EU-funded researchers in the UK have found that the joint damage caused by rheumatoid arthritis may be partly due to antibodies produced within joints themselves. Their findings shed light on why drugs that clear antibody-producing B cells from the bloodstream do not always lead to improvements in rheumatoid arthritis, and point to an enzyme called 'activation-induced cytidine deaminase' (AID) as a potential target for the development of drugs to treat this debilitating disease.
The findings, which are published in the journal PLoS Medicine, are an outcome of INNOCHEM ('Innovative chemokine-based therapeutic strategies for autoimmunity and chronic inflammation'), a five-year project funded with nearly EUR 12 million by the EU's Sixth Framework Programme (FP6) under the 'Life sciences, genomics and biotechnology for health' Thematic area. INNOCHEM focuses on the development of therapeutic strategies for autoimmunity and chronic inflammation.
Rheumatoid arthritis (RA), an autoimmune condition that damages the joints, affects around 1% of the population. It affects women three times more than men and can develop at any age (although cases are rare under the age of 15). In patients with RA, the immune system starts to attack tissues lining the joints (synovium) for reasons that are largely unknown. The synovium becomes chronically inflamed, and the body releases chemicals that damage all the tissues in the joint. Eventually, the joint can become so damaged that it can no longer move. There is no cure for RA, but recently developed therapies can slow down its progression by blocking chemicals believed to cause joint damage.
Researchers from the London School of Medicine and King's College London in the UK collected synovial tissue from 55 patients with rheumatoid arthritis. They then analysed the samples, investigating tiny structures in the joint lining that mimic the key functions of lymph nodes that produce antibodies; specifically, these structures support the production of the antibodies that may play a central role in the destruction of the joint.
They focused on the fact that people with RA often produce autoantibodies called anti-citrullinated protein/peptide antibodies (ACPAs). According to the study, "The elucidation of the mechanisms coupling chronic inflammation and the production of disease-specific autoantibodies within RA synovium is of pivotal importance because ACPA are highly disease specific markers of RA, are strongly associated with a more destructive arthritis and are independent predictors of a poorer prognosis."
Using a range of techniques, they investigated whether the lymph structures that contained follicular dendritic cells (FDC), produced the AID enzyme, which is pivotal in two important immune responses. They found that all of the FDC-containing structures did produce AID, and that these AID-containing structures were surrounded by B cells that produce ACPAs.
The researchers then transplanted synovium from RA patients under the skin of mice that lack an immune system in order to determine whether the cells were coming from the joints themselves or from elsewhere in the body. Four weeks later, they found that the transplanted tissue was still producing AID and the level of expression correlated with human ACPA levels in the blood of the mice. Also, the B cells in the transplant were still being produced.
According to an accompanying editorial, the findings show that "the ectopic lymphoid structures present in the synovium of some patients with rheumatoid arthritis are functional and are able to make ACPA. Because ACPA may be responsible for joint damage, the survival of these structures could, therefore, be involved in the development and progression of rheumatoid arthritis."
Although more experiments are needed to confirm the present findings, the authors conclude: "These data elucidate the mechanism of production of ACPA in the synovial membrane and thereby provide evidence of a pivotal role for AID in the pathogenesis of RA. We therefore propose that AID may be targeted for the development of novel therapeutic agents."
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