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Role of T Cells in the Pathogenesis of Rheumatoid Arthritis: Focus on Immunometabolism Dysfunctions

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Abstract—

Evidence demonstrated that metabolic-associated T cell abnormalities could be detected in the early stage of RA development. In this context, molecular evaluations have revealed changes in metabolic pathways, leading to the aggressive phenotype of RA T cells. A growing list of genes is downregulated or upregulated in RA T cells, and most of these genes with abnormal expression fall into the category of metabolic pathways. It has been shown that RA T cells shunt glucose towards the pentose phosphate pathway (PPP), which is associated with a high level of nicotinamide adenine dinucleotide phosphate (NADPH) and intermediate molecules. An increased level of NADPH inhibits ATM activation and thereby increases the proliferation capabilities of the RA T cells. Defects in the DNA repair nuclease MRE11A cause failures in repairing mitochondrial DNA, resulting in inhibiting the fatty acid oxidation pathway and further elevated cytoplasmic lipid droplets. Accumulated lipid droplets employ to generate lipid membranes for the cell building program and are also used to form the front-end membrane ruffles that are accomplices with invasive phenotypes of RA T cells. Metabolic pathway involvement in RA pathogenesis expands the pathogenic concept of the disease beyond the common view of autoimmunity triggered by autoantigen recognition. Increased knowledge about metabolic pathways’ implications in RA pathogenesis paves the way to understand better the environment/gene interactions and host/microbiota interactions and introduce potential therapeutic approaches. This review summarized emerging data about the roles of T cells in RA pathogenesis with a focus on immunometabolism dysfunctions and how these metabolic alterations can affect the disease process.

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References

  1. Aletaha, D., and J.S. Smolen. 2018. Diagnosis and management of rheumatoid arthritis: A review. Journal of the American Medical Association 320 (13): 1360–1372.

    Article  PubMed  Google Scholar 

  2. Karami, J., et al. 2021. Evaluation of TAK-242 (Resatorvid) effects on inflammatory status of fibroblast-like synoviocytes in rheumatoid arthritis and trauma patients. Iranian Journal of Allergy, Asthma and Immunology 20 (4): 453–464.

    PubMed  Google Scholar 

  3. Masoumi, M., et al. 2021. Destructive roles of fibroblast-like synoviocytes in chronic inflammation and joint damage in rheumatoid arthritis. Inflammation 44 (2): 466–479.

    Article  CAS  PubMed  Google Scholar 

  4. Karami, J., et al. 2019. Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 702: 8–16.

    Article  CAS  PubMed  Google Scholar 

  5. Alizadeh, Z., et al. 2016. STAT4 rs7574865 polymorphism in Iranian patients with rheumatoid arthritis. Indian Journal of Rheumatology 11 (2): 78–81.

    Google Scholar 

  6. Karami, J., et al. 2019. Epigenetics in rheumatoid arthritis; fibroblast-like synoviocytes as an emerging paradigm in the disease pathogenesis. Immunology and cell biology 98 (3): 171–186.

    Article  Google Scholar 

  7. Aslani, S., et al. 2016. Epigenetic alterations underlying autoimmune diseases. Autoimmunity 49 (2): 69–83.

    Article  CAS  PubMed  Google Scholar 

  8. Weyand, C.M., M. Zeisbrich, and J.J. Goronzy. 2017. Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Current opinion in immunology 46: 112–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rao, D.A. 2018. T cells that help B cells in chronically inflamed tissues. Frontiers in immunology 9: 1924.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hu, X.-X., et al. 2019. T-cells interact with B cells, dendritic cells, and fibroblast-like synoviocytes as hub-like key cells in rheumatoid arthritis. International immunopharmacology 70: 428–434.

    Article  CAS  PubMed  Google Scholar 

  11. Chemin, K., C. Gerstner, and V. Malmström. 2019. Effector functions of CD4+ T cells at the site of local autoimmune inflammation–lessons from rheumatoid arthritis. Frontiers in immunology 10: 353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wehr, P., et al. 2019. Dendritic cells, T cells and their interaction in rheumatoid arthritis. Clinical & Experimental Immunology 196 (1): 12–27.

    Article  CAS  Google Scholar 

  13. Weyand, C.M., B. Wu, and J.J. Goronzy. 2020. The metabolic signature of T cells in rheumatoid arthritis. Current opinion in rheumatology 32 (2): 159–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dekkers, J., et al. 2016. The role of anticitrullinated protein antibodies in the early stages of rheumatoid arthritis. Current opinion in rheumatology 28 (3): 275–281.

    Article  CAS  PubMed  Google Scholar 

  15. Koppejan, H., et al. 2016. Role of anti–carbamylated protein antibodies compared to anti–citrullinated protein antibodies in indigenous North Americans with rheumatoid arthritis, their first-degree relatives, and healthy controls. Arthritis & Rheumatology 68 (9): 2090–2098.

    Article  CAS  Google Scholar 

  16. Conigliaro, P., et al. 2016. Autoantibodies in inflammatory arthritis. Autoimmunity reviews 15 (7): 673–683.

    Article  CAS  PubMed  Google Scholar 

  17. Yang, Z., et al. 2015. T-cell metabolism in autoimmune disease. Arthritis research & therapy 17 (1): 1–10.

    Article  Google Scholar 

  18. Weyand, C.M., Y. Shen, and J.J. Goronzy. 2018. Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radical Biology and Medicine 125: 36–43.

    Article  CAS  PubMed  Google Scholar 

  19. Goronzy, J.J., and C.M. Weyand. 2017. Successful and maladaptive T cell aging. Immunity 46 (3): 364–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weyand, C.M., and J.J. Goronzy. 2017. Immunometabolism in early and late stages of rheumatoid arthritis. Nature Reviews Rheumatology 13 (5): 291–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Weyand, C.M., and J.J. Goronzy. 2018. A mitochondrial checkpoint in autoimmune disease. Cell metabolism 28 (2): 185–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, Y., et al. 2019. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell metabolism 30 (3): 477–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Masoumi, M., et al. 2020. Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis. International immunopharmacology 89: 107064.

    Article  CAS  PubMed  Google Scholar 

  24. Shirai, T., et al. 2016. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. Journal of Experimental Medicine 213 (3): 337–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meednu, N., et al. 2016. Production of RANKL by memory B cells: A link between B cells and bone erosion in rheumatoid arthritis. Arthritis & rheumatology 68 (4): 805–816.

    Article  CAS  Google Scholar 

  26. Podojil, J.R., and S.D. Miller. 2009. Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunological reviews 229 (1): 337–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luo, P., et al. 2022. Immunomodulatory role of T helper cells in rheumatoid arthritis: A comprehensive research review. Bone & Joint Research 11 (7): 426–438.

    Article  Google Scholar 

  28. Cope, A.P., H. Schulze-Koops, and M. Aringer. 2007. The central role of T cells in rheumatoid arthritis. Clinical and experimental rheumatology 25 (5): S4.

    CAS  PubMed  Google Scholar 

  29. Alunno, A., et al. 2015. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediators of inflammation 2015: 751793.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Al-Saadany, H.M., et al. 2016. Th-17 cells and serum IL-17 in rheumatoid arthritis patients: Correlation with disease activity and severity. The Egyptian Rheumatologist 38 (1): 1–7.

    Article  Google Scholar 

  31. Schulze-Koops, H., and J.R. Kalden. 2001. The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Practice & Research Clinical Rheumatology 15 (5): 677–691.

    Article  CAS  Google Scholar 

  32. Ciccia, F., et al. 2015. Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis. Rheumatology 54 (12): 2264–2272.

    Article  CAS  PubMed  Google Scholar 

  33. Chowdhury, K., et al. 2018. Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis. Arthritis research & therapy 20 (1): 1–12.

    Article  Google Scholar 

  34. Cooles, F.A., J.D. Isaacs, and A.E. Anderson. 2013. Treg cells in rheumatoid arthritis: An update. Current rheumatology reports 15 (9): 352.

    Article  PubMed  Google Scholar 

  35. Boissier, M.-C., et al. 2009. Regulatory T cells (Treg) in rheumatoid arthritis. Joint, Bone, Spine 76 (1): 10–14.

    Article  CAS  PubMed  Google Scholar 

  36. Morita, T., et al. 2016. The proportion of regulatory T cells in patients with rheumatoid arthritis: A meta-analysis. PLoS ONE 11 (9): e0162306.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Rapetti, L., et al. 2015. B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis. Annals of the rheumatic diseases 74 (1): 294–302.

    Article  CAS  PubMed  Google Scholar 

  38. Al-Zifzaf, D.S., et al. 2015. FoxP3+ T regulatory cells in Rheumatoid arthritis and the imbalance of the Treg/TH17 cytokine axis. The Egyptian Rheumatologist 37 (1): 7–15.

    Article  Google Scholar 

  39. Rao, D.A., et al. 2017. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542 (7639): 110–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zeng, H., and H. Chi. 2013. mTOR and lymphocyte metabolism. Current opinion in immunology 25 (3): 347–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pollizzi, K.N., and J.D. Powell. 2014. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nature Reviews Immunology 14 (7): 435–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chapman, N.M., M.R. Boothby, and H. Chi. 2020. Metabolic coordination of T cell quiescence and activation. Nature Reviews Immunology 20 (1): 55–70.

    Article  CAS  PubMed  Google Scholar 

  43. Chiaranunt, P., J.L. Ferrara, and C.A. Byersdorfer. 2015. Rethinking the paradigm: How comparative studies on fatty acid oxidation inform our understanding of T cell metabolism. Molecular immunology 68 (2): 564–574.

    Article  CAS  PubMed  Google Scholar 

  44. Howie, D., et al. 2018. The role of lipid metabolism in T lymphocyte differentiation and survival. Frontiers in immunology 8: 1949.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Angajala, A., et al. 2018. Diverse roles of mitochondria in immune responses: Novel insights into immuno-metabolism. Frontiers in immunology 9: 1605.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Maciolek, J.A., J.A. Pasternak, and H.L. Wilson. 2014. Metabolism of activated T lymphocytes. Current opinion in immunology 27: 60–74.

    Article  CAS  PubMed  Google Scholar 

  47. Samanta, D., and G.L. Semenza. 2018. Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1870 (1): 15–22.

    Article  CAS  PubMed  Google Scholar 

  48. Johnson, M.O., et al. 2016. Nutrients and the microenvironment to feed a T cell army. In Seminars in immunology. Elsevier.

    Google Scholar 

  49. Desdín-Micó, G., G. Soto-Heredero, and M. Mittelbrunn. 2018. Mitochondrial activity in T cells. Mitochondrion 41: 51–57.

    Article  PubMed  Google Scholar 

  50. Yang, Z., J.J. Goronzy, and C.M. Weyand. 2014. The glycolytic enzyme PFKFB3/phosphofructokinase regulates autophagy. Autophagy 10 (2): 382–383.

    Article  CAS  PubMed  Google Scholar 

  51. Yang, Z., et al. 2016. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Science translational medicine 8 (331): 331ra38.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang, Z., et al. 2013. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. Journal of Experimental Medicine 210 (10): 2119–2134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tripmacher, R., et al. 2008. Human CD4+ T cells maintain specific functions even under conditions of extremely restricted ATP production. European journal of immunology 38 (6): 1631–1642.

    Article  CAS  PubMed  Google Scholar 

  54. Bono, M.R., et al. 2015. CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression. FEBS letters 589 (22): 3454–3460.

    Article  CAS  PubMed  Google Scholar 

  55. Raker, V.K., C. Becker, and K. Steinbrink. 2016. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Frontiers in immunology 7: 123.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Howie, D., H. Waldmann, and S. Cobbold. 2014. Nutrient sensing via mTOR in T cells maintains a tolerogenic microenvironment. Frontiers in immunology 5: 409.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fang, F., et al. 2016. Expression of CD39 on activated T cells impairs their survival in older individuals. Cell reports 14 (5): 1218–1231.

    Article  CAS  PubMed  Google Scholar 

  58. Haas, R., et al. 2016. Intermediates of metabolism: From bystanders to signalling molecules. Trends in biochemical sciences 41 (5): 460–471.

    Article  CAS  PubMed  Google Scholar 

  59. Zhou, R.-P., et al. 2016. Novel insights into acid-sensing ion channels: Implications for degenerative diseases. Aging and disease 7 (4): 491.

    Article  PubMed  Google Scholar 

  60. Osmakov, D., Y.A. Andreev, and S. Kozlov. 2014. Acid-sensing ion channels and their modulators. Biochemistry (Moscow) 79 (13): 1528–1545.

    Article  CAS  PubMed  Google Scholar 

  61. Haas, R., et al. 2015. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS biology 13 (7): e1002202.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Weyand, C.M., and J.J. Goronzy. 2020. Immunometabolism in the development of rheumatoid arthritis. Immunological reviews 294 (1): 177–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shen, Y., et al. 2017. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nature immunology 18 (9): 1025–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pietrocola, F., et al. 2015. Acetyl coenzyme A: A central metabolite and second messenger. Cell metabolism 21 (6): 805–821.

    Article  CAS  PubMed  Google Scholar 

  65. Nguyen, T.B., and J.A. Olzmann. 2017. Lipid droplets and lipotoxicity during autophagy. Autophagy 13 (11): 2002–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Saka, H.A., and R. Valdivia. 2012. Emerging roles for lipid droplets in immunity and host-pathogen interactions. Annual review of cell and developmental biology 28: 411–437.

    Article  CAS  PubMed  Google Scholar 

  67. Cohen, S. 2018. Lipid droplets as organelles. International review of cell and molecular biology 337: 83–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Henne, M. 2019. And three’sa party: Lysosomes, lipid droplets, and the ER in lipid trafficking and cell homeostasis. Current opinion in cell biology 59: 40–49.

    Article  CAS  PubMed  Google Scholar 

  69. Yang, Z., J.J. Goronzy, and C.M. Weyand. 2015. Autophagy in autoimmune disease. Journal of molecular medicine 93 (7): 707–717.

    Article  CAS  PubMed  Google Scholar 

  70. Karami, J., et al. 2020. Role of autophagy in the pathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches. Life sciences 254: 117734.

    Article  CAS  PubMed  Google Scholar 

  71. Henne, M., J.M. Goodman, and H. Hariri. 2020. Spatial compartmentalization of lipid droplet biogenesis. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1865 (1): 158499.

    CAS  PubMed  Google Scholar 

  72. Kidani, Y., et al. 2013. Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nature immunology 14 (5): 489–499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yang, W., et al. 2016. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531 (7596): 651–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Eddy, R.J., et al. 2017. Tumor cell invadopodia: Invasive protrusions that orchestrate metastasis. Trends in cell biology 27 (8): 595–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vignali, P.D., J. Barbi, and F. Pan. 2017. Metabolic regulation of T cell immunity. In Immune Metabolism in Health and Tumor, 87–130. Dordrecht: Springer.

    Chapter  Google Scholar 

  76. Myers, D.R., B. Wheeler, and J.P. Roose. 2019. mTOR and other effector kinase signals that impact T cell function and activity. Immunological reviews 291 (1): 134–153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wen, Z., et al. 2019. N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation. Nature immunology 20 (3): 313–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lin, S.-C., and D.G. Hardie. 2018. AMPK: Sensing glucose as well as cellular energy status. Cell metabolism 27 (2): 299–313.

    Article  CAS  PubMed  Google Scholar 

  79. Kim, J., and K.-L. Guan. 2019. mTOR as a central hub of nutrient signalling and cell growth. Nature cell biology 21 (1): 63–71.

    Article  CAS  PubMed  Google Scholar 

  80. Wolfson, R.L., and D.M. Sabatini. 2017. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell metabolism 26 (2): 301–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lamming, D.W., and L. Bar-Peled. 2019. Lysosome: The metabolic signaling hub. Traffic 20 (1): 27–38.

    Article  CAS  PubMed  Google Scholar 

  82. Liang, J., et al. 2015. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nature communications 6 (1): 1–14.

    Article  Google Scholar 

  83. Udenwobele, D.I., et al. 2017. Myristoylation: An important protein modification in the immune response. Frontiers in immunology 8: 751.

    Article  PubMed  PubMed Central  Google Scholar 

  84. O’Neill, J.S., and K.A. Feeney. 2014. Circadian redox and metabolic oscillations in mammalian systems. Antioxidants & redox signaling 20 (18): 2966–2981.

    Article  CAS  Google Scholar 

  85. Putker, M., H.R. Vos, and T.B. Dansen. 2014. Intermolecular disulfide-dependent redox signalling. Biochemical Society Transactions 42 (4): 971–978.

    Article  CAS  PubMed  Google Scholar 

  86. Sauer, H., M. Wartenberg, and J. Hescheler. 2001. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cellular physiology and biochemistry 11 (4): 173–186.

    Article  CAS  PubMed  Google Scholar 

  87. Forman, H.J., J.M. Fukuto, and M. Torres. 2004. Redox signaling: Thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. American Journal of Physiology-Cell Physiology 287 (2): C246–C256.

    Article  CAS  PubMed  Google Scholar 

  88. Mittler, R. 2017. ROS are good. Trends in plant science 22 (1): 11–19.

    Article  CAS  PubMed  Google Scholar 

  89. Paull, T.T. 2015. Mechanisms of ATM activation. Annual review of biochemistry 84: 711–738.

    Article  CAS  PubMed  Google Scholar 

  90. Yau, A.C., and R. Holmdahl. 2016. Rheumatoid arthritis: Identifying and characterising polymorphisms using rat models. Disease models & mechanisms 9 (10): 1111–1123.

    Article  CAS  Google Scholar 

  91. Holmdahl, R., et al. 2016. Ncf1 polymorphism reveals oxidative regulation of autoimmune chronic inflammation. Immunological reviews 269 (1): 228–247.

    Article  CAS  PubMed  Google Scholar 

  92. Olofsson, P., and R. Holmdahl. 2003. Positional cloning of Ncf1–a piece in the puzzle of arthritis genetics. Scandinavian journal of immunology 58 (2): 155–164.

    Article  CAS  PubMed  Google Scholar 

  93. Gelderman, K.A., et al. 2007. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. The Journal of clinical investigation 117 (10): 3020–3028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gelderman, K.A., et al. 2006. T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proceedings of the National Academy of Sciences 103 (34): 12831–12836.

    Article  CAS  Google Scholar 

  95. Kelkka, T., et al. 2014. Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature. Antioxidants & redox signaling 21 (16): 2231–2245.

    Article  CAS  Google Scholar 

  96. Kienhöfer, D., S. Boeltz, and M. Hoffmann. 2016. Reactive oxygen homeostasis–the balance for preventing autoimmunity. Lupus 25 (8): 943–954.

    Article  PubMed  Google Scholar 

  97. Gelderman, K.A., et al. 2007. Rheumatoid arthritis: The role of reactive oxygen species in disease development and therapeutic strategies. Antioxidants & Redox Signaling 9 (10): 1541–1568.

    Article  CAS  Google Scholar 

  98. Li, Y., J.J. Goronzy, and C.M. Weyand. 2018. DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Experimental gerontology 105: 118–127.

    Article  CAS  PubMed  Google Scholar 

  99. Schönland, S.O., et al. 2003. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proceedings of the National Academy of Sciences 100 (23): 13471–13476.

    Article  Google Scholar 

  100. Koetz, K., et al. 2000. T cell homeostasis in patients with rheumatoid arthritis. Proceedings of the National Academy of Sciences 97 (16): 9203–9208.

    Article  CAS  Google Scholar 

  101. Goronzy, J.J., et al. 2018. Epigenetics of T cell aging. Journal of leukocyte biology 104 (4): 691–699.

    Article  CAS  PubMed  Google Scholar 

  102. McGuire, P.J. 2019. Mitochondrial dysfunction and the aging immune system. Biology 8 (2): 26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, Y., et al. 2016. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45 (4): 903–916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Williams, G.J., S.P. Lees-Miller, and J.A. Tainer. 2010. Mre11–Rad50–Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks. DNA Repair 9 (12): 1299–1306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shao, L., et al. 2009. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. Journal of Experimental Medicine 206 (6): 1435–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Winchester, R., et al. 2016. Association of elevations of specific T cell and monocyte subpopulations in rheumatoid arthritis with subclinical coronary artery atherosclerosis. Arthritis & Rheumatology 68 (1): 92–102.

    Article  CAS  Google Scholar 

  107. Iyama, T., and D.M. Wilson III. 2013. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair 12 (8): 620–636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Biton, S., A. Barzilai, and Y. Shiloh. 2008. The neurological phenotype of ataxia-telangiectasia: Solving a persistent puzzle. DNA Repair 7 (7): 1028–1038.

    Article  CAS  PubMed  Google Scholar 

  109. Krüger, A., and M. Ralser. 2011. ATM is a redox sensor linking genome stability and carbon metabolism. Science signaling 4 (167): pe17.

    Article  PubMed  Google Scholar 

  110. Weyand, C.M., Z. Yang, and J.J. Goronzy. 2014. T cell aging in rheumatoid arthritis. Current opinion in rheumatology 26 (1): 93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Westbrook, A.M., and R.H. Schiestl. 2010. Atm-deficient mice exhibit increased sensitivity to dextran sulfate sodium–induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer research 70 (5): 1875–1884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mousavi, M.J., et al. 2021. Transformation of fibroblast-like synoviocytes in rheumatoid arthritis; from a friend to foe. Autoimmunity Highlights 12 (1): 3.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Sanz-Moreno, V., et al. 2008. Rac activation and inactivation control plasticity of tumor cell movement. Cell 135 (3): 510–523.

    Article  CAS  PubMed  Google Scholar 

  114. Gaylo, A., et al. 2016. T cell interstitial migration: Motility cues from the inflamed tissue for micro-and macro-positioning. Frontiers in immunology 7: 428.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Korpos, E., et al. 2010. Role of the extracellular matrix in lymphocyte migration. Cell and tissue research 339 (1): 47–57.

    Article  CAS  PubMed  Google Scholar 

  116. Hind, L.E., W.J. Vincent, and A. Huttenlocher. 2016. Leading from the back: The role of the uropod in neutrophil polarization and migration. Developmental cell 38 (2): 161–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Alonso, F., et al. 2019. Variations on the theme of podosomes: A matter of context. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1866 (4): 545–553.

    Article  CAS  PubMed  Google Scholar 

  118. Courtneidge, S.A. 2012. Cell migration and invasion in human disease: The Tks adaptor proteins. Biochemical Society Transactions 40 (1): 129–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Moreno-Aurioles, V., and F. Sobrino. 1991. Glucocorticoids inhibit fructose 2, 6-bisphosphate synthesis in rat thymocytes. Opposite effect of cycloheximide. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1091 (1): 96–100.

    Article  CAS  PubMed  Google Scholar 

  120. He, X., et al. 2011. Mycophenolic acid-mediated suppression of human CD4+ T cells: More than mere guanine nucleotide deprivation. American Journal of Transplantation 11 (3): 439–449.

    Article  CAS  PubMed  Google Scholar 

  121. Ma, E.H., et al. 2017. Serine is an essential metabolite for effector T cell expansion. Cell metabolism 25 (2): 345–357.

    Article  CAS  PubMed  Google Scholar 

  122. Shuvalov, O., et al. 2017. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget 8 (14): 23955.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Clinical Research and Development Center, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran

    Maryam Masoumi

  2. Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Samira Alesaeidi

  3. Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Hossein Khorramdelazad

  4. Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mousa Behzadi

  5. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Rasoul Baharlou

  6. Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Shahin Alizadeh-Fanalou

  7. Molecular and Medicine Research Center, Khomein University of Medical Sciences, Khomein, Iran

    Jafar Karami

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  1. Maryam Masoumi
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  2. Samira Alesaeidi
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  5. Rasoul Baharlou
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Contributions

M-M and J-K conceived and designed the study. S-A, M-B, and Sh-AF contributed in comprehensive research and writing the original-draft. R-B and H-Kh participated in manuscript editing and design the figures. All authors read and approved the final manuscript.

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Correspondence to Shahin Alizadeh-Fanalou or Jafar Karami.

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Masoumi, M., Alesaeidi, S., Khorramdelazad, H. et al. Role of T Cells in the Pathogenesis of Rheumatoid Arthritis: Focus on Immunometabolism Dysfunctions. Inflammation 46, 88–102 (2023). https://doi.org/10.1007/s10753-022-01751-9

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