Rheumatoid arthritis. The role of neutrophil activation.
Neutrophils constitute over 90% of cells found in the synovial fluid of rheumatoid arthritis (RA) patients. Since such fluids also contain immune complexes (IgG-IgG and IgG-IgM rheumatoid factors) and complement split products (C5, C5A, DES, ARG, C3B, etc.), all of the reactants are present for a local Arthus lesion. Moreover, neutrophils from RA patients endocytose these immune complexes and complement components in vivo and in vitro. In consequence, it has been suggested that lysosomal enzymes and other mediators of inflammation released by neutrophils after uptake of immune complexes (in the bulk phase or on the surface) account, at least in part, for rheumatoid inflammation. Secretion of lysosomal hydrolases, especially neutral proteases, which provoke tissue injury and generation of reactive oxygen species (e.g. O2) is part of a stimulus-secretion response to a variety of secretagogues, including immune complexes and complement components. However, the pathways of secretion and O2 generation are stimulus-specific and can be dissected to establish cause and effect relationships by (a) kinetic analysis, (b) varying the stimulus, (c) use of impermeant reagents to block discrete responses. Neutrophils also generate products of 11-cyclo-oxygenase (e.g., PGE2, TXA2) and of the 5- and 15-lipoxygenase (mono-, di and tri-hetes, LTB4 and their isomers). However, the cyclo-oxygenase products (except TXA2) do not cause inflammation acting alone; indeed, they inhibit the function of neutrophils, platelets, macrophages and mast cells. The most potent proinflammatory agent yet identified as a product of arachidonate is LTB4. LTB4 is a potent Ca ionophore, a strong chemo-attractant, induces local inflammation, and activates neutrophils.
D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002449:Cell Aggregation; D006801:Humans; D008564:Membrane Potentials; D009504:Neutrophils / Q000502:physiology*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D009712:Nucleotides, Cyclic; D010743:Phospholipids; D011506:Proteins; D013481:Superoxides; D002118:Calcium