Investigators from VIB (Flanders Institute for Biotechnology) and Ghent University have revealed that a defective gene can contribute to the onset of rheumatoid arthritis, an inflammation of the joints which is often-crippling and affects around 1% of the world’s population. Up till now, the underlying molecular mechanism of the disease was largely unclear. In the Investigation, published in Nature Genetics, the investigators show that a cell-specific defect in the expression of the A20 gene (TNFAIP3) can influence the development of rheumatoid arthritis in mice, thus identifying A20 as a potential target for the generation of new drugs.

Rheumatoid arthritis (RA)

A chronic advancing joint disease that begins with the inflammation of the synovial membrane and soft tissues around the joints, however, it often spreads to cartilage and bones. For the patient RA is extremely painful. Even though the cause remains unknown, autoimmunity plays a key role. Although RA cannot be cured, the progression of the disease can be slowed down.

Protein A20

A20 is an intracellular negative regulator of the NF-kb transcription factor, which plays a crucial role in the generation of the inflammatory response. Excessive activation of NF-kb can cause a wide range of inflammatory diseases, including arthritis. The investigation group of Rudi Beyaert studies the molecular mechanisms that control NF-kb activation and previous in vitro studies already indicated a crucial role for A20. In addition, genome-wide association investigations in humans recently indicated that defects in A20 may contribute to many autoimmune diseases, including RA.

Mouse Model for RA

VIB investigators led by Geert van Loo and Rudi Beyaert at Ghent University have created mice with myeloid cells unable of producing A20. In cooperation with Dirk Elewaut, rheumatologist at Ghent University Hospital (Ghent University), who co-supervised the investigation, they discovered that these mice had raised levels of pro-inflammatory cytokines in their blood and joints, and spontaneously developed RA with severe inflammation and osteoporosis. Interestingly, the arthritis in this mouse model was not reliant on TNF, a cytokine that usually plays a key role in several inflammatory diseases including RA. Conversely, they were able to demonstrate a role for IL-6 and Toll0like receptor 4 (TLR4).

Impact

The investigation confirms the key role of A20 in the control of inflammatory responses and indicates that a defect in A20 in myeloid cells can increase RA that does not respond to anti-TNF treatment. From a therapeutic point of view, this finding is extremely significant, considering anti-TNF therapy fails in 30% of RA patients. Therefore, the A20-deficient mice represent an interesting new mouse model for the investigation of new therapeutics for RA.

The VIB investigators recently demonstrated in collaboration with Bart Lambrecht (Ghent University Hospital, Ghent University), that the mice missing A20 in dendritic cells, (a specific myeloid cell type) also develop an autoimmune pathology that in this case indicates more similarities with systemic lupus erythematosus, which is characterized by acute and chronic inflammation of various tissues of the human body (Kool et al., Immunity 2011)

Written by Grace Rattue