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PREVENTRA Report Summary

Project ID: 250167
Funded under: FP7-IDEAS-ERC
Country: Sweden

Final Report Summary - PREVENTRA (Genes, environment and immunity in the pathogenesis of rheumatoid arthritis)

Rheumatoid arthritis (RA) has over recent years emerged as a disease where the major and antibody-positive subset offers a prototype for an understanding of the longitudinal development of disease. In preventRA my research team have contributed to this understanding, mainly by defining how gene-environment interactions can trigger RA-associated immunity towards post-translationally modified (mainly citrullinated) autoantigens in the lungs and how this autoimmunity may mature over time before onset of disease. More recently, we have also generated exciting new data on how this immunity may target bones and joints and cause additional RA-associated symptoms such as joint pain.

The original aims of preventRA were (1) To obtain new understanding of how environmental and life style factors interact with genes to induce immune reactions able to cause the different forms of arthritis that are defined as RA; (2) To use this understanding to develop prevention and targeted therapy for different forms of RA, and to enable efficient and eventually curative therapy.

Major achievements in the project have been:

• We have by studying interactions between genes, environment and immune reactions in RA been able to define which immune reactions that are initiated before onset of disease in the lungs, and how such immune reactions can be triggered by different noxious agents to which the lungs are exposed (i.e smoking and textile dust). We have demonstrated the presence of distinct, modified (by citrullination) proteins in lungs of RA patients, and how immune reactions are triggered against these specific autoantigens. The increased understanding of environmental and life style factors that trigger disease in genetically susceptible individuals, has led to a number of prevention programs for RA that are in use worldwide.

• The presence of antibodies binding citrullinated proteins (ACPA) constitutes an important criterium for diagnosing RA today. These antibodies can appear many years prior to disease onset. Hence a certain concentration, fine specificity, or combination of antibodies may be needed to pass the threshold of disease. We have, in this project, been able to demonstrate ACPA-mediated effector functions not previously known.

We have generated large series of human monoclonal antibodies derived from single B cells/plasma cells from joints of RA patients, to be used for a variety of functional studies. For example have we seen that ACPAs can promote osteoclast differentiation and activity, and interestingly, also to provoke pain in an inflammation-independent fashion. Most interestingly, this ACPA-induced osteoclast activation is dependent on specific citrullinating enzymes (PADs) and on production and function of the chemokine IL-8. We have demonstrated that ACPA also can induce joint pain via release of IL-8 from osteoclasts where IL-8 causes pain from binding to specific chemokine receptors of nociceptive nerves. Taken together, we have clarified important molecular mechanisms in early phases of RA, thereby taking an important step towards the final goal of preventing RA.

Overall our project has contributed to a new paradigm for understanding and preventing RA and has laid the ground for clinical trials that on one hand aim at re-regulating the disease-inducing immunity (tolerizing therapies) and on the other hand target novel mechanisms including PAD enzymes and IL-8 dependent mechanisms.

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