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Rheumatoid Arthritis and Periodontal Inflammatory Disease (RAPID)

Final Report Summary - RAPID (Rheumatoid Arthritis and Periodontal Inflammatory Disease (RAPID))

The RAPID ITN project (290246) is an Initial Training Network training of spread across 14 Partners in 7 countries, under the coordination of the University of Birmingham, UK.
The key research goal of RAPID is to improve the understanding of the pathogenesis of rheumatoid arthritis (RA) and periodontitis (PD) and their inter-relationships. Our vision is that enhanced biological understanding in this area will generation new avenues to the development of new approaches to disease prevention, early diagnosis and novel therapies. RAPID aims to establish a first class, dynamic training programme for early career researchers who will be able to advance both fields by working across sectors and disciplines.
The research undertaken in RAPID aims to: examine the susceptibility factors and immune responses in both RA and PD to identify pathways common to both diseases; identify potential biomarkers; and identify potential mechanisms of the breakdown of self-tolerance.
The fellows working on the project have concentrated their research on the following areas:
> Randomised controlled clinical feasibility trial on the effect of periodontal therapy on rheumatologic parameters in patient with rheumatoid arthritis and chronic periodontitis (UOB)
> Biomarker studies in cohorts of patients with RA, with and without Periodontitis (KI)
> Study on Porphyromonas gingivalis, a major virulence factor of human chronic periodontitis. (UJ)
> LS visited the lab seminar series at the DRFZ and could improve her lab skills in the microbiology area. (Charite)
> Dentition status and the risk of chronic diseases: the role of inflammation, autoimmunity and oral microbiota (DIFE).
> Molecular structure-function analysis of proteins of biomedical relevance (CSIC)
> Effect of PAD4 in periodontitis, autoimmunity and inflammation (GLAS)
> PAD effects on T cell function and during inflammation (ASTON)
> Systems biology analysis of the relation RA, PD. (AX)
> Developing a high-throughput assay for neutrophil extracellular traps analysis (IMAGEN)
> Analysis of epidemiological data of the Study of Health in Pomerania (prediction model for periodontitis, vitamin D as a risk factor for periodontitis, interaction and mediation between periodontitis and diabetes regarding mortality) (EMAUG)
> Structure determination of PPAD, and measurements of immune response to P. gingivalis (UOXF)
> the role of carbamylation of peptides and proteins as immunomodulatory factor, and the immunogenic potential of the carbamylation (UiB).

Research highlights during the project include:
> Recruitment of patients with both RA and moderate to severe peeriodontitis into a clinical trial is feasible. Retention and delivery of periodontal intervention and follow-up is challenging, with significant drop-out and volatility of disease activity casting doubt on the feasibility of a pivotal RCT. Data also suggest that longer-term RCT using harder endpoints may not be feasible due to ethical and logistic considerations. (UOB)
> The demonstration that antibodies to P. gingivalis associate with RA, specifically ACPA+ RA, and that there is a biological interaction between these antibodies and RA risk factors (smoking and HLA-SE). Moreover, that the antibodies appear before RA diagnosis (KI).
> We have shown that P. gingivalis produces virulence factors, especially peptidyl arginine deiminasea, an enzyme unique for prokaryotes , which may constitute a mechanistic link explaining correlation between periodontitis and rheumatoid arthritis. In addition we revealed potentially pathogenic consequences of ctitrullination of cathelicidine LL-37. Finally, we tested human PAD inhibitors for ability to block neutrophil extracellular nets (NETs) formation. (UJ)
> LS presented her work in the DRFZ lab seminar series in an oral presentation entitled “The impact of Porphyromonas gingivalis on angiogenesis in Rheumatoid Arthritis” on Tuesday, 28 April 2015. (Charite)
> There is a link between the number of teeth and myocardial infarction and to a less extent, stroke. The diversity of saliva bacteria community may explain the relation and we could show that Porphyromonas gingivalis is an important bacterial candidate for tooth loss. In this context, low grade inflammation and anti-citrulline immunity might provide the background for the action of this bacterium (DIFE).
> Citrullation of peripheral blood mononuclear cells (PBMC) by peptidyl arginine deiminase (PAD) impairs T cell activation; PAD treatment of PBMC downregulates of hexokinase 3 (HK3) and upregulates of argininosuccinate synthase 1 (ASS1); Lower HK3 expression decreases energy availability for cell proliferation and an increase in ASS1 decreases pyrimidine synthesis and cell proliferation; CD8+ but not CD4+ T cells from people with PID displayed a phenotype that typical of citrullinated cells (ASTON)
> Two main highlights were the structure analysis of P. gingivalis PPAD and E. coli α2-macroglobulin (CSIC)
> PAD4 was redundant in animal models of experimental periodontitis, innate inflammation and early arthritis. However, PAD4 appeared to be required for normal functioning of the antigen specific T cell response, and this role differed between males and females pointing to PAD4 exhibiting sex dependent differential behaviour (GLAS).
> Systems biology analysis of RA/PD relation identified 33 PD related proteins as possible cross-talks between the pathologies, almost all of them related with inflammation and innate immune system. In case of PD/RA comorbidity a prominent role for VEGFA is seen compared to RA alone, link to the activation of LPS signalling (bacterial detection, innate immunity) due to PD. (AX)
> Development and optimization of a high-throughput assay for NETs analysis; High-throughput screening of modulatory compound library on neutrophils; Identification of modulatory molecules for NET release. (IMAGEN).
> The prediction model may serve as basis for publicly available periodontitis risk estimation. However, the results concerning the effect of vitamin D on periodontitis as well as the interaction of periodontitis with diabetes on mortality were ambiguous (EMAUG).
> A manuscript on vitamin E and periodontitis in NHANES has been published in the Journal of Nutrition, and a manuscript on vitamin B12 and periodontitis in SHIP cohort is being submitted for publication (URV).
> The crystal structure of a highly active form of PPAD was solved and the specificity of PPAD for C-terminal arginine residues shown; mass spectrometry mapped citrullinated sites in gingival crevicular fluid (GCF) and identified one novel citrullinated peptide CK13 (444TSNASGR-cit-TSDV-cit-RP458), which gave elevated antibody responses in RA patients. (UOXF)
> Carbamylation of the IgG1 take place on Fc fragment of the protein and severely impact classical activation pathway of complement; Carbamylation is immunogenic and may serve as a diagnostic biomarker and disease progression marker in primary Sjögren syndrome; LL-37 the most important human cationic bactericidal peptide undergoes rapid carbamylation that severly impacts its immunomodulatory and bactericidal properties; Carbamylation of the fibrinogen takes polavce inuremic patients and impacts blood cogulation process (UiB).

So far this work has produced 87 peer-reviewed publications, as well as RAPID Fellows having presented their work at 96 conferences, workshops, and invited talks.
RAPID has also been involved in the organisation of three workshops to date, two held in Madrid and one in Potsdam. The first two were held in Madrid between (6th to 10th May 2013; and 26rh to 31st of May 2014; focused on Macromolecular crystallography. In both cases, the financial assistance by RAPID was acknowledged (see links above). The second workshop held in Potsdam, between (12th to 23rd August 2013), was the International Summer School in Nutritional Epidemiology. These were open to all RAPID Fellows that wished to attend.
RAPID has held two network meetings in the last reporting period: Between 27th to 29th May 2015, the network meeting in Kos included presentations by all fellows on their research projects as well as presentations by investigators and network wide discussions on the current status of the field and future directions. Associated Partner Oral Health Innovations Ltd. delivered a workshop on entrepreneurship, which discussed the opportunities and challenges of founding a start-up in the life sciences sector.
Between 23rd and 25th October 2014, a workshop in Munich was organised by Associated Partner 4SC and covered commercialisation of research including IP protection as well as career opportunities in biotech. The Munich meeting also included a grant writing workshop for the RAPID Fellows.
The project website can be found at: