Our current work into the contribution of complement toward the initiation and the course of autoimmune diseases will be aimed towards understanding the mechanisms how C1q protects against autoimmunity and on how the cell-cell communication is influenced by complement.
The classical pathway on complement is initiated by C1q. Worldwide there are only a few individuals that because of a mutation do not produce C1q. Nearly all of these persons have the severe autoimmune disease Systemic Lupus Erythematosus (SLE). We have established that small genetic variations in the C1q genes do also impact on the development of the autoimmune disease RA (4). In addition we have identified a new case of C1q deficiency and identified the molecular mechanisms behind this deficiency (5).
Complement activation is clearly not only an issue in case of arthritis, but unfortunately contributes to tissue damage in many (auto) immune conditions. From some of these other conditions it became clear that genetic variants of complement inhibitor factor H (CFH) have a major impact on the initiation/severity of the disease. We have studied whether these genetic variants would impact on the development of RA, but found no evidence to support a contribution despite the fact that we analysed this in nearly 20.000 individuals (3).
Studies into the complement activating potential of ACPA (Anti-Citrullinated Protein Antibodies) has revealed that these, RA specific autoantibodies, activate complement strongly, both via the classical pathway but also via the alternative pathway (2).
Our research aims to elucidate the relative importance of complement activation on the process of inflammation and damage to the joint.
The complement system consists of series of proteins present in blood and other body fluids. There are three pathways of complement activations, each triggered by their own activation molecule (1). Complement activation can lead to the death of a cell, for example a bacterium, by inserting pores into its membrane. However, a more important immunological mechanisms is the activation of immune cells that express receptors for activated complement fragments. These activated immune cells are now superior in fighting infections, but again these cells can now also contribute to tissue damage. The disease process of Rheumatoid Arthritis (RA) is characterized by inflammation of the joints. Studies into the mediators involved in this inflammation, both in patients as well as in animal models have indicated that next to a cellular component also a humoral reaction takes place. This humoral immune response involves both binding of autoantibodies and activation of the complement system. Complement is part of the innate immune system and plays an important role in the defence against infections. Unfortunately, complement can also contribute to tissue damage in several diseases.
- Daha,N.A., N.K.Banda, A.Roos, F.J.Beurskens, J.M.Bakker, M.R.Daha, and L.A.Trouw. 2011. Complement activation by (auto-) antibodies. Mol.Immunol. 48:1656-1665.
- Trouw,L.A., E.M.Haisma, E.W.Levarht, W.D.van der, A.Ioan-Facsinay, M.R.Daha, T.W.Huizinga, and R.E.Toes. 2009. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 60:1923-1931.
- Trouw,L.A., S.Bohringer, N.A.Daha, E.A.Stahl, S.Raychaudhuri, F.A.Kurreeman, G.Stoeken-Rijsbergen, J.J.Houwing-Duistermaat, T.W.Huizinga, and R.E.Toes. 2011. The major risk alleles of age-related macular degeneration (AMD) in CFH do not play a major role in rheumatoid arthritis (RA). Clin.Exp.Immunol. 166:333-337.
- Trouw,L.A., N.Daha, F.A.Kurreeman, S.Bohringer, G.N.Goulielmos, H.J.Westra, A.Zhernakova, L.Franke, E.A.Stahl, E.W.Levarht, G.Stoeken-Rijsbergen, W.Verduijn, A.Roos, Y.Li, J.J.Houwing-Duistermaat, T.W.Huizinga, and R.E.Toes. 2013. Genetic variants in the region of the C1q genes are associated with Rheumatoid Arthritis. Clin.Exp.Immunol. 2013 Jul;173(1):76-83
- van Schaarenburg,R.A., N.A.Daha, J.J.Schonkeren, E.W.Nivine Levarht, D.J.van Gijlswijk-Janssen, F.A.Kurreeman, A.Roos, K.C.van, C.A.Koelman, M.R.Ernst-Kruis, R.E.Toes, T.W.Huizinga, A.C.Lankester, and L.A.Trouw. 2014. Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections. Immunobiology. 2014 Oct 18.