Elsevier

Clinical Immunology

Volume 107, Issue 3, June 2003, Pages 140-151
Clinical Immunology

Short analytical review
The complement system as a therapeutic target in autoimmunity

https://doi.org/10.1016/S1521-6616(03)00034-2Get rights and content

Introduction

The complement system is a central component of innate immunity [1] and is functionally linked to both the activation and regulatory as well as the effector arms of adaptive immunity [2], [3], [4], [5], [6]. Although the major function of complement has been thought to be recognition and elimination of pathogens through direct killing [7] or stimulation of phagocytosis [8], complement has also been shown more recently to play a central role in enhancing humoral immunity to T-dependent and T-independent foreign antigens (Ags) [6], [9], [10], [11], modifying cellular immunity [12] and regulating tolerance to certain self Ags [6], [13], [14], [15].

In addition to important roles in normal host responses to self and foreign Ags, the complement system is increasingly recognized to be causally involved in tissue injury during ischemic, inflammatory, and autoimmune diseases. Because of this, complement is an attractive therapeutic target for a wide range of diseases. In addition, the complement system may in some instances act relatively independently of other pro-inflammatory pathways, such as cytokines, which might allow for synergistic or additive therapeutic strategies with this increasingly used class of anti-inflammatory drugs [16]. In some disease settings, complement also exhibits activities in vivo that are independent of, or parallel to, Fc receptors, another important mediator of tissue injury [17], [18]. This article reviews the rationale for the use of therapeutic complement inhibitory strategies as well as the clinical and preclinical evidence supporting the use of complement modifying drugs in autoimmune diseases.

Section snippets

Complement activation mechanisms

Complement is activated by three mechanisms which, in toto, allow the system to respond to inflammatory, infectious, ischemic, or necrotic events as well as foreign and self-antigens (Ags) [5], [19], [20], [21] (Table 1). The first mechanism is the classical pathway, which is activated by IgM and certain IgG isotypes when they bind Ag (Fig. 1), resulting in increased affinity of the Fc domains for the first component of complement C1q [22]. Classical pathway components that are potential

Inhibition of complement activation pathway components as a therapeutic strategy

An attractive idea is to block the activation of soluble complement proteins, such as C3 and C5, or other individual members of the activation pathways. This strategy should allow for the effective blockade not only of the soluble protein that was targeted and receptors for its own activation fragments but also fragments resulting from activation of later proteins in the pathway and is in principle a more robust means of blocking many receptors simultaneously. A major target of this strategy is

Inhibition of complement receptors or the MAC as a therapeutic strategy

There are several complement receptors whose biologic roles strongly suggest that they would be appropriate therapeutic targets in autoimmune diseases. For example, activation of C3 by convertases assembled through any of the three pathways leads to cleavage of C3 with generation of the fragments C3a and C3b (Fig. 1). C3a is a small anaphylotoxin that binds to receptors on leukocytes and other cells, resulting in activation and release of soluble inflammatory mediators (reviewed in [76]). C3b

Examples of autoimmune diseases in which the complement system is a rational therapeutic target

Because many ways to block specific components of the complement system have become available over the last several years, and new tools such as gene-targeted mice have been developed, substantially more is known about the role of complement in the development of autoimmune diseases. This section will review experimental and human clinical studies which indicate that manipulation of complement system activities is a rational approach for the treatment of several types of autoimmune diseases.

Additional therapeutic strategies that modify complement activities

In addition to the inhibitory strategies outlined above, other strategies are either being utilized to modify complement activities or will be assessed in the near future. One strategy seeks to reverse the effects of complete complement deficiencies of classical pathway components that lead to autoimmune disease. The best example of this is the use of replacement doses of early classical pathway components, such as C2, in isolated patients with refractory disease [159]. Although this strategy

Conclusion

The complement system plays an important role in protection from infection with foreign pathogens and in the regulation of self-tolerance through clearance of apoptotic cells. In many inflammatory and autoimmune diseases, the injurious aspects of this system, which should be targeted to foreign pathogens, instead damages self-cells and tissues. This is true of both autoantibody- and cellular immune-mediated autoimmune diseases. The mechanisms of injury by complement are under study in many

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References (161)

  • R.J. Quigg et al.

    Immune complex glomerulonephritis in C4- and C3-deficient mice

    Kidney Intl.

    (1998)
  • I.J. Laudes et al.

    Anti-C5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis

    Am. J. Pathol.

    (2002)
  • A.E. Fiane et al.

    Modulation of fluid-phase complement activation inhibits hyperacute rejection in a porcine-to-human xenograft model

    Transplant. Proc.

    (2000)
  • R.A. Wetsel

    Structure, function and cellular expression of complement anaphylatoxin receptors

    Curr. Opin. Immunol.

    (1995)
  • M.L. Shin et al.

    Membrane attack by complementassembly and biology of terminal complement complexes

    Biomembranes

    (1996)
  • J.M. Ahearn et al.

    Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21)

    Adv. Immunol.

    (1989)
  • M.C. Carroll

    CD21/CD35 in B cell activation

    Semin. Immunol.

    (1998)
  • L.B. Klickstein et al.

    Complement receptor type 1 (CR1, CD35) is a receptor for C1q

    Immunity

    (1997)
  • D. Hourcade et al.

    The regulators of complement activation (RCA) gene cluster

    Adv. Immunol.

    (1989)
  • M. Krych et al.

    Structure-function analysis of the active sites of complement receptor type 1

    J. Biol. Chem.

    (1998)
  • B.O. Smith et al.

    Structure of the C3b binding site of CR1 (CD35), the immune adherence receptor

    Cell

    (2002)
  • T.F. Tedder et al.

    The CD19/CD21 signal transduction complex of B lymphocytes

    Immunol. Today

    (1994)
  • D.T. Fearon et al.

    The instructive role of innate immunity in the acquired immune response

    Science

    (1996)
  • K.R. Kalli et al.

    Therapeutic uses of recombinant complement protein inhibitors

    Springer Semin. Immunopathol.

    (1994)
  • F.D. Moore

    Therapeutic regulation of the complement system in acute injury states

    Adv. Immunol.

    (1994)
  • V.M. Holers

    Complement

  • M.C. Carroll

    The role of complement in B cell activation and tolerance

    Adv. Immunol.

    (2000)
  • M.M. Frank et al.

    Complement resistance in microbes

    Springer Semin. Immunopath.

    (1994)
  • H. Molina et al.

    Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2

    Proc. Natl. Acad. Sci. USA

    (1996)
  • Z. Kaya et al.

    Contribution of the innate immune system to autoimmune myocarditisa role for complement

    Nature Immunol.

    (2001)
  • X. Wu et al.

    A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus

    J. Immunol.

    (2002)
  • M. Feldmann et al.

    The role of TNF alpha and IL-1 in rheumatoid arthritis

    Curr. Directions Autoimmunity

    (2001)
  • D.T. Fearon et al.

    The instructive role of innate immunity in the acquired immune response

    Science

    (1996)
  • A.P. Dalmasso

    Complement in the pathophysiology and diagnosis of human diseases

    CRC Crit. Rev. Clin. Lab. Sci.

    (1986)
  • M.C. Carroll

    The role of complement and complement receptors in the induction and regulation of immunity

    Annu. Rev. Immunol.

    (1998)
  • P.J. Lachmann et al.

    Initiation of complement activation

    Springer Semin. Immunopathol.

    (1984)
  • D.M. Steel et al.

    The major acute phase reactantsC-reactive protein, serum amyloid P component and serum amyloid A protein

    Immunol. Today

    (1996)
  • H. Gewurz et al.

    Structure and function of the pentraxins

    Curr. Opin. Immunol.

    (1996)
  • M.C. Bickerstaff et al.

    Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity

    Nature Med.

    (1999)
  • D. Bharadwaj et al.

    The major receptor for C-reactive protein on leukocytes is Fc receptor II

    J. Exp. Med.

    (1999)
  • D. Bharadwaj et al.

    Serum amyloid P component binds to Fc gamma receptors and opsonizes particles for phagocytosis

    J. Immunol.

    (2001)
  • K.B. Bodman-Smith et al.

    C-reactive protein-mediated phagocytosis and phospholipase D signalling through the high-affinity receptor for immunoglobulin G

    Immunology

    (2002)
  • M. Griselli et al.

    C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction

    J. Exp. Med.

    (1999)
  • D. Gershov et al.

    C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune responseimplications for systemic autoimmunity

    J. Exp. Med.

    (2000)
  • M.R. Weiser et al.

    Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement

    J. Exp. Med.

    (1996)
  • S.D. Fleming et al.

    Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire

    J. Immunol.

    (2002)
  • S.J. Kim et al.

    I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation

    J. Exp. Med.

    (2002)
  • L.C. Korb et al.

    C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes

    J. Immunol.

    (1997)
  • A. Kagiyama et al.

    Molecular basis of complement activation in ischemic myocardiumidentification of specific molecules of mitochondrial origin that bind human C1q and fix complement

    Circ. Res.

    (1989)
  • K.B.M. Reid et al.

    Mammalian lectins in activation and clearance mechanisms involving the complement system

    Springer Semin. Immunopathol.

    (1994)
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