Venables Group | Citrullination in Inflammation
Our main focus is to discover the causes of Rheumatoid Arthritis and contribute to the strategies for prevention and cure of this condition.
Professor Venables's interest in citrullination - the conversion of the aminoacid arginine to citrulline, in proteins - started with the discovery of antibodies to citrullinated protein/peptide antigens as diagnostic markers in rheumatoid arthritis (RA), an autoimmune disease.
These autoantibodies are measured by generic tests such as anti-cyclic citrulinated peptides (CCP) assays. Although excellent tests for clinical diagnosis, these tests do not discriminate between the specific in-vivo proteins that actually drive the autoimmune response leading to the peculiarly destructive joint disease that characterises RA.
More than 20 potential citrullinated autoantigens have been described in RA, though only four, citrullinated fibrinogen, vimentin, collagen and a-enolase, have been thoroughly characterised, epitope-mapped and animal models established.
Citrullinated a-enolase was discovered by the Venables group over 10 years ago and having shown that it was a true autoantigen in approximately 50% of RA patients, we then went on to map its immunodominant epitope(s) to a peptide designated citrullinated enolase peptide-1 (CEP-1). Anti-CEP-1 is linked to the subset of RA in which smoking and shared epitope are major interacting gene/environment risk factors. Antibodies to the CEP-1 peptide have also been linked to Porphyromonas gingivalis infection, and we have shown that immunising DR4 transgenic mice with P. gingivalis enolase induces an erosive arthritis and autoantibodies to mammalian enolase. All of these developments show that defining an autoantibody to a specific antigen in RA supports the gene/environment/autoimmunity paradigm and provides indications of the upstream events in pathogenesis. Thus the approach of defining specific autoantigens begins to indicate the cause of the disease and hence strategies for prevention and cure.
Given that defining citrullinated a-enolase as an autoantigen has been a successful tool for investigating the causes of a subset of RA, our current research programme is focussed on the following:
- Characterisation of the unique bacterial citrullinating enzyme encoded by P. gingivalis (PPAD) as a bacterial protein with the capability of inducing the autoantigens that drive autoimmunity in RA;
- Discovery of more citrullinated autoantigens (beyond the 4 already described) with the aim of developing assays for further immunogenetic and clinical subsets of RA;
- Development of peptidyl arginine deiminase inhibitors for preventing the generation of the autoantigens that drive autoimmunity in RA;
- Investigation of the pro-inflammatory effects of citrullinated proteins and their potential pathogenic effects in chronic inflammation and cancer.