Understanding immune reactions that cause arthritis, a key element in development of new therapies

Purpose and goal

Although major progress has been made in RA research, there is still not a cure for this debilitating chronic syndrome. It is becoming ever more apparent that RA represents a collection of distinct disease subsets, with different, in addition to shared, risk factors and pathogenic pathways. The patient group with antibodies to citrullinated alpha-enolase (anti-CEP-1) is emerging as one such major subset. In order to identify individuals at risk of developing disease; engineer efficient individual treatments; target drugs to the right patients at the right time; and ultimately, permanently change the chronic destructive behaviour of the immune system in RA, we need to understand the specificity and pathogenic mechanisms of the underlying autoimmune reactions. Hence, the ambition of the project is to provide a new basis for antigen-specific diagnostics and therapeutics in RA, using citrullinated alpha-enolase as the prime prototype.

Expected results and effects

We expect that results from the planned project will lead to major down-stream efforts from other scientists and diagnostic and pharmaceutical companies, in developing diagnostic tests and therapies that specifically target immune functions that are dependent on autoimmunity to antigens such as citrullinated alpha-enolase.

Planned approach and implementation

Studies into aetiology and pathogenesis of autoimmunity in RA, with citrullinated alpha-enoalse as a prototype, will be done at KIR and KI, using complementary methods/approaches. (i) Identification/detection of antigens (IHC, 2DE, immunoblot, IP); (ii) development of human monoclonal antibodies with various ACPA fine-specificities (in collaboration with scientists in Berlin); (iii) evaluation of new antigens/characterisation of new RA subsets (using large patient cohorts of well-characterised RA cases/controls); (iv) development of a commercial anti-CEP-1 assay, and a multiplex assay detecting several ACPAs, for diagnostic/prognostic clinical/scientific use (in collaboration with industry); (v) development of antigen-specific therapies (will be initiated using animal models on regulation and pathogenicity of anti-citrullinated alpha-enolase immunity).