Rheumatoid Arthritis: Grabiec AM

Grabiec AM, Tak PP, Reedquist KA. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Arthritis Res Ther. · Pubmed #18983693 links to  free full text

Abstract: Cellular activation, proliferation and survival in chronic inflammatory diseases is regulated not only by engagement of signal trans-duction pathways that modulate transcription factors required for these processes, but also by epigenetic regulation of transcription factor access to gene promoter regions. Histone acetyl transferases coordinate the recruitment and activation of transcription factors with conformational changes in histones that allow gene promoter exposure. Histone deacetylases (HDACs) counteract histone acetyl transferase activity through the targeting of both histones as well as nonhistone signal transduction proteins important in inflammation. Numerous studies have indicated that depressed HDAC activity in patients with inflammatory airway diseases may contribute to local proinflammatory cytokine production and diminish patient responses to corticosteroid treatment. Recent observations that HDAC activity is depressed in rheumatoid arthritis patient synovial tissue have predicted that strategies restoring HDAC function may be therapeutic in this disease as well. Pharmacological inhibitors of HDAC activity, however, have demonstrated potent therapeutic effects in animal models of arthritis and other chronic inflammatory diseases. In the present review we assess and reconcile these outwardly paradoxical study results to provide a working model for how alterations in HDAC activity may contribute to pathology in rheumatoid arthritis, and highlight key questions to be answered in the preclinical evaluation of compounds modulating these enzymes.

Abreu JR, Grabiec AM, Krausz S, Spijker R, Burakowski T, Maslinski W, Eldering E, Tak PP, Reedquist KA. · Academic Medical Center, University of Amsterdam, The Netherlands. · J Immunol. · Pubmed #19525395 No free full text.

Abstract: Genetic associations and the clinical success of compounds targeting TCR costimulatory proteins suggest an active role for TCR signaling in the initiation and perpetuation of rheumatoid arthritis (RA). Paradoxically, T cells isolated from affected joints in RA show impaired proliferative and cytokine responses following stimulation with mitogens and recall Ags attributed in part to chronic T cell exposure to oxidative stress and inflammatory cytokines. Therefore, it is uncertain how local autoreactive TCR signaling contributes to pathology in established RA. Using single-cell analysis, we show that in contrast to results obtained in bulk culture assays, T cells from the synovial fluid of RA patients proliferate and produce cytokines (IL-2, TNF-alpha, and IFN-gamma) as efficiently, if not more so, than T cells isolated from healthy donors and RA patient peripheral blood following TCR/CD28 stimulation. RA synovial fluid T cell hyporesponsiveness observed in bulk cultures can be attributed to spontaneous apoptosis ex vivo, which is associated with altered ratios of proapoptotic Noxa and anti-apoptotic Mcl-1 expression. The absence of RA synovial T cell proliferation and cytokine production in situ, despite the capacity of these cells to support productive TCR signaling, suggests that T cells contribute to local pathology in established RA by TCR-independent mechanisms.