Biomedical subjects
Gerald Weissmann
Publications and source records attributed to Gerald Weissmann.
Cortisone and the burning cross. The story of Percy Julian.
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Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis.
Rheumatoid arthritis (RA) and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings. One oral pathogen strongly implicated in the pathogenesis of periodontal disease, Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. We suggest that individuals predisposed to periodontal infection are exposed to antigens generated by PAD, with de-iminated fibrin as a likely candidate, which become systemic immunogens and lead to intraarticular inflammation. PAD engendered antigens lead to production of rheumatoid factor-containing immune complexes and provoke local inflammation, both in gingiva and synovium via Fc and C5a receptors.
Pathogenesis of rheumatoid arthritis.
Although widely diverse mechanisms have been held responsible for tissue damage in rheumatoid arthritis (RA), it is likely that immune complexes are the underlying cause. Self-aggregating complexes of 7s rheumatoid factors in synovial fluid are a distinguishing feature of RA, whilst circulating complexes of 19s rheumatoid factor directed against the hinge region of 7s immunoglobulins are perhaps less specific. Other autoimmune complexes, such as those containing antibodies directed against citrullinated peptides, have been identified and may be more specific for RA, although the antigens against which these antibodies are directed have not been fully characterized. Together with phagocytic cells such as neutrophils, immune complexes are critical to the pathogenesis of RA; their effects are mediated by a complex cascade involving complement activation and stimulation of phagocytes via C5a and Fc receptors. These mechanisms result in a release of mediators of inflammation and joint destruction: cytokines, metalloproteinases, and reactive oxygen intermediates. This article will review recent, and some not too recent, progress made towards working out the pathogenesis of RA.
Lewis Thomas (1913-1993). The element of style.
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Non-prostaglandin effects of aspirin III and salicylate: inhibition of integrin-dependent human neutrophil aggregation and inflammation in COX 2- and NF kappa B (P105)-knockout mice.
Two, non-prostaglandin effects of antiinflammatory levels of salicylates (i.e. aspirin III) are shown here: 1) Exposure of neutrophils to aspirin or sodium salicylate inhibited Erk activity and integrin-dependent aggregation of neutrophils, consistent with antiinflammation but not COX inhibition. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and neutrophil aggregation by FMLP and arachidonic acid. Thus, the antiinflammatory effects of salicylates may be mediated by inhibition of Erk signaling required for integrin-mediated responses. 2) Acute inflammation was induced in murine air-pouches of wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50 of NF kappa B. The antiinflammatory effects of aspirin and sodium salicylate were independent of the presence of COX-2 or p105 component of NF kappa B or the levels of prostaglandins at the inflammatory site. In contrast, glucocorticoid action depended on the p105.