Why do leucocytes accumulate within chronically inflamed joints?

Chronic inflammation is characterized by the accumulation of leucocytes within tissues. In rheumatoid arthritis the inflammatory infiltrate shares many architectural features with lymphoid tissue. For example, CD4 T cells and B cells accumulate in perivascular lymphoid structures within synovial tissue. CD8 T cells and neutrophils are found predominantly within synovial fluid. What drives these distinctive lymphoid microstructures and the relative contribution of lymphocytes and stromal cells such as fibroblasts to this process is the subject of this review. Cellular interactions between leucocytes and stromal cells such as macrophages and fibroblasts are important in generating tumour necrosis factor-alpha within the inflamed synovium. Therefore understanding how leucocytes accumulate within the inflamed synovium is likely to provide new therapeutic approaches to modify the inflammatory process. We have found that fibroblasts play a dominant role in defining the disordered synovial microenvironment in rheumatoid arthritis. Through their production of a variety of cytokines (interferon-beta, transforming growth factor-beta) and constitutive chemokines (stromal cell-derived factor-1, CXCL12) they directly alter the behaviour of lymphocytes that accumulate within chronically inflamed joints leading to their inappropriate survival and retention. We have extended these observations to another chronic persistent rheumatic disease, Sjögren's syndrome, and found that ectopic production of the constitutive B cell-attracting chemokine BCA-1 (CXCL13) is associated with lymphocyte accumulation and lymphoid tissue formation. These findings suggest that stromal cells such as fibroblasts play an important role in the switch from acute resolving to chronic persistent arthritis by allowing lymphocytes to accumulate in the wrong place at the wrong time.