{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:56:00Z","timestamp":1787583360362,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,11,8]],"date-time":"2020-11-08T00:00:00Z","timestamp":1604793600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SO 1402\/1\u20101"],"award-info":[{"award-number":["SO 1402\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>CD8+ T cells contribute to rheumatoid arthritis (RA) by releasing proinflammatory and cytolytic mediators, even in a challenging hypoxic and nutrient\u2010poor microenvironment such as the synovial membrane. This study was undertaken to explore the mechanisms through which CD8+ T cells meet their metabolic demands in the blood and synovial membrane of patients with RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Purified blood CD8+ T cells from patients with RA, patients with psoriatic arthritis (PsA), and patients with spondyloarthritis (SpA), as well as healthy control subjects, and CD8+ T cells from RA synovial membrane were stimulated in medium containing\n                      <jats:sup>13<\/jats:sup>\n                      C\u2010labeled metabolic substrates in the presence or absence of metabolic inhibitors, under conditions of normoxia or hypoxia. The production of metabolic intermediates was quantified by\n                      <jats:sup>1<\/jats:sup>\n                      H\u2010nuclear magnetic resonance. The expression of metabolic enzymes, transcription factors, and immune effector molecules was assessed at both the messenger RNA (mRNA) and protein levels. CD8+ T cell functional studies were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RA blood CD8+ T cells met their metabolic demands through aerobic glycolysis, production of uniformly\n                      <jats:sup>13<\/jats:sup>\n                      C\u2010enriched lactate in the RA blood (2.6 to 3.7\u2013fold higher than in patients with SpA, patients with PsA, and healthy controls;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.01), and induction of glutaminolysis. Overexpression of Warburg effect\u2013linked enzymes in all RA CD8+ T cell subsets maintained this metabolic profile, conferring to the cells the capacity to proliferate under hypoxia and low\u2010glucose conditions. In all RA CD8+ T cell subsets, lactate dehydrogenase A (LDHA) was overexpressed at the mRNA level (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.03 versus controls; n = 6 per group) and protein level (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05 versus controls; n = 17 RA patients, n = 9 controls). In RA blood, inhibition of LDHA with FX11 led to reductions in lipogenesis, migration and proliferation of CD8+ T cells, and CD8+ T cell effector functions, while production of reactive oxygen species was increased by 1.5\u2010fold (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.03 versus controls). Following inhibition of LDHA with FX11, RA CD8+ T cells lost their capacity to induce healthy B cells to develop a proinflammatory phenotype. Similar metabolic alterations were observed in RA CD8+ T cells from the synovial membrane.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Remodeling glucose and glutamine metabolism in RA CD8+ T cells by targeting LDHA activity can reduce the deleterious inflammatory and cytolytic contributions of these cells to the development of autoimmunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.41420","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T03:22:03Z","timestamp":1593487323000},"page":"2050-2064","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Effect of Increased Lactate Dehydrogenase A Activity and Aerobic Glycolysis on the Proinflammatory Profile of Autoimmune CD8+ T Cells in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-0590","authenticated-orcid":false,"given":"M. Margarida","family":"Souto\u2010Carneiro","sequence":"first","affiliation":[{"name":"University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel D.","family":"Klika","sequence":"additional","affiliation":[{"name":"German Cancer Research Center  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica T.","family":"Abreu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 P.","family":"Meyer","sequence":"additional","affiliation":[{"name":"University Hospital Heidelberg, Heidelberg, Germany, and Zentrum f\u00fcr Kinder\u2010 und Jugendmedizin University Hospital Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Saffrich","sequence":"additional","affiliation":[{"name":"Medical Faculty Mannheim University Hospital Heidelberg, Heidelberg, Germany, and Deutsches Rotes Kreuz Baden\u2010W\u00fcrttemberg\u2013Hessen  Mannheim Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Sandhoff","sequence":"additional","affiliation":[{"name":"German Cancer Research Center  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Jennemann","sequence":"additional","affiliation":[{"name":"German Cancer Research Center  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska V.","family":"Kraus","sequence":"additional","affiliation":[{"name":"University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Tykocinski","sequence":"additional","affiliation":[{"name":"University Hospital Heidelberg  Heidelberg 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