Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive arthropathy. In spite of the prominence of the synovial inflammation, autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. Additional systemic immunological abnormalities include a defect that can best be summarized as accelerated immune aging. A putative role of age-dependent immune dysfunction in RA pathogenesis resonates with epidemiological data that RA is a disease of the second half of life with increasing incidence in the elderly. We have hypothesized that a defect in regulating T cell activation thresholds contributes to the tolerance failure and possibly also to the accelerated cellular aging. T cell activation thresholds are regulated by the signal strength originating from T-cell receptor (TCR) stimulation and by signals from costimulatory and coinhibitory cell surface receptors. We have found an increased responsiveness of the ERK pathway in RA T cells that is central to TCR calibration and amplifying signal strength and have proposed that mechanisms controlling the Raf-MEK-ERK module in T cells from RA patients have been reset to favor sustained signaling, thereby impairing peripheral immune tolerance. Our preliminary studies have identified several possible mechanisms causing this hyperresponsiveness including the increased transcription of B-RAF and K-RAS and the induction of a positive feedback loop induced by the homeostatic cytokines IL7 and IL15. The objective of the current application is to determine whether a characterization of these signaling abnormalities in individual RA patients is useful for patient classification and treatment design.
Specific Aim 1 will explore the hypothesis that subsets of RA patients can be defined which differ in their mechanism to hyperstimulate the ERK pathway.
Specific Aim 2 will determine whether the findings are limited to RA or also extend to other frequent arthritides such as psoriatic arthritis.
In Specific Aim 3, we will determine whether existing standard (methotrexate, leflunomide or TNF inhibition) and newly emerging treatment approaches such as JAK3 inhibition are able to correct the signaling abnormalities In Specific Aim 4, we will examine the functional consequences of increased ERK responsiveness for T cell tolerance and T cell differentiation.
Rheumatoid arthritis is the most frequent inflammatory disease in the VA rheumatology practice. The introduction of cytokine inhibitors has reduced the inflammatory burden and improved the management of the disease. However, they do not induce lasting remissions while their chronic administration compromises the immune competence of the patient. Insights into pathogenetic mechanisms upstream of the effector pathways will be necessary to prevent or cure disease. If our model is correct that recalibration of the ERK signaling pathway, in part due to lymphopenia and the compensatory activity of homeostatic cytokines, predispose for disease, attenuation of the ERK signaling pathway would be an elegant therapeutic approach to induce remissions and eventually allow prophylactic treatment with the goal to prevent disease.
|Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2018) Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis. Circulation 137:1934-1948|
|Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2018) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol 105:118-127|
|Goronzy, Jörg J; Hu, Bin; Kim, Chulwoo et al. (2018) Epigenetics of T cell aging. J Leukoc Biol 104:691-699|
|Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715|
|Weyand, Cornelia M; Shen, Yi; Goronzy, Jorg J (2018) Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med 125:36-43|
|Gustafson, Claire E; Qi, Qian; Hutter-Saunders, Jessica et al. (2017) Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging. Front Immunol 8:692|
|Shen, Yi; Wen, Zhenke; Li, Yinyin et al. (2017) Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol 18:1025-1034|
|Watanabe, Ryu; Shirai, Tsuyoshi; Namkoong, Hong et al. (2017) Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest 127:2725-2738|
|Weyand, Cornelia M; Zeisbrich, Markus; Goronzy, Jörg J (2017) Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr Opin Immunol 46:112-120|
|Moskowitz, David M; Zhang, David W; Hu, Bin et al. (2017) Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol 2:|
Showing the most recent 10 out of 28 publications