Elsevier

Molecular Immunology

Volume 45, Issue 15, September 2008, Pages 3865-3877
Molecular Immunology

Review
The complement system in the peripheral nerve: Friend or foe?

https://doi.org/10.1016/j.molimm.2008.06.018Get rights and content

Abstract

The complement (C) system plays a central role in innate immunity and bridges innate and adaptive immune responses. A fine balance of C activation and regulation mediates the elimination of invading pathogens and the protection of the host from excessive C deposition on healthy tissues. If this delicate balance is disrupted, the C system may cause injury and contribute to the pathogenesis of various diseases, including neuropathies. Here we review evidence indicating that C factors and regulators are locally synthesized in the peripheral nerve and we discuss the evidence supporting the protective or detrimental role of C activation in health, injury and disease of the peripheral nerve.

Introduction

Complement was discovered in the 1890s (von Fodor, 1887, Nuttall, 1888, Buchner, 1889) as a heat-sensitive serum factor capable of lysing bacteria in the presence of the heat-stable antibody (Bordet, 1895). Molecular biology profoundly transformed our understanding of the complement system and from its original description as “complement” to humoral immunity (Ehrlich and Morgenroth, 1899) today it represents a key component of the innate immune system, defending the host against infections, bridging innate and adaptive immunity and disposing of immune complexes and apoptotic cells (Walport, 2001a, Walport, 2001b). Paradoxically, the same system responsible for such beneficial effects can be deleterious to the host. To prevent complement-mediated tissue injury, over 30 soluble and membrane-bound complement proteins are engaged in a fine coordination of activation and regulation. However, if the regulatory machinery fails, the complement system can contribute to tissue injury and the pathogenesis of various diseases.

The local synthesis of factors and regulators of the complement cascade in the peripheral nerve has been established (de Jonge et al., 2004) but its role in peripheral nerve health, injury and disease remains controversial. Local production of complement factors including regulators of complement activity in the peripheral nerve could protect the healthy nerve from infections. On the other hand, it could erroneously target self tissues. It could facilitate regeneration of injured axons by assisting in the efficient clearance of myelin debris, thought to be inhibitory for axon growth, but it could also exacerbate tissue damage during degeneration hampering the correct regeneration of the nerve. In addition, like it has been proposed for other diseases, complement could contribute to the pathogenesis and progression of neuropathies. Here we will review the evidence supporting the protective and detrimental role of the complement system in the peripheral nerve.

Section snippets

A fine balance of activation and regulation

Activation of the complement system is rapid and efficient. Soluble complement components are present in the blood, body fluids and tissues to readily trigger a defense reaction against external (i.e. pathogens) or internal (i.e. autoimmunity) danger signals (Kohl, 2006). Complement activation can occur via three routes: the classical, the lectin and the alternative pathway. The classical pathway is activated by the recognition of an antigen–antibody complex by C1q. Upon binding, C1r cleaves

Complement as friend

For over 700 million years, the complement system has provided protection against microbial infections (Sunyer et al., 1998), yet its function extends beyond a simple defense mechanism. Today it is clear that the complement system is a key regulator of various stages of an inflammatory reaction. These events are mediated by the potent complement anaphylatoxins C3a and C5a which propagate the immune reaction by binding to their receptors (C3aR, C5aR, C5L2) on the host cell (reviewed by van

Complement as foe

Disruption of the delicate balance between complement activation and regulation is implicated in the pathogenesis, propagation and exacerbation of numerous diseases. Excessive complement activation results from the propagation of an inflammatory reaction or from alterations in the expression and function of complement regulatory proteins.

Complement activation, especially C5a production, plays a major role in the pathogenesis of inflammatory disorders including ischemia/reperfusion injury,

Local synthesis of complement in the peripheral nerve

The primary site of synthesis of plasma complement proteins is liver. Extrahepatic complement biosynthesis occurs in many tissues and it may account for the rapid and efficient ability of the complement system to initiate and propagate an inflammatory response. Local production of complement proteins is especially important in tissues where the access to plasma proteins is hindered by a blood–tissue barrier (Morgan and Gasque, 1997, Laufer et al., 2001).

The brain, shielded by the blood–brain

Complement activation in peripheral nerve degeneration

Transection or crush injury to peripheral nerves results in the disintegration of the axons in the distal stump of the traumatized nerve, a process known as Wallerian degeneration (WD) (Waller, 1850). The initial morphological changes are visible as early as 12 h after injury and include loss of axonal content. Approximately 2–3 days later, the first changes in myelin structure occur. Myelin collapses into ellipsoids in the distal stump and in the most distal end of the proximal stump up to the

Effect of post-traumatic complement activation on peripheral nerve regeneration

Damaged peripheral axons often achieve a good morphological regeneration but regain function slowly and incompletely (Baker et al., 1994, Lundborg and Rosen, 2007). Peripheral nerve regeneration after injury requires axons to re-enter the Schwann cell tubes injured at the lesion site. The search of axons for the appropriate Schwann cell tube is represented by the axonal branches emerging from the tip of the proximal undamaged nerve stump. Once in the distal stump, the axons need to re-navigate

Complement activation in peripheral nerve disease

Activation of the complement system occurs in both chronic and acute diseases of the PNS (Table 3).

Complement regulation in peripheral nerve injury and disease: a therapeutic approach

The implication of complement activation in the initiation, propagation or exacerbation of PNS injury and disease, make it a potential target for therapeutic intervention. A number of complement inhibitors and modulators have been developed and have recently been reviewed by Ricklin and Lambris (2007). Various steps of the proteolytic cascade and its (positive and negative) regulators have been targeted in PNS injury and disease and they are currently in the stage of preclinical development (

Conclusions

It is evident that the complement system plays both a protective and detrimental role in the peripheral nerve. The beneficial effects of complement in immune surveillance and possibly in regulating energy metabolism in the microenvironment of the nerve need to be balanced against the heavy weight of its damaging effects as key determinant of early axon loss and regeneration after injury and in acute PNS diseases. Specific modulation of the complement system at the terminal level of the cascade,

Acknowledgements

We thank Prof. H. Willison for permission to reproduce Fig. 3 and critically reading the manuscript.

References (154)

  • P. Gasque et al.

    Complement components of the innate immune system in health and disease in the CNS

    Immunopharmacology

    (2000)
  • K.P. Giese et al.

    Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons

    Cell

    (1992)
  • D.E. Hourcade

    The role of properdin in the assembly of the alternative pathway C3 convertases of complement

    J. Biol. Chem.

    (2006)
  • S. Jung et al.

    Soluble complement receptor type 1 inhibits experimental autoimmune neuritis in Lewis rats

    Neurosci. Lett.

    (1995)
  • R. Kiefer et al.

    The role of macrophages in immune-mediated damage to the peripheral nervous system

    Prog. Neurobiol.

    (2001)
  • I. Kobsar et al.

    Macrophage-related demyelination in peripheral nerves of mice deficient in the gap junction protein connexin 32

    Neurosci. Lett.

    (2002)
  • J. Laufer et al.

    Extrahepatic synthesis of complement proteins in inflammation

    Mol. Immunol.

    (2001)
  • X. Luo et al.

    C1q-calreticulin induced oxidative neurotoxicity: relevance for the neuropathogenesis of Alzheimer's disease

    J. Neuroimmunol.

    (2003)
  • M.M. Markiewski et al.

    The role of complement in inflammatory diseases from behind the scenes into the spotlight

    Am. J. Pathol.

    (2007)
  • R. Martini et al.

    Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients

    Lancet Neurol.

    (2004)
  • P. Mattsson et al.

    Complement activation and CD59 expression in the motor facial nucleus following intracranial transection of the facial nerve in the adult rat

    J. Neuroimmunol.

    (1998)
  • P.L. McGeer et al.

    The possible role of complement activation in Alzheimer disease

    Trends Mol. Med.

    (2002)
  • L. McKerracher et al.

    Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth

    Neuron

    (1994)
  • D.M. Menichella et al.

    Protein zero is necessary for E-cadherin-mediated adherens junction formation in Schwann cells

    Mol. Cell Neurosci.

    (2001)
  • B.P. Morgan et al.

    Expression of complement in the bra role in health F disease

    Immunol. Today

    (1996)
  • G.M. Pasinetti

    Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: the role of the complement system

    Neurobiol. Aging

    (1996)
  • J.P. Atkinson et al.

    Bypassing complement: evolutionary lessons and future implications

    J. Clin. Invest.

    (2006)
  • R.S. Baker et al.

    Aberrant reinnervation of facial musculature in a subhuman primate: a correlative analysis of eyelid kinematics, muscle synkinesis, and motoneuron localization

    Neurology

    (1994)
  • S.R. Barnum

    Complement biosynthesis in the central nervous system

    Crit. Rev. Oral Biol. Med.

    (1995)
  • J. Bordet

    Les leukocytes et les proprietes actives du serum chez les vaccines

    Ann. Inst. Pasteur (Paris)

    (1895)
  • M.C. Brown et al.

    Consequences of slow Wallerian degeneration for regenerating motor and sensory axons

    J. Neurobiol.

    (1992)
  • W. Bruck et al.

    Anti-macrophage CR3 antibody blocks myelin phagocytosis by macrophages in vitro

    Acta Neuropathol.

    (1990)
  • H. Buchner

    Uaber die naehere Natur der bakterientodtenden Substanz in Blutserum

    Zbl. Bakt. (Naturwiss.)

    (1889)
  • S. Carenini et al.

    The role of macrophages in demyelinating peripheral nervous system of mice heterozygously deficient in p0

    J. Cell Biol.

    (2001)
  • D.F. Carney et al.

    Elimination of terminal complement complexes in the plasma membrane of nucleated cells: influence of extracellular Ca2+ and association with cellular Ca2+

    J. Immunol.

    (1986)
  • J. Charcot et al.

    Sue une forme particulaire d’atrophie musculaire progressive souvent familial debutant par les jamber et atteingnant plus tard les mains

    Rev. Med.

    (1886)
  • M.S. Chen et al.

    Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1

    Nature

    (2000)
  • S. Chen et al.

    Long-term consequences of impaired regeneration on facial motoneurons in the C57BL/Ola mouse

    J. Comp. Neurol.

    (1993)
  • N.R. Cooper

    Formation and function of a complex of the C3 proactivator with a protein from cobra venom

    J. Exp. Med.

    (1973)
  • A.T. Dailey et al.

    Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration

    J. Neurosci.

    (1998)
  • J.G. Damoiseaux et al.

    Heterogeneity of macrophages in the rat evidenced by variability in determinants: two new anti-rat macrophage antibodies against a heterodimer of 160 and 95 kd (CD11/CD18)

    J. Leukoc. Biol.

    (1989)
  • S.M. Dashiell et al.

    Sublytic terminal complement complexes decrease P0 Gene expression in Schwann cells

    J. Neurochem.

    (1999)
  • S.M. Dashiell et al.

    Terminal complement complexes concomitantly stimulate proliferation and rescue of Schwann cells from apoptosis

    Glia

    (2000)
  • S.M. Dashiell et al.

    Dibutyryl cyclic AMP and inflammatory cytokines mediate C3 expression in Schwann cells

    Glia

    (1997)
  • S. David et al.

    JNK1 activation mediates C5b-9-induced P0 mRNA instability and P0 gene expression in Schwann cells

    J. Peripher. Nerv. Syst.

    (2006)
  • R.R. de Jonge et al.

    Expression of complement components in the peripheral nervous system

    Hum. Mol. Genet.

    (2004)
  • B.A. DeJong et al.

    A role for complement in phagocytosis of myelin

    Neurochem. Res.

    (1997)
  • M. Donaghy et al.

    Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation

    J. Neurol. Neurosurg. Psychiatry

    (2000)
  • P.J. Dyck et al.

    Prednisone-responsive hereditary motor and sensory neuropathy

    Mayo Clin. Proc.

    (1982)
  • P. Ehrlich et al.

    Zur Theorie der Lysenwirkung

    Berlin Klin. Wschr.

    (1899)
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