Protein Triggering Joint Inflammation in Rheumatoid Arthritis Identified

Autoimmune disease researchers have identified a protein in the joints of patients with rheumatoid arthritis that may be responsible for activating the system of Toll-like receptors that triggers the release of inflammatory agents into the joints. Rheumatoid arthritis is a debilitating and painful disease with no cure.

The protein, tenascin-C is a type of extracellular matrix glycoprotein. The tenascins are abundant in the extracellular matrix of developing vertebrate embryos, and they reappear around healing wounds and in the stroma of some tumors. The object of the current study was to study the interaction between tenascin-C and toll-like receptor 4 (TLR4). TLR4 is a membrane protein that detects lipopolysaccharide on Gram-negative bacteria and is important in the activation of the innate immune system. The toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. Previous studies have shown that an arthritis mouse model lacking TLR4 did not develop chronic joint inflammation.

To study the interaction between tenascin-C and TLR4 investigators at Imperial College London (UK) genetically engineered a line of mice to lack the gene that produces tenascin-C. They reported in the June 28, 2009, online edition of the journal Nature that mice not expressing tenascin-C showed rapid resolution of acute joint inflammation and were protected from erosive arthritis. In contrast, injection of tenascin-C into the joints promoted inflammation.

In another series of experiments, the investigators showed that treatment of human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis with tenascin-C induced synthesis of proinflammatory cytokines via activation of TLR4.

"We have uncovered one way that the immune system may be triggered to attack the joints in patients with rheumatoid arthritis," said first author, Dr Kim Midwood, a lecturer in rheumatology at Imperial College London. "We hope our new findings can be used to develop new therapies that interfere with tenascin-C activation of the immune system and that these will reduce the painful inflammation that is a hallmark of this condition."

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Imperial College London