Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of the synovial joint. Cartilage autoantigens, such as type II collagen (CII), are believed to contribute to disease pathology. Matrix metalloproteinases (MMP) and cysteine proteases, including the true collagenases MMP 1, 8, 13 and cathepsin K, secreted by activated synovial fibroblasts in response to inflammatory cytokines, lead to cleavage and release of CII from cartilage. The central hypothesis is that collagenase digestion of CII potentiates the ability of MHCII+ dendritic cells (DC) to mediate the further processing and presentation of CII to T cells, enabling an anti-CII adaptive immune response. The proposed experiments will study whether the collagenase digestion of CII results in optimal CII presentation by DC. The completion of these studies will help clarify the pathways of cartilage degradation involving collagenases important in immune response to self-antigens in RA.
Aim 1 : Determine the role of MMP in extracellular CII degradation and augmentation of MHCII mediated presentation of CII epitopes by DC.
Aim 2 : Determine the role of cathepsin K in the processing and presentation of native CII by DC.
| Guo, Zhigang; Chavez, Valerie; Singh, Purnima et al. (2008) Comprehensive mapping of the C-terminus of flap endonuclease-1 reveals distinct interaction sites for five proteins that represent different DNA replication and repair pathways. J Mol Biol 377:679-90 |
