Premature aging of the stromal microenvironment in rheumatoid arthritis: Towards prevention of disease by targeting cellular aging

Research output: PhD ThesisPhd-Thesis - Research and graduation internal


Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial joints. Despite current treatment options curative treatment is non-existing. To ultimately cure disease, we are investigating potential drivers of disease. Premature aging of the immune system has been shown in T cells from RA patients, but it is unclear whether this is cause or consequence of disease. Because the stromal microenvironment has a major influence on T cell survival and homeostasis, this thesis aimed to investigate premature aging and function of the stromal microenvironment during the earliest phases of autoimmunity, using RA as a model disease. In individuals at risk of developing RA (RA-risk) systemic autoimmunity precedes synovial tissue inflammation. This allowed us to investigate whether the stromal microenvironment is already altered in absence of inflammation. Synovial biopsy studies revealed alterations in adaptive immune responses and lipid metabolism associated with future arthritis development. As RA-risk individuals don’t present overt synovial tissue inflammation, we postulate that synovial changes in these individuals are attributed to resident synovial tissue cells such as fibroblasts. Moreover, we found that fibroblasts isolated from synovium and lymph nodes from RA-risk individuals already display impaired cellular metabolism in absence of inflammation, which may drive immune cell activation. In addition, we demonstrated that fibroblasts from lymph nodes exhibit characteristics of cellular senescence, indicative of premature aging already during the earliest stages of RA. Interventions to target senescent cells partially restored age-associated characteristics in fibroblasts from RA-risk and RA patients and show potential for further exploration.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Amsterdam
  • van Baarsen, Lisa, Supervisor
  • Houtkooper, RHL, Co-supervisor
  • van Baarsen, E.G.M., Supervisor, External person
Award date17 Mar 2023
Print ISBNs9789464197266
Publication statusPublished - 2023

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