Danger within : HMGB1 as a mediator of arthritis

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Women's and Children's Health

Sammanfattning: Chronic arthritis occurs in childhood as juvenile idiopathic arthritis and in adults most commonly as rheumatoid arthritis. The clinical expression of these diseases differ and it is presently unknown to what extent they share pathogenic mechanisms. Optimal modes of therapy in adults generally coincide with those in children. Patients with chronic arthritis do not only suffer from fatigue and recurrent joint inflammation but also the risk of irreversible joint destruction, functional disability and even early death. Anti-inflammatory, immunomodulatory compounds and physical therapy provide the best chances of preserving joint function and improving quality of life in these patients. However, many patients do not respond satisfactory to present therapies, indicating a need for further understanding of disease mechanisms providing tools to target novel mediators of disease. One such pro-inflammatory molecule of interest is the protein high mobility group box chromosomal protein 1 (HMGB1). Aim: The purpose of my thesis was to evaluate a role of HMGB1 in chronic joint inflammation and the possibility of using HMGB1 as a target molecule for therapy. Results: HMGB1 was demonstrated to be prominently expressed as an extracellular and cytoplasmic protein in synovial tissue in preclinical models of arthritis. This distribution differed distinctly from that in articular tissue in control animals, where the HMGB1 localization was mainly intranuclear. Aberrant, extranuclear HMGB1 expression in synovitis and elevated synovial fluid HMGB1 levels were also verified in samples from patients with rheumatoid arthritis. Longitudinal studies of proinflammatory mediators during the course of collagen type II-induced arthritis in rats indicated that aberrant HMGB1 expression preceded clinical symptoms and coincided with onset of TNF and IL-1 production. Maximal HMGB1 protein and mRNA synthesis occurred in areas of cartilage and bone destruction. The functional importance of increased HMGB1 expression was evaluated in other studies of collagen-induced arthritis using HMGB1-specific therapeutic intervention. Polyclonal anti-HMGB1 antibodies as well as truncated HMGB1, acting as a receptor antagonist, ameliorated established arthritis and reduced the histological severity of the synovitis including IL-1beta expression. Synovial biopsy specimens were taken arthroscopically before and during therapy with TNF blocking treatment in nine patients with rheumatoid arthritis in order to investigate a relationship between HMGB1 and the central mediator of arthritis TNF. HMGB1 expression was not influenced by the anti-TNF therapy, suggesting that the two studied molecules perform independently or that HMGB1 acts up-stream of TNF in the pro-inflammatory cascade. Since chronic arthritis often depends on activation of T lymphocytes in an adaptive immune response I also investigated whether HMGB1 may influence T cell performance. HMGB1 acted as a proliferative signal for cultured purified human CD4+ or CD8+ T cells when the cells were stimulated in a suboptimal way, but had no detectable effect on resting T cells. Conclusion: The successful clinical outcome observed in preclinical models of arthritis with HMGB1-specific treatment is encouraging. Future studies are warranted to elucidate the most effective strategies for counteracting extracellular HMGB1-induced inflammation and determine the nature of side effects that may develop using HMGB1 as a target molecule in chronic inflammatory conditions.

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