. Autoantibodies against complement components can even be present in healthy individuals, indicating that the development of pathology most likely requires the simultaneous action of multiple processes. Since autoantibodies against complement components may cause depletion of circulating complement levels, leading to a secondary complement deficiency, it is imaginable that this process leads to an increased susceptibility to infections. In the present review, we describe autoantibodies against complement components and their subsequent effects.

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.

References (69)

  • G. Moroni et al.

    Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis

    Am. J. Kidney Dis.

    (2001)
  • Z. Prohaszka et al.

    C1q autoantibodies in HIV infection: correlation to elevated levels of autoantibodies against 60-kDa heat-shock proteins

    Clin. Immunol.

    (1999)
  • D.B. Rubinstein et al.

    Autoantibodies to leukocyte alphaMbeta2 integrin glycoproteins in HIV infection

    Clin. Immunol.

    (1999)
  • R.E. Spitzer et al.

    On the origin of C3 nephritic factor (antibody to the alternative pathway C3 convertase): evidence for the Adam and Eve concept of autoantibody production

    Clin. Immunol. Immunopathol.

    (1992)
  • Y. Tanuma et al.

    Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF

    Clin. Immunol. Immunopathol.

    (1990)
  • S. Uwatoko et al.

    Characterization of C1q-binding IgG complexes in systemic lupus erythematosus

    Clin. Immunol. Immunopathol.

    (1984)
  • Agnello, V., Koffler, D., Eisenberg, J.W., Winchester, R.J., Kundel, H.G., 1971. C1q precipitins in the sera of...
  • Alsenz, J., Loos, M., 1989. The acquired C1-INH deficiencies with autoantibodies (AAE type II). Behring Inst Mitt...
  • U. Antes et al.

    Evidence for the presence of autoantibodies to the collagen-like portion of C1q in systemic lupus erythematosus

    Arthritis Rheum.

    (1988)
  • C.M. Arroyave et al.

    Serum factors activating the alternative complement pathway in autoimmune disease: description of two different factors from patients with systemic lupus erythematosus

    J. Immunol.

    (1976)
  • M. Barel et al.

    Autoantibodies against gp140, the Epstein–Barr virus and C3d receptor in sera from rheumatoid arthritis patients

    Eur. J. Immunol.

    (1986)
  • I.E. Coremans et al.

    Antibodies against C1q in anti-glomerular basement membrane nephritis

    Clin. Exp. Immunol.

    (1992)
  • I.E. Coremans et al.

    Stabilization of glomerular deposits of C1q by antibodies against C1q in mice

    J. Clin. Lab. Immunol.

    (1995)
  • M.R. Daha et al.

    Further evidence for the antibody nature of C3 nephritic factor (C3NeF)

    J. Immunol.

    (1979)
  • M.R. Daha et al.

    Relative resistance of the F-42-stabilized classical pathway C3 convertase to inactivation by C4-binding protein

    J. Immunol.

    (1980)
  • M.R. Daha et al.

    C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase

    J. Immunol.

    (1976)
  • M.R. Daha et al.

    Formation in the presence of C3 nephritic factor (C3NeF) of an alternative pathway C3 convertase containing uncleaved B

    Immunology

    (1976)
  • M.R. Daha et al.

    Heterogeneity, polypeptide chain composition and antigenic reactivity of C3 nephritic factor

    J. Immunol.

    (1978)
  • P. Eggleton et al.

    Pathophysiological roles of calreticulin in autoimmune disease

    Scand. J. Immunol.

    (1999)
  • P. Eggleton et al.

    Fine specificity of autoantibodies to calreticulin: epitope mapping and characterization

    Clin. Exp. Immunol.

    (2000)
  • V. Fremeaux-Bacchi et al.

    Autoantibodies to the collagen-like region of C1q are strongly associated with classical pathway-mediated hypocomplementemia in systemic lupus erythematosus

    Lupus

    (1996)
  • T. Fujita et al.

    C4 nephritic factor in a patient with chronic glomerulonephritis

    J. Clin. Lab. Immunol.

    (1987)
  • H. Gewurz et al.

    The complement profile in acute glomerulonephritis systemic lupus erythematosus and hypocomplementemic chronic glomerulonephritis. Contrasts and experimental correlations

    Int. Arch. Allergy Appl. Immunol.

    (1968)
  • I. Gigli et al.

    Regulation and deregulation of the fluid-phase classical pathway C3 convertase

    J. Immunol.

    (1985)
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