Susceptibility genes (HLA, other)

Failure of tolerance, unregulated lymphocyte activation

T and B cell responses to self antigens (including antigens in joint tissues)

Fibroblasts Chondrocytes Synovial cells

Release of collagenase, stromelysin, elastase, PGE₂, and other enzymes

Pannus formation; destruction of bone, cartilage; fibrosis; ankylosis

Environmental factors (e.g., infection, smoking)

Enzymatic modification (e.g., citrullination) of self protein

asca