ReviewC1q, antibodies and anti-C1q autoantibodies
Section snippets
Introduction on complement
The complement system is traditionally considered to be an integral part of the innate immune defence against pathogens. Initially the main function of complement was considered to be lysis of targets such as bacteria. Also the assays used for clinical routine diagnostics to determine the classical and alternative activity of complement, such as CH-50 and AP-50, respectively, were based on cellular lysis, in this case of erythrocytes. Nowadays we appreciate that the function of complement is
C1q gene and protein
The genes C1QA, C1QB and C1QC are located on the p-arm of chromosome 1 (chromosomal location: 1p34–1p36.3). These genes encode for the constituents of the C1q molecule, the C1q A, B and C peptide chains that each form one helical strand and all contain a short N-terminal region, a collagen-like region and a C-terminal globular region (gC1q domain) (Fig. 1). The collagen-like regions assemble into helical conformations. Six of these structural triple helix units form, because of non-covalent
C1q production
In contrast to most other complement factors, C1q is not produced by hepatocytes but mainly by macrophages and immature dendritic cells (Castellano et al., 2004a, Castellano et al., 2010). Following their maturation, dendritic cells completely shut down C1q production (Castellano et al., 2004a, Castellano et al., 2010) suggesting a role for C1q in adaptive immune responses (Castellano et al., 2004b, van Kooten et al., 2008). Indeed, a role for C1q in adaptive immunity can also be concluded from
C1q traditional and non-traditional roles
The traditional view on the role of C1q is restricted to the activation of the classical pathway following its binding to ligand-bound IgM or multimeric IgG (Daha et al., 2011). The list of ligands for C1q has grown considerably, now also including DNA (Van Schravendijk and Dwek, 1982), CRP (Jiang et al., 1991) and matrix molecules such as Decorin (Groeneveld et al., 2005, Krumdieck et al., 1992, Sjoberg et al., 2005).
Genetic deficiency of C1q is strongly associated with development of Systemic
C1q binding to immunoglobulins: monomeric versus hexameric
C1-driven complement activation can be triggered via the binding of C1q to the Fc-region of IgM or IgG and activation of C1r-C1s tetramer (review Gal et al., 2009). For IgM, the most efficient activation is associated with the hexameric form, representing a minor fraction of total IgM (5% of total IgM) (Randall et al., 1990). Hexameric IgM (IgMh) differs from pentameric IgM (IgMp) in the absence of J-chain, which is an evolutionary conserved peptide that covalently links pentameric IgM and
C1q and pathological immunecomplexes
The new understanding that IgG antibodies form hexamers on the cell surface following antigen binding which is critical for optimal C1q binding, complement activation and complement-mediated damage or killing (Diebolder et al., 2014) might also give insight into the pathological impact of ICs. Papp et al. demonstrated that the potential pathological impact of ICs is also dependent on the IC signature, the antibody classes and subclasses and the antigen to which the ICs are directed to (Papp et
C1q and IC processing
Complement is an important system in the processing of ICs by prevention of IC precipitation (PIP) and by solubilizing already existing ICs (SOL) (Naama et al., 1985). PIP is primarily mediated by activation of the classical complement pathway (Schifferli et al., 1982), being initiated by binding of C1q. Subsequently, classical pathway activation may lead to the covalent binding of C4b and C3b to the ICs (Naama et al., 1984). This incorporation interferes with Fc-mediated interactions of
Anti-C1q autoantibodies
For a wide variety of complement proteins autoantibodies have been described that target these proteins (Trouw et al., 2001). Binding of autoantibodies to complement fragments can have major functional consequences and lead to tissue injury, especially in the kidney (Dragon-Durey et al., 2013). Already in the early eighties of the previous century it was noticed that in the C1q-based assays that were used to detect circulating ICs, also monomeric IgG molecules, via their Fab domains, were
Anti-C1q methods of detection
Several assays have been developed for the detection of anti-C1q autoantibodies (Mahler et al., 2013). Initially assays were employed that used a direct coating of intact C1q. In order to differentiate between the binding of ICs and binding of anti-C1q autoantibodies the samples had to be incubated in a buffer containing 1 M NaCl (Kohro-Kawata et al., 2002). C1q does not bind ICs in this condition whereas the higher affinity of anti-C1q autoantibodies still allows interaction with C1q. Most of
Anti-C1q and clinical consequences
The initial observations of anti-C1q autoantibodies and the first clinical associations between the presence of anti-C1q and clinical presentation were made in SLE patients (Siegert et al., 1991). As reviewed in more detail elsewhere, over the years especially the association between anti-C1q antibodies and renal involvement in SLE has received much attention (Mahler et al., 2013, Orbai et al., 2015, Seelen et al., 2003). The sudden involvement of renal inflammation in the complex disease SLE
Future implications
Now that we have a much better understanding of the molecular basis of the interaction of C1q with immunoglobulins we can use this knowledge to optimize therapeutic strategies. Not only can we modify currently used biologicals to enhance their interaction with C1q and subsequent complement activation, but we can also start to interfere in the complement-mediated damage inflicted by the deposition of autoantibodies in tissues as well as the pathological function of anti-C1q autoantibodies.
Conclusions
Clearly the interaction of C1q with ICs plays an important role in the immune defence against infections but may also contribute to tissue damage when self-tissue is targeted. A process further complicated by the action of anti-C1q autoantibodies. Over the years Prof. Dr. M.R. Daha and his team have unravelled many of the biological functions of C1q as well as anti-C1q antibodies. These studies include the full spectrum from epidemiological studies in rheumatic and renal diseases, to
Acknowledgements
We would like to thank Joost P.M. Melis and Kristin Strumane, both from Genmab and Paul W.H.I. Parren (Genmab and Leiden University Medical Centre) for critically reading the manuscript and artistic input on the figures.
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