CHRONIC INFLAMMATION AND IMMUNOMODULATION OF CONNECTIVE TISSUE METABOLISM

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Mononuclear cell recruitment and activation are central to the initiation, augmentation and perpetuation of chronic inflammatory lesions. Investigations in this laboratory continue to examine mechanisms of monocyte directed migration (chemotaxis) toward inflammatory stimuli. In order to study simultaneous cell surface chemotactic receptor expression on individual cells, two different color fluorescent chemotactic ligand probes, FITC-C5a and TR-FMLP, were developed and characterized. The majority of peripheral blood monocytes were found to co-express C5a and FMLP chemotactic receptor as determined by flow microflorometry. In contrast, monocytes obtained from chronically inflamed synovium of rheumatoid arthritis patients did not migrate to C5a nor did they express C5a receptors, whereas FMLP receptors and chemotaxis to FMLP were normal. This differential regulation of chemotactic ligand receptor expression and function also occurs following in vitro monocyte activation and may provide insight into mechanisms of chemotaxis abnormalities in certain diseases. Not only are synovial inflammatory cells abnormal in their response to chemotactic stimuli, but recent studies also demonstrate abnormal production of a chemoattractant by synovial inflammatory T lymphocytes. Synovia from anergic arthritis patients which have a heavy mononuclear cell infiltrate produce excess amounts of lymphocyte derived chemotractic factor (LDCF), whereas synovia from nonanergic patients which are relatively hypocellular do not produce LDCF. Thus, the production of LDCF by anergic synovia may provide a critical stimulus in the continual monocnuclear cell infiltrate seen in these patients. Once mononuclear cells are recruited to the inflammed synovium they generate other cytokines which enhance and perpetuate the inflammatory lesion. One of these cytokiens, fibroblast activating factor (FAF), stiulates synovial fibroplasia leading to excessive collagenese and prostaglandin synthesis involved in joint destruction. Because of its potential key involvement in the pathogenesis of rheumatoid synovial lesions, efforts are being directed at characterizing and cloning FAF.