The initiating event in cell activation is unknown in most autoimmune diseases. The role of infection is clear in some cases, especially in reactive arthritis; however, there is little evidence of a specific organism in other spondyloarthropathies. Common pathways of cell-cell interaction and activation manifest in inflammation, but subtle differences may exist. The presence of T cells, macrophages, and B-lymphocytes suggest an autoimmune mechanism; the arthritogenic peptide theory has been proposed. Furthermore, the association of spondyloarthropathies with HLA-B27 suggests it may be important in synovial T-cell activation. Other cell types involved in the process of bone and cartilage destruction, including fibroblasts and osteoclasts, may also be activated. Endothelial activation and angiogenesis may be a critical primary event in these diseases. Finally, trauma (physical or psychological) in the form of stress may be an important factor; the nervous system and neuropeptides may play a role in cell activation and initiation of arthritis.