Research Update

Arthritis Queensland cares for Queenslanders living with arthritis by supporting research. In 1992, we provided the seed funding for the AQ Chair of Rheumatology at the Diamantina Institute (D.I.). This funding has continued each year since.

By Professor Ranjeny Thomas
Arthritis Qld Chair of Rheumatology
The University of Queensland Diamantina Institute
Faculty of Medicine and Biomedical Sciences.
Edited by: Fiona McMilla
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My team and I are developing and commercialising antigen-specific immunotherapy for rheumatoid arthritis using a cutting-edge nanoparticle platform technology. Over the past 2 years I have been leading a scientific team based at the Translational Research Institute (TRI) which interacts closely with a team at Janssen Biotech Inc. (USA) to undertake the pre-clinical development of this technology so that it can be tested in early-phase clinical trials in RA patients.

The majority of RA patients are ‘ACPA positive’, meaning they have an immune reaction to protein fragments called ‘citrullinated peptides’. These peptides are normally present in the body and increase in times of biological stress, including inflammation. Genetic variations associated with RA risk introduce minor changes in a protein called HLA-DRβ1, which helps the immune system distinguish between ‘self’ and ‘foreign’. It was thought these genetic variations must influence the way the HLA-DRβ1 protein presents citrullinated peptides to the body’s immune system, thus causing the immune system to mistake these self peptides as dangerous.

To find out if this was really the case, my team and I collaborated with colleagues at Monash University to solve the structures of two different forms of the protein: the citrullinated form and the ‘healthy’ form. As expected, RA-associated HLA-DRβ1 variants hold onto citrullinated but not non-citrullinated peptides. Contrary to previous theory though, HLA-DRβ1 variants associated with resistance to RA hold onto citrullinated peptides in the same way. The main difference was that resistant DRβ1 variants also hold on to normal non-citrullinated peptides.

This research found that the important difference in the susceptibility and resistance HLA- DRβ1 variants lies in how they deal with non-citrullinated peptides. So, for people who are prone to ACPA positive RA, their form of the HLA-DRβ1 protein is picky. It doesn’t like the non-citrullinated form of the peptides. Instead it only holds citrullinated peptides. This means it’s always presenting a citrullinated peptide to the immune system, including during development and during infection. When this happens during the development, the immune system’s development of response mechanisms becomes limited to citrullinated and not to normal peptides. When this happens during infection, it can increase the chance of mistakes occurring, causing strong reactions to the body’s proteins when they should have been limited to an infection.

Such a mistaken immune reaction should be kept in check by a special group of cells that teaches immune tolerance toward self peptides, including citrullinated peptides. Yet in RA this response is deficient. We went on to show that this crucial population of “regulatory cells” responding towards citrullinated peptides is smaller in ACPA-positive RA patients than in healthy people — there simply aren’t enough of them to quell an anti-self immune reaction. After disease development, inflammation increases, even more citrullinated peptides are produced, and the immune cells which respond to citrullinated peptides expand.

As a result of this research, we have shown how the genetic susceptibility to RA intersects with the immune response to citrullinated peptides, and that the immune cell repertoire develops differently in people prone to RA. This greatly improves our understanding of how RA develops. The findings also highlight the importance of the therapeutic strategy we are developing, designed to turn off the unwanted immune reaction in patients with high-risk RA genes. It works in part by giving the “tolerance teaching” regulatory cells a much needed boost. We are hoping to commence clinical trials in 2016.