The complement system in systemic autoimmune disease

https://doi.org/10.1016/j.jaut.2009.11.014Get rights and content

Abstract

Complement is part of the innate immune system. Its major function is recognition and elimination of pathogens via direct killing and/or stimulation of phagocytosis. Activation of the complement system is, however, also involved in the pathogenesis of the systemic autoimmune diseases. Activation via the classical pathway has long been recognized in immune complex-mediated diseases such as cryoglobulinemic vasculitis and systemic lupus erythematosus (SLE). In SLE, the role of complement is somewhat paradoxical. It is involved in autoantibody-initiated tissue damage on the one hand, but, on the other hand, it appears to have protective features as hereditary deficiencies of classical pathway components are associated with an increased risk for SLE. There is increasing evidence that the alternative pathway of complement, even more than the classical pathway, is involved in many systemic autoimmune diseases. This is true for IgA-dominant Henoch Schönlein Purpura, in which additional activation of the lectin pathway contributes to more severe disease. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis the complement system was considered not to be involved since immunoglobulin deposition is generally absent in the lesions. However, recent studies, both in human and animal models, demonstrated complement activation via the alternative pathway as a major pathogenic mechanism. Insight into the role of the various pathways of complement in the systemic autoimmune diseases including the vasculitides opens up new ways of treatment by blocking effector pathways of complement. This has been demonstrated for monoclonal antibodies to C5 or C5a in experimental anti-phospholipid antibody syndrome and ANCA-associated vasculitis.

Section snippets

Three activating pathways of complement

Complement is part of the innate immune system and is one of the main effector mechanisms of antibody-mediated immunity. The complement system comprises more than 30 plasma and membrane-bound proteins [1], [2].

Activation of the complement system involves participation of a large number of plasma proteins including C1q, C1r, C1s, C2 through C9, factor B, factor D, and properdin. There are three pathways of complement activation, i.e. the classical, alternative and lectin pathway. All three

The complement system and systemic small vessel vasculitis

Vasculitis is an inflammatory process of blood vessels, histopathologically characterized by inflammation and fibrinoid necrosis of the vessel wall. An attempt to classify the diverse forms of vasculitis resulted in the Chapel Hill international consensus definitions, which used the vessel size and the histopathology of the lesions as the main determinants of classification [21].

The complement system and anti-glomerular basement membrane disease

Anti-glomerular basement membrane (anti-GBM) disease is a rare but life-threatening disease caused by IgG autoantibodies against the glomerular basement membrane. Typical manifestations of anti-GBM disease are rapidly progressive glomerulonephritis accompanied by pulmonary hemorrhage. Anti-GBM disease is one of the few human autoimmune diseases in which the pathogenic autoantigen has been identified. It is designated as the Goodpasture antigen and comprises the noncollagenous domain (NC1) of

The complement system and systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by multi-organ involvement, including serosa, joints, central nervous system, skin and kidneys, in association with an array of autoantibodies, in particular antibodies to double stranded DNA.

The role of complement in the pathogenesis of SLE is paradoxical. On the one hand, complement components appear to mediate autoantibody-initiated tissue damage. On the other hand, the complement system appears to

The complement system and anti-phospholipid antibody syndrome

The anti-phospholipid antibody syndrome (APS) is a clinical condition characterized by arterial and venous thrombosis and pregnancy complications in association with anti-phospholipid (aPL) antibodies. In addition to recurrent miscarriage and fetal death, pregnancy complications in women with APS include preeclampsia, placental insufficiency, and fetal growth restriction. Using a murine model of APS induced by passive transfer of human anti-phospholipid antibodies, it has been shown that

The complement system and systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of skin and internal organs, with skin thickening either restricted to distal extremities and face (limited disease), or affecting also proximal extremities and/or trunk (diffuse disease). Both endothelium, epithelium, fibroblasts, the innate and adaptive immune system are involved in its pathogenesis. Endothelial cell damage may be the initiating factor. The immunopathological events in SSc have not been

The complement system and primary Sjögren's syndrome

Primary Sjögren's syndrome is a systemic autoimmune disease that presents with sicca symptoms of mucosa surfaces, in particular the eyes (xerophthalmia) and mouth (xerostomia). The histological hallmark is a focal lymphocytic infiltration of the exocrine glands.

A large number of autoantibodies have been reported in primary Sjogren's syndrome. In some cases the antibodies correlate with the extent and severity of disease. In particular, antibodies to the ubiquitous autoantigens 52-kDa SSA/Ro,

The complement system and dermatomyositis

The inflammatory myopathies are a heterogeneous group of subacute, chronic, or acutely acquired diseases of skeletal muscle. They have in common the presence of moderate to severe muscle weakness and inflammation. On the basis of well-defined clinical, demographic, histological, and immunopathological criteria, the inflammatory myopathies form three major and discrete groups: polymyositis, dermatomyositis, and sporadic inclusion-body myositis [101].

Dermatomyositis is a complement-mediated

The complement system and rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovium and subsequent destruction of cartilage and bone. There is abundant evidence that complement activation is involved in the pathogenesis of RA.

In RA, accelerated consumption and a responsive hyper-production of complement components have been reported in synovial fluids. Compatible with complement consumption, complement activity of joint fluid from patients with RA was shown to be significantly

Conclusion

The complement system participates in the pathogenesis of many systemic autoimmune diseases. Besides the classical pathway via immune complex formation, e.g. in. cryoglobulinemic vasculitis and systemic lupus erythematosus, also the alternative pathway is involved. Increasing evidence shows the role of complement activation via the alternative pathway in many classical immune-complex mediated diseases. Because of the major role of complement in mediating target organ damage, approaches to

Conflict of interest

None declared.

References (121)

  • D. Huugen et al.

    Inhibition of complement factor C5 protects against antimyeloperoxidase antibody-mediated glomerulonephritis in mice

    Kidney Int

    (2007)
  • P.J. Bansal et al.

    Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement

    Ann Allergy Asthma Immunol

    (2004)
  • D.J. Schlieben et al.

    Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs

    Am J Kidney Dis

    (2005)
  • M.A. Little et al.

    Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo

    Blood

    (2005)
  • H. Xiao et al.

    The role of neutrophils in the induction of glomerulonephritis by antimyeloperoxidase antibodies

    Am J Pathol

    (2005)
  • J.S. Navratil et al.

    Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance

    Immunopharmacology

    (1999)
  • M. Bijl et al.

    New insights into the pathogenesis of systemic lupus erythematosus (SLE): the role of apoptosis

    Neth J Med

    (2001)
  • J.E. Salmon et al.

    Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation

    J Reprod Immunol

    (2008)
  • I. Batal et al.

    Renal biopsy findings predicting outcome in scleroderma renal crisis

    Hum Pathol

    (2009)
  • M.J. Walport

    Complement. First of two parts

    N Engl J Med

    (2001)
  • M.J. Walport

    Complement. Second of two parts

    N Engl J Med

    (2001)
  • A.J. Nauta et al.

    Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells

    J Immunol

    (2004)
  • W. Xu et al.

    Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation

    J Immunol

    (2008)
  • H. Gaarkeuken et al.

    Complement activation by tubular cells is mediated by properdin binding

    Am J Physiol Renal Physiol

    (2008)
  • B. Selander et al.

    Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2

    J Clin Invest

    (2006)
  • M.R. Daha et al.

    Compliments from complement: a fourth pathway of complement activation?

    Nephrol Dial Transplant

    (2006)
  • T. Fujita et al.

    The lectin-complement pathway–its role in innate immunity and evolution

    Immunol Rev

    (2004)
  • M.C. Moffitt et al.

    Complement resistance in microbes

    Springer Semin Immunopathol

    (1994)
  • P.W. Dempsey et al.

    C3d of complement as a molecular adjuvant: bridging innate and acquired immunity

    Science

    (1996)
  • M. Boes et al.

    A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection

    J Exp Med

    (1998)
  • K.A. Davies et al.

    Complement deficiency and immune complex disease

    Springer Semin Immunopathol

    (1994)
  • L.C. Korb et al.

    C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited

    J Immunol

    (1997)
  • 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 response: implications for systemic autoimmunity

    J Exp Med

    (2000)
  • D. Mevorach et al.

    Complement-dependent clearance of apoptotic cells by human macrophages

    J Exp Med

    (1998)
  • P.R. Taylor et al.

    A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo

    J Exp Med

    (2000)
  • V.M. Holers

    The spectrum of complement alternative pathway-mediated diseases

    Immunol Rev

    (2008)
  • J.C. Jennette et al.

    Nomenclature of systemic vasculitides: the proposal of an international consensus conference

    Arthritis Rheum

    (1994)
  • D. Saadoun et al.

    Hepatitis C-associated mixed cryoglobulinemia: a crossroad between autoimmunity and lymphoproliferation

    Rheumatology

    (2007)
  • C. Ferri et al.

    Cryoglobulinemic vasculitis

    Curr Opin Rheumatol

    (2006)
  • J.M. Pawlotsky et al.

    Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes

    Ann Intern Med

    (1995)
  • R.J. Johnson et al.

    Membranoproliferative glomerulonephritis associated with hepatitis C virus infection

    N Engl J Med

    (1993)
  • H. Yamabe et al.

    Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan

    J Am Soc Nephrol

    (1995)
  • M.C. Bene et al.

    Composition of mesangial deposits in IgA nephropathy: complement factors

    Nephron

    (1987)
  • A. Roos et al.

    Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease

    J Am Soc Nephrol

    (2006)
  • M. Espinosa et al.

    Mesangial C4d deposition: a new prognostic factor in IgA nephropathy

    Nephrol Dial Transplant

    (2009)
  • R.A. Watts et al.

    Epidemiology of vasculitis in Europe

    Ann Rheum Dis

    (2001)
  • M. Chen et al.

    Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients

    Medicine (Baltimore)

    (2008)
  • M. Shingu et al.

    Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils

    Clin Exp Immunol

    (1992)
  • P. Venge et al.

    Cationic proteins of human granulocytes. VI. Effects on the complement system and mediation of chemotactic activity

    J Immunol

    (1975)
  • A. Schreiber et al.

    C5a receptor mediates neutrophil activation and ANCA-Induced glomerulonephritis

    J Am Soc Nephrol

    (2009)
  • Cited by (277)

    • The primitive complement system in molluscs

      2023, Developmental and Comparative Immunology
      Citation Excerpt :

      It is found that the domains involved in the complement system like C1q, fibrinogen-like (FBG), complement control protein (CCP), complement urchin-bone (CUB), carbohydrate-recognition domain (CRD), thrombospondin type 1 repeats (TSP1) and low-density lipoprotein a (LDLa) are greatly expanded in molluscs, indicating that the components of complement system are more complex and diverse in molluscs. C3 is the core component in the complement system, which is composed of three polypeptide chains (α, β, and γ) and can be activated to generate multiple active fragments (Chen et al., 2010; Gros et al., 2008; Zhu et al., 2005). Until now, C3 homologues have been identified in several molluscan species, such as Pacific oyster C. gigas (Wang et al., 2017), pearl oyster Pinctada fucata (Wang et al., 2021), Yesso scallop Patinopecten yessoensis (Liao et al., 2018), thick shell mussel Mytilus coruscus (Chen et al., 2018b), razor clam Sinonovacula constricta (Peng et al., 2016), pearl mussel Hyriopsis cumingii (Wang et al., 2019), carpet-shell clam Ruditapes decussatus (Prado-Alvarez et al., 2009), and Hawaiian bobtail squid Euprymna scolopes (Castillo et al., 2009).

    • Comprehensive overview of autoantibody isotype and subclass distribution

      2022, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus
    View full text