Elsevier

Clinica Chimica Acta

Volume 465, February 2017, Pages 123-130
Clinica Chimica Acta

Review
Complement in autoimmune diseases

https://doi.org/10.1016/j.cca.2016.12.017Get rights and content

Highlights

  • Complement is an important evolutionary conserved element of the innate immune system.

  • Human complement system comprises more than 20 proteins which are present as inactive precursors.

  • Complement is the final effector mediating tissue damage and injury in a host of autoimmune disease.

  • Inherited deficiencies of early complement components lead to a lupus-like manifestations

  • Deficiencies of component of alternative pathway leads to monogenic forms of atypical haemolytic uremic syndrome

Abstract

The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector.

Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial “double edged sword”. On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases.

Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity.

Introduction

The complement system is a part of the innate immunological armamentarium that comprises of effector molecules and receptors that help in both fighting against the invasion of pathogens and regulation of the immune system. Paul Ehrlich, in the year 1899, introduced the term ‘complements’ for heat labile substances in sera that were responsible for antimicrobial immunity in addition to antibodies [1], [2]. Ever since its first description, a number of complement components were subsequently discovered and were numbered according to the order of discovery. Extensive research has been done till date to understand various aspects and functions of the complement system and its role in the pathogenesis of autoimmune diseases. One of the most important reasons for tissue insults and end organ damage in autoimmune diseases is the excessive activation of the complement pathway [3], [4]. Paradoxically, deficiencies of certain components of complement pathways also result in manifestations of autoimmune diseases such as systemic lupus erythematosus (SLE) [3], [4]. This topical review focuses on the role of complement system in the pathogenesis of various systemic autoimmune disorders and its therapeutic implications. (See Fig. 1.) (See Table 1.)

Section snippets

Mechanism of complement system activation and its functions

Activation of complement pathway can occur by three different mechanisms. All the three mechanisms converge at the activation of C3 and C5, and finally result in the formation of the membrane attack complex (MAC). MAC disrupts the cell membrane, by forming pores on the cell membrane, and causing osmotic cell lysis [2].

The first mechanism is the activation of classical pathway by immune complex deposits (IgG or IgM). The complement binding site in the Fc portion of the antibody gets exposed

Inherent deficiencies of complement components

Deficiencies of early complement components are known to predispose to various autoimmune conditions, especially early-onset SLE or a lupus-like disease [10]. One of the mechanisms hypothesized for the development of autoimmunity in complement-deficient patients is a defective disposal of apoptotic debris and immune complex deposits. The mechanism is also called ‘waste-disposal’ hypothesis [11]. Inefficient clearance of apoptotic leftovers act as a source of autoantigens and probably triggers

Acquired deficiencies of complement components

Antibodies directed against the complement components are detected in patients with SLE. These auto-antibodies are generally directed at the neoepitopes of the complement components that are exposed in the activated state. The presence of these auto-antibodies might potentially result in a complement-deficient state that would further enhance the propagation of autoimmune process.

Autoimmune diseases and complements

Complement-mediated tissue damage is described in multitude of autoimmune conditions. Most common of it are SLE, various vasculitic conditions, dermatomyositis, and rheumatoid arthritis.

Laboratory assessment

Most commonly tested complement components in serum are C3 and C4. In order to prevent in vitro activation of complements, plasma should be separated immediately the collected samples and stored at − 80 °C. Nephelometry, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and western blots are the various techniques used for the measurement of complement components such as C1q, C1r, C1s, C2, C3, C4, and various complement split products [3]. ELISA tests have also been developed to test

Therapeutic strategies

As it is evident that complements play a major role in the tissue damage in autoimmune diseases, targeting complement components could serve as a potential therapeutic regimen in autoimmune disorders. Suppressing excess complement activation could theoretically decrease the inflammatory damage. Monoclonal antibody directed against C5 (eculizumab) serve as an effective therapeutic option in the management of atypical hemolytic uremic syndrome caused by uncontrolled activation of alternate

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