Elsevier

Clinical Immunology

Volume 148, Issue 3, September 2013, Pages 313-321
Clinical Immunology

Review
Targeting the complement system in systemic lupus erythematosus and other diseases

https://doi.org/10.1016/j.clim.2013.02.014Get rights and content

Highlights

  • Activation of the complement system can occur through one of three pathways.

  • Murine models define various roles of each complement pathway to host defense.

  • The application of complement inhibitors to SLE appears scientifically justified.

Abstract

The importance of the complement system in the pathogenesis of systemic lupus erythematosus (SLE) has long been recognized. However, despite an unprecedented amount of SLE clinical trial activities ongoing at this time, complement inhibitors have been omitted from the therapeutic assault on this disease. We review data generated from murine lupus that provide scientific support for the study of human SLE. Also reviewed is the sole study of a complement inhibitor, eculizumab, performed in patients with SLE. We conclude with a review of other inflammatory diseases where ongoing programs might provide the groundwork for the development of complement inhibitors in SLE.

Introduction

The complement system as a potential therapeutic target has long been acknowledged, though unraveling its complex, and often divergent effects, has been quite challenging (Fig. 1). When left unregulated, the complement system can result in widespread tissue damage. Indeed, systemic complement activation, with complement fragment generation, local deposition and ensuing inflammation, is the pathologic hallmark of systemic lupus erythematosus (SLE). Paradoxically, genetic deficiencies in the classical components of complement are directly linked to the development of SLE and highlight the importance of this pathway in facilitating apoptotic cell and immune complex clearance [1]. It has become increasingly recognized that complement is not only a vital component of the innate immune system, but it also modulates the adaptive immune response [2] through modification of T cell immunity [3], development of natural antibodies [4], and regulation of autoreactive B-cells [5].

Activation of the complement system can occur through one of three pathways [6]. Initiation of classical pathway activation most notably occurs through interactions between C1q and IgM or IgG. Other triggers include C-reactive protein, endothelial neoepitopes in ischemic tissue, apoptotic bodies, and serum amyloid P [7]. Deficiencies in C1q, C4 and C2 are most consistently linked with autoimmune rheumatic illnesses in both murine models and in man [6], [8], highlighting this pathway's beneficial contribution to regulation of apoptotic cell clearance, the humoral immune system and autoreactive B-cells.

The lectin pathway is activated by the interaction of mannose binding lectin (MBL) to repeating carbohydrate residues on infectious agents. This interaction leads to a classical pathway-like series of cleavage steps of MBL-associated serine proteases (MASP-1, MASP-2 and MASP-3) followed by complement pathway assembly [6]. Deficiencies are associated with both infections [9] and SLE [10].

The third activation pathway is the alternative pathway. Activation of the alternative pathway does not require prior exposure to an antigen. Deposition of cleaved C3 results in amplification of the immune response on the cell surface [7]. Deficiencies of C3 have been linked with infections. Data from C3−/− mice do not indicate a phenotype different from controls, in terms of autoimmunity [11], [12]. However, subsequent support of the alternative pathway in the development of lupus was made with the finding of protection against renal disease in fB−/− MRL/lpr mice [13]. Damage presumably occurs from immune complex processing errors in the C3−/− model and subsequent non-complement-mediated damage [12]. This demonstrates the fine balance between the beneficial effects of immune complex handling and the inflammatory damage of unregulated complement activation [7].

Knowledge gained from murine models has provided greater insights into the relative contributions of each arm of the complement system to host defense and inflammation. Furthermore, the recent approval of eculizumab, an anti-C5 monoclonal antibody, has led to renewed interest in these agents for the treatment of SLE as well as other inflammatory diseases. We next review the experience with complement inhibitors in murine models of SLE.

Section snippets

Pre-clinical models

One of the earliest therapeutic targets examined was C5 [14] (Table 1). Cleavage of C5 following complement activation results in the formation of both C5a, a potent anaphylatoxin, and the lytic terminal complement membrane attack complex, C5–9. The effect of blocking terminal complement activation through the direct inhibition of C5 was examined in NZB/W F1 mice. Although this strain spontaneously develops an autoimmune syndrome marked by high titer antinuclear antibodies and

Conclusions

Although the human clinical experience with complement inhibitors in the rheumatic diseases has been scant, their use in SLE appears scientifically justified. Candidate molecules are plentiful, but selection of a specific target could be confounded by safety concerns. While a reduction in disease activity and prevention of tissue damage are the ultimate goals of therapy, these favorable outcomes must be balanced by a preservation of immune clearance mechanisms and lack of infectious

Conflict of interest statement

The author(s) declare that there are no conflicts of interest.

References (79)

  • A. Haverich

    Pexelizumab reduces death and myocardial infarction in higher risk cardiac surgical patients

    Ann. Thorac. Surg.

    (2006)
  • J.S. Li

    Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass

    Am. Hear. J.

    (2004)
  • S. Keshavjee

    A randomized, placebo-controlled trial of complement inhibition in ischemia–reperfusion injury after lung transplantation in human beings

    J. Thorac. Cardiovasc. Surg.

    (2005)
  • T.M. Woodruff et al.

    Inhibiting the C5–C5a receptor axis

    Mol. Immunol.

    (2011)
  • M.C. Carroll

    The lupus paradox

    Nat. Genet.

    (1998)
  • Z. Kaya

    Contribution of the innate immune system to autoimmune myocarditis: a role for complement

    Nat. Immunol.

    (2001)
  • S.D. Fleming

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

    J. Immunol.

    (2002)
  • M.C. Carroll

    The role of complement in B cell activation and tolerance

    Adv. Immunol.

    (2000)
  • M.L. Barilla-LaBarca et al.

    Rheumatic syndromes associated with complement deficiency

    Curr. Opin. Rheumatol.

    (2003)
  • V.M. Holers

    The spectrum of complement alternative pathway-mediated diseases

    Immunol. Rev.

    (2008)
  • M.C. Pickering

    Systemic lupus erythematosus, complement deficiency, and apoptosis

    Adv. Immunol.

    (2000)
  • M.W. Turner et al.

    Mannose-binding lectin: structure, function, genetics and disease associations

    Rev. Immunogenet.

    (2000)
  • Y.H. Lee

    The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis

    Arthritis Rheum.

    (2005)
  • S. Einav

    Complement C4 is protective for lupus disease independent of C3

    J. Immunol.

    (2002)
  • H. Sekine

    Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice

    J. Immunol.

    (2001)
  • H. Watanabe

    Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B

    J. Immunol.

    (2000)
  • Y. Wang

    Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • M.L. Barilla-LaBarca et al.

    Regulation of the classical complement pathway: role of membrane cofactor protein (MCP; CD46)

    Mol. Immunol.

    (1999)
  • X. Wu

    Membrane protein Crry maintains homeostasis of the complement system

    J. Immunol.

    (2008)
  • M.L. Barilla-LaBarca

    Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells

    J. Immunol.

    (2002)
  • L. Bao

    Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice

    J. Am. Soc. Nephrol.

    (2003)
  • C. Atkinson

    Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection

    J. Clin. Investig.

    (2005)
  • H. Sekine

    The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice

    Arthritis Rheum.

    (2011)
  • C. Xu

    A critical role for murine complement regulator crry in fetomaternal tolerance

    Science

    (2000)
  • J.M. Thurman et al.

    The central role of the alternative complement pathway in human disease

    J. Immunol.

    (2006)
  • V.M. Holers

    Complement C3 activation is required for antiphospholipid antibody-induced fetal loss

    J. Exp. Med.

    (2002)
  • W. Lloyd et al.

    Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE)

    Medicine (Baltimore)

    (1981)
  • J.P. Atkinson

    Complement activation and complement receptors in systemic lupus erythematosus

    Springer Semin. Immunopathol.

    (1986)
  • M. Dall'Era

    Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide

    Arthritis Care Res. (Hoboken)

    (2011)
  • Cited by (83)

    • Gene polymorphisms within regions of complement component C1q in HIV associated preeclampsia

      2023, European Journal of Obstetrics and Gynecology and Reproductive Biology
    • Challenges in systemic lupus erythematosus: From bench to bedside

      2023, Translational Autoimmunity: Volume 6: Advances in Autoimmune Rheumatic Diseases
    • Complement and SLE

      2021, Lahita’s Systemic Lupus Erythematosus
    • Mechanisms of tissue injury in lupus nephritis

      2021, Lahita’s Systemic Lupus Erythematosus
    View all citing articles on Scopus
    View full text