Proteoglycan Aggrecan Conducting T Cell Activation and Apoptosis in a Murine Model of Rheumatoid Arthritis

Figure 2

Potential role of the P135 epitope found in the G3 domain of PG aggrecan in the development of arthritis. Importantly, this epitope shares a significant sequence homology with the HLA-DRB1 “shared epitope” sequence (QKRSS in p135 versus QKRAA in HLA). Age-related release of the G3 domain of PG aggrecan could lead to the activation and differentiation of autoreactive T cells. T cell tolerance could be broken by several factors including neoepitope formation (e.g., citrullination) or molecular mimicry mechanisms (for more details see Section 6). Activated P135-specific T cells could “home” into the joints, where further activation would lead to cytokine release and the activation of B cells and macrophages. The initiation of the joint inflammation could perpetuate PG aggrecan degradation; the proteolysis and increased citrullination could pave the way for “epitope spreading.” The involvement of the G1 domain contributes to the activation of even more autoreactive T cells taking the autoimmune attack of the joints into a final irreversible stage.