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Defect in A20 gene expression can contribute to onset of rheumatoid arthritis

Date:
August 16, 2011
Source:
VIB (the Flanders Institute for Biotechnology)
Summary:
Researchers in Belgium have shown that a defective gene can contribute to the onset of rheumatoid arthritis, an often-crippling inflammation of the joints that afflicts about one percent of the world's population.

Researchers from VIB (Flanders Institute for Biotechnology) and Ghent University have shown that a defective gene can contribute to the onset of rheumatoid arthritis, an often-crippling inflammation of the joints that afflicts about 1% of the world's population. Until now, the underlying molecular mechanism of the disease was largely unclear.

In the study, published in Nature Genetics, the researchers demonstrate that a cell-specific defect in the expression of the A20 gene (TNFAIP3) can contribute to the development of rheumatoid arthritis in mice, thereby identifying A20 as a possible target for the generation of new drugs.

Rheumatoid arthritis (RA)

RA is a chronic progressive joint disease that starts with the inflammation of the synovial membrane and soft tissues around the joints, but often spreads to cartilage and bones. The disease is very painful for the patient. Although the cause of rheumatoid arthritis remains unknown, autoimmunity plays a crucial role. Currently, the progression of the disease can be slowed down, but RA cannot be cured.

Protein A20

A20 is an intracellular negative regulator of the NF-kB transcription factor, which plays a key role in the generation of the inflammatory response. Excessive activation of NF-kB can lead to a whole range of inflammatory diseases, including arthritis. The research group of Rudi Beyaert investigates the molecular mechanisms that control NF-kB activation and earlier in vitro research already indicated a key role for A20. Moreover, genome-wide association studies in humans recently suggested that defects in A20 could contribute to several autoimmune diseases, including RA.

Mouse Model for RA

VIB researchers led by Geert van Loo and Rudi Beyaert at Ghent University have developed mice with myeloid cells incapable of producing A20. In collaboration with Dirk Elewaut, rheumatologist at Ghent University Hospital (Ghent University), who co-supervised the research, they found that these mice had elevated 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 dependent on TNF, a cytokine that normally plays an essential role in many inflammatory diseases including RA. On the other hand, they were able to demonstrate a role for IL-6 and Toll-like receptor 4 (TLR4).

Impact

The study confirms the crucial role of A20 in the control of inflammatory responses and shows that a defect in A20 in myeloid cells can give rise to RA that is not responsive to anti-TNF treatment. From a therapeutic perspective, this is a very important finding, since anti-TNF therapy fails in 30% of RA patients. The A20-deficient mice are therefore an interesting new mouse model for the study of new therapeutics for RA.

In collaboration with Bart Lambrecht (Ghent University Hospital, Ghent University), the VIB researchers recently demonstrated that mice lacking A20 in dendritic cells, a specific myeloid cell type, also develop an autoimmune pathology that in this case shows 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).


Story Source:

The above story is based on materials provided by VIB (the Flanders Institute for Biotechnology). Note: Materials may be edited for content and length.


Journal References:

  1. Mourad Matmati, Peggy Jacques, Jonathan Maelfait, Eveline Verheugen, Mirjam Kool, Mozes Sze, Lies Geboes, Els Louagie, Conor Mc Guire, Lars Vereecke, Yuanyuan Chu, Louis Boon, Steven Staelens, Patrick Matthys, Bart N Lambrecht, Marc Schmidt-Supprian, Manolis Pasparakis, Dirk Elewaut, Rudi Beyaert, Geert van Loo. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nature Genetics, 2011; DOI: 10.1038/ng.874
  2. Mirjam Kool, Geert vanLoo, Wim Waelput, Sofie DePrijck, Femke Muskens, Mozes Sze, Jens vanPraet, Filipe Branco-Madeira, Sophie Janssens, Boris Reizis, Dirk Elewaut, Rudi Beyaert, Hamida Hammad, BartN. Lambrecht. The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity. Immunity, 2011; 35 (1): 82 DOI: 10.1016/j.immuni.2011.05.013

Cite This Page:

VIB (the Flanders Institute for Biotechnology). "Defect in A20 gene expression can contribute to onset of rheumatoid arthritis." ScienceDaily. ScienceDaily, 16 August 2011. <www.sciencedaily.com/releases/2011/08/110816111303.htm>.
VIB (the Flanders Institute for Biotechnology). (2011, August 16). Defect in A20 gene expression can contribute to onset of rheumatoid arthritis. ScienceDaily. Retrieved October 22, 2014 from www.sciencedaily.com/releases/2011/08/110816111303.htm
VIB (the Flanders Institute for Biotechnology). "Defect in A20 gene expression can contribute to onset of rheumatoid arthritis." ScienceDaily. www.sciencedaily.com/releases/2011/08/110816111303.htm (accessed October 22, 2014).

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