Hamdan Medical Journal (previously the Journal of Medical Sciences)
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Cytokines, Chemokines and Proteinases in Autoimmune Diseases
Chemotactic cytokines or chemokines form a family of pro-inflammatory proteins that are functionally linked to various classes of proteases, including matrix metalloproteinases (MMPs). Both families of molecules are key players in the migration of inflammatory cells in autoimmune diseases. For example, the human chemokine interleukin- 8 acts as a fast secretagogue of gelatinase B in granulocytes and is increased in the synovial fluid of arthritis patients and may locally recruit and activate neutrophils. The latter leukocytes are the most abundant inflammatory cell type in the joints of patients with rheumatoid arthritis. In the inflamed joint, the activity of matrix remodeling enzymes contributes to the breakdown of cartilage constituents. For instance, gelatinase B (MMP-9) was documented to cleave type II collagen in 25 fragments. Several of these fragments contain the intact immunodominant epitopes that were discovered by epitope scanning experiments with lymphocytes from rheumatoid arthritis patients. Gelatinase B thus helps to generate immunodominant peptides that stimulate T lymphocytes and thus maintain the activation of the specific arm of immunity in arthritic diseases. Furthermore, with the use of highly specific monoclonal antibodies, the presence of gelatinase B was detected by immunohistochemistry in the lesions of patients with various autoimmune diseases. Studies in rheumatoid arthritis and multiple sclerosis led us to postulate the “Remnant Epitopes Generate Autoimmunity” or REGA model for autoimmunity. This model is based on the pathophysiological role of three major classes of molecules involved in a specific primary immune defense mechanisms: the cytokines, the chemokines and the proteases.