Project 442728

Rheumatoid arthritis is often diagnosed at late stage resulting in greater damage than if the diagnosis was made earlier. It commonly involves a dysregulation of disease-fighting defence proteins alongside an amplification of inflammation. We discovered that when the proinflammatory IFNgamma is cut by a macrophage protease its activity is dampened leading to a more effective resolution of inflammation. We are only just starting to learn about disease/defense-modifying effects and mechanisms caused by these cuts. These crucial discoveries were made possible by our mass spectrometry technique known as N-terminomics, which is a method that uniquely identifies the cut ends of proteins by selectively purifying them from the rest of the proteins. As some cuts are formed only during active disease, these segments can become valuable disease indicators to develop new clinical diagnostics and to dissect the biological mechanisms. Through identifying cut protein ends in rheumatoid arthritis, we will reveal damaging and protecting proteases that can be targeted or avoided to improve our understanding of inflammatory exacerbation. As IFNgamma and other defense proteins can be alike in many autoimmune joint diseases, our results may be broadly applicable. We aim to develop methods to detect inflammatory joint diseases earlier to allow more effective disease management to reduce long-term disability.