Aggrecan in cartilage forms aggregates with hyaluronan and link protein, embedded in a collagen network. It accounts for the compressive stiffness and resilience of the hyaline cartilage. Many forms of inflammatory arthritis were shown to be accompanied with aggrecan degradation and loss from the cartilage. The loss of this major component of cartilage renders the tissue more vulnerable when exposed to abrasive forces. Therefore, aggrecan degradation may significantly contribute to cartilage destruction in arthritis. Furthermore, fragments of degraded aggrecan are released during joint inflammation. Thus, molecules of an avascular, immune-privileged tissue (hyaline cartilage) may become accessible to the cells of the immune system. Similarly, there is a "leakage" of aggrecan fragments from cartilage during aging and after joint injury, which may also lead to autosensibilisation. Autoimmune reactivity to aggrecan can be detected in human joint diseases, as well as in animal models of arthritis. The epitopes involved in these processes are currently being identified. Recent data from work with mice suggest a strong immune response focused to the N-terminal G1 domain of aggrecan that leads to arthritis and spondylitis.