ReviewComplement in autoimmune diseases
Graphical abstract
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
References (124)
- et al.
Early complement proteases: C1r, C1s and MASPs. A structural insight into activation and functions
Mol. Immunol.
(2009) - et al.
Complement and toll-like receptors: key regulators of adaptive immune responses
Mol. Immunol.
(2006) Classical pathway deficiencies - a short analytical review
Mol. Immunol.
(2015)Complement and autoimmunity
Biomed. Pharmacother.
(2003)- et al.
A critical role for complement in maintenance of self-tolerance
Immunity
(1998) - et al.
Clinical presentation of human C1q deficiency: how much of a lupus?
Mol. Immunol.
(2015) - et al.
Complement protein C1q induces maturation of human dendritic cells
Mol. Immunol.
(2007) - et al.
Molecular, genetic and epidemiologic studies on selective complete C1q deficiency in Turkey
Immunobiology
(2000) - et al.
Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family
Kidney Int.
(1996) - et al.
Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene
Mol. Immunol.
(2008)