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The immunology of rheumatoid arthritis

Abstract

The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.

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Fig. 1: Evolution of rheumatoid arthritis over an individual’s lifetime.
Fig. 2: DNA repair deficits in rheumatoid arthritis.
Fig. 3: Metabolic reprogramming and proinflammatory effector functions in RA T cells.

References

  1. Myasoedova, E., Davis, J., Matteson, E. L. & Crowson, C. S. Is the epidemiology of rheumatoid arthritis changing? Results from a population-based incidence study, 1985–2014. Ann. Rheum. Dis. 79, 440–444 (2020).

    PubMed  Google Scholar 

  2. Mahler, M., Martinez-Prat, L., Sparks, J. A. & Deane, K. D. Precision medicine in the care of rheumatoid arthritis: focus on prediction and prevention of future clinically-apparent disease. Autoimmun. Rev. 19, 102506 (2020).

    PubMed  Google Scholar 

  3. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Alarcón, G. S. Epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 21, 589–604 (1995).

    PubMed  Google Scholar 

  5. Viatte, S. et al. Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA 313, 1645–1656 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. Okada, Y. et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum. Mol. Genet. 23, 6916–6926 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Amariuta, T., Luo, Y., Knevel, R., Okada, Y. & Raychaudhuri, S. Advances in genetics toward identifying pathogenic cell states of rheumatoid arthritis. Immunol. Rev. 294, 188–204 (2020).

    CAS  PubMed  Google Scholar 

  8. Hu, X. et al. Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells. PLoS Genet. 10, e1004404 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573–583 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    CAS  PubMed  Google Scholar 

  12. McClain, M. T. et al. The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum. 50, 1226–1232 (2004).

    PubMed  Google Scholar 

  13. Aho, K., Heliövaara, M., Maatela, J., Tuomi, T. & Palosuo, T. Rheumatoid factors antedating clinical rheumatoid arthritis. J. Rheumatol. 18, 1282–1284 (1991).

    CAS  PubMed  Google Scholar 

  14. Deane, K. D., Norris, J. M. & Holers, V. M. Preclinical rheumatoid arthritis: identification, evaluation, and future directions for investigation. Rheum. Dis. Clin. North Am. 36, 213–241 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. van Delft, M. A. M. & Huizinga, T. W. J. An overview of autoantibodies in rheumatoid arthritis. J. Autoimmun. 110, 102392 (2020).

    PubMed  Google Scholar 

  16. Ligier, S., Fortin, P. R. & Newkirk, M. M. A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE. Br. J. Rheumatol. 37, 1307–1314 (1998).

    CAS  PubMed  Google Scholar 

  17. Raposo, B. et al. T cells specific for post-translational modifications escape intrathymic tolerance induction. Nat. Commun. 9, 353 (2018).

    PubMed  PubMed Central  Google Scholar 

  18. Berglin, E. et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther. 6, R303–R308 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Johansson, M., Arlestig, L., Hallmans, G. & Rantapää-Dahlqvist, S. PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res. Ther. 8, R19 (2006).

    PubMed  Google Scholar 

  20. Ge, C. & Holmdahl, R. The structure, specificity and function of anti-citrullinated protein antibodies. Nat. Rev. Rheumatol. 15, 503–508 (2019).

    CAS  PubMed  Google Scholar 

  21. Kissel, T. et al. Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications. Ann. Rheum. Dis. 79, 472–480 (2020).

    CAS  PubMed  Google Scholar 

  22. Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).

    CAS  PubMed  Google Scholar 

  23. Holers, V. M. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat. Rev. Rheumatol. 14, 542–557 (2018).

    PubMed  PubMed Central  Google Scholar 

  24. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 5, 178ra140 (2013).

    Google Scholar 

  25. Carmona-Rivera, C. et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. Schönland, S. O. et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc. Natl Acad. Sci. USA 100, 13471–13476 (2003).

    PubMed  Google Scholar 

  27. Waase, I., Kayser, C., Carlson, P. J., Goronzy, J. J. & Weyand, C. M. Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum. 39, 904–913 (1996).

    CAS  PubMed  Google Scholar 

  28. Gerlag, D. M. et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann. Rheum. Dis. 78, 179–185 (2019).

    CAS  PubMed  Google Scholar 

  29. Kissel, T. et al. On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis. Ann. Rheum. Dis. 78, 1616–1620 (2019).

    CAS  PubMed  Google Scholar 

  30. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2, e01202 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. Humby, F. et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Ann. Rheum. Dis. 78, 761–772 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis, M. J. et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 28, 2455–2470.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ponchel, F. et al. T-cell subset abnormalities predict progression along the Inflammatory Arthritis disease continuum: implications for management. Sci. Rep. 10, 3669 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bader, L. et al. Candidate markers for stratification and classification in rheumatoid arthritis. Front. Immunol. 10, 1488 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pitaksalee, R. et al. Differential CpG DNA methylation in peripheral naive CD4+ T-cells in early rheumatoid arthritis patients. Clin. Epigenetics 12, 54 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tuncel, J. et al. Self-reactive T cells induce and perpetuate chronic relapsing arthritis. Arthritis Res. Ther. 22, 95 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Weyand, C. M. & Goronzy, J. J. Immunometabolism in early and late stages of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 291–301 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Weyand, C. M., Shen, Y. & Goronzy, J. J. Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic. Biol. Med. 125, 36–43 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu, B., Goronzy, J. J. & Weyand, C. M. Metabolic fitness of T cells in autoimmune disease. Immunometabolism 2, e200017 (2020).

    PubMed  PubMed Central  Google Scholar 

  40. Li, Y., Goronzy, J. J. & Weyand, C. M. DNA damage, metabolism and aging in pro-inflammatory T cells: rheumatoid arthritis as a model system. Exp. Gerontol. 105, 118–127 (2018).

    CAS  PubMed  Google Scholar 

  41. Wagner, U. G., Koetz, K., Weyand, C. M. & Goronzy, J. J. Perturbation of the T cell repertoire in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 95, 14447–14452 (1998).

    CAS  PubMed  Google Scholar 

  42. Koetz, K. et al. T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 9203–9208 (2000).

    CAS  PubMed  Google Scholar 

  43. Burgoyne, C. H. et al. Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse. Ann. Rheum. Dis. 67, 750–757 (2008).

    CAS  PubMed  Google Scholar 

  44. Ponchel, F. et al. Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 100, 4550–4556 (2002).

    CAS  PubMed  Google Scholar 

  45. Weyand, C. M., Fujii, H., Shao, L. & Goronzy, J. J. Rejuvenating the immune system in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 583–588 (2009).

    CAS  PubMed  Google Scholar 

  46. Weyand, C. M., Shao, L. & Goronzy, J. J. Immune aging and rheumatoid arthritis. Rheum. Dis. Clin. North Am. 36, 297–310 (2010).

    PubMed  PubMed Central  Google Scholar 

  47. Weyand, C. M., Yang, Z. & Goronzy, J. J. T cell aging in rheumatoid arthritis. Curr. Opin. Rheumatol. 26, 93–100 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Goronzy, J. J., Li, G., Yang, Z. & Weyand, C. M. The Janus head of T cell aging—autoimmunity and immunodeficiency. Front. Immunol. 4, 131 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Shao, L. et al. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J. Exp. Med. 206, 1435–1449 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Burger, K., Ketley, R. F. & Gullerova, M. Beyond the trinity of ATM, ATR, and DNA-PK: multiple kinases shape the DNA damage response in concert with RNA metabolism. Front. Mol. Biosci. 6, 61 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra338 (2016).

    Google Scholar 

  53. Amsen, D., Backer, R. A. & Helbig, C. Decisions on the road to memory. Adv. Exp. Med. Biol. 785, 107–120 (2013).

    CAS  PubMed  Google Scholar 

  54. Shao, L., Goronzy, J. J. & Weyand, C. M. DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis. EMBO Mol. Med. 2, 415–427 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, Y. et al. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell Metab. 30, 477–492 e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Syed, A. & Tainer, J. A. The MRE11–RAD50–NBS1 complex conducts the orchestration of damage signaling and outcomes to stress in DNA replication and repair. Annu. Rev. Biochem. 87, 263–294 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mathur, A., Hayward, J. A. & Man, S. M. Molecular mechanisms of inflammasome signaling. J. Leukoc. Biol. 103, 233–257 (2018).

    CAS  PubMed  Google Scholar 

  58. Mehta, P. & Manson, J. J. What is the clinical relevance of TNF inhibitor immunogenicity in the management of patients with rheumatoid arthritis? Front. Immunol. 11, 589 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Balsa, A. et al. Drug immunogenicity in patients with inflammatory arthritis and secondary failure to tumour necrosis factor inhibitor therapies: the REASON study. Rheumatology (Oxford) 57, 688–693 (2018).

    CAS  Google Scholar 

  60. Ponchel, F. et al. Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia. Arthritis Res. Ther. 7, R80–R92 (2005).

    CAS  PubMed  Google Scholar 

  61. Schmidt, D., Goronzy, J. J. & Weyand, C. M. CD4+ CD7 CD28 T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J. Clin. Invest. 97, 2027–2037 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Weyand, C. M., Brandes, J. C., Schmidt, D., Fulbright, J. W. & Goronzy, J. J. Functional properties of CD4+ CD28 T cells in the aging immune system. Mech. Ageing Dev. 102, 131–147 (1998).

    CAS  PubMed  Google Scholar 

  63. Yamada, H. et al. Interleukin-15 selectively expands CD57+ CD28 CD4+ T cells, which are increased in active rheumatoid arthritis. Clin. Immunol. 124, 328–335 (2007).

    CAS  PubMed  Google Scholar 

  64. Weyand, C. M., Fulbright, J. W. & Goronzy, J. J. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp. Gerontol. 38, 833–841 (2003).

    CAS  PubMed  Google Scholar 

  65. Liuzzo, G. et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 100, 2135–2139 (1999).

    CAS  PubMed  Google Scholar 

  66. Liuzzo, G. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888 (2000).

    CAS  PubMed  Google Scholar 

  67. Gerli, R. et al. CD4+CD28 T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation 109, 2744–2748 (2004).

    CAS  PubMed  Google Scholar 

  68. Ormseth, M. J. et al. Telomere length and coronary atherosclerosis in rheumatoid arthritis. J. Rheumatol. 43, 1469–1474 (2016).

    PubMed  PubMed Central  Google Scholar 

  69. Liuzzo, G. et al. Molecular fingerprint of interferon-γ signaling in unstable angina. Circulation 103, 1509–1514 (2001).

    CAS  PubMed  Google Scholar 

  70. Fasth, A. E. R., Björkström, N. K., Anthoni, M., Malmberg, K.-J. & Malmström, V. Activating NK-cell receptors co-stimulate CD4+CD28 T cells in patients with rheumatoid arthritis. Eur. J. Immunol. 40, 378–387 (2010).

    CAS  PubMed  Google Scholar 

  71. Warrington, K. J., Takemura, S., Goronzy, J. J. & Weyand, C. M. CD4+,CD28– T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum. 44, 13–20 (2001).

    CAS  PubMed  Google Scholar 

  72. Snyder, M. R., Nakajima, T., Leibson, P. J., Weyand, C. M. & Goronzy, J. J. Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms. J. Immunol. 173, 3725–3731 (2004).

    CAS  PubMed  Google Scholar 

  73. Snyder, M. R., Lucas, M., Vivier, E., Weyand, C. M. & Goronzy, J. J. Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. J. Exp. Med. 197, 437–449 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Pereira, B. I. et al. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat. Immunol. 21, 684–694 (2020).

    CAS  PubMed  Google Scholar 

  75. Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. Fonseka, C. Y. et al. Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis. Sci. Transl. Med. 10, eaaq0305 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. Colmegna, I. et al. Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum. 58, 990–1000 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Makowski, L., Chaib, M. & Rathmell, J. C. Immunometabolism: from basic mechanisms to translation. Immunol. Rev. 295, 5–14 (2020).

    CAS  PubMed  Google Scholar 

  79. Shen, Y. et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat. Immunol. 18, 1025–1034 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  82. Yang, Z., Matteson, E. L., Goronzy, J. J. & Weyand, C. M. T-cell metabolism in autoimmune disease. Arthritis Res. Ther. 17, 29 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Weyand, C. M., Wu, B. & Goronzy, J. J. The metabolic signature of T cells in rheumatoid arthritis. Curr. Opin. Rheumatol. 32, 159–167 (2020).

    CAS  PubMed  Google Scholar 

  84. Ling, G. S. et al. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360, 558–563 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wen, Z. et al. N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation. Nat. Immunol. 20, 313–325 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Krishnan, S. et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J. Immunol. 172, 7821–7831 (2004).

    CAS  PubMed  Google Scholar 

  87. Fernandez, D. & Perl, A. Metabolic control of T cell activation and death in SLE. Autoimmun. Rev. 8, 184–189 (2009).

    CAS  PubMed  Google Scholar 

  88. Fernandez, D. R. et al. Activation of mammalian target of rapamycin controls the loss of TCRζ in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J. Immunol. 182, 2063–2073 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Choi, S.-C. et al. Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells. Nat. Commun. 9, 4369 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. Kono, M. et al. Pyruvate dehydrogenase phosphatase catalytic subunit 2 limits Th17 differentiation. Proc. Natl Acad. Sci. USA 115, 9288–9293 (2018).

    CAS  PubMed  Google Scholar 

  91. Kono, M. et al. Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation. JCI Insight 4, e127395 (2019).

    PubMed Central  Google Scholar 

  92. Taylor, P. C. & Law, S. T. When the first visit to the rheumatologist is established rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 33, 101479 (2020).

    Google Scholar 

  93. Verburg, R. J. et al. Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration. Ann. Rheum. Dis. 64, 1397–1405 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Law, S. T. & Taylor, P. C. Role of biological agents in treatment of rheumatoid arthritis. Pharmacol. Res. 150, 104497 (2019).

    CAS  PubMed  Google Scholar 

  95. Nygaard, G. & Firestein, G. S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16, 316–333 (2020).

    PubMed  Google Scholar 

  96. Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).

    CAS  PubMed  Google Scholar 

  97. Grumbach, I. M. & Nguyen, E. K. Metabolic stress: mitochondrial function in neointimal formation. Arterioscler. Thromb. Vasc. Biol. 39, 991–997 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wadey, K., Lopes, J., Bendeck, M. & George, S. Role of smooth muscle cells in coronary artery bypass grafting failure. Cardiovasc. Res. 114, 601–610 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Tinajero, M. G. & Gotlieb, A. I. Recent developments in vascular adventitial pathobiology: the dynamic adventitia as a complex regulator of vascular disease. Am. J. Pathol. 190, 520–534 (2020).

    CAS  PubMed  Google Scholar 

  100. Croft, A. P. et al. Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage. Arthritis Res. Ther. 18, 270 (2016).

    PubMed  PubMed Central  Google Scholar 

  101. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    PubMed  PubMed Central  Google Scholar 

  102. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Finch, R. et al. Results of a phase 2 study of RG6125, an anti-cadherin-11 monoclonal antibody, in rheumatoid arthritis patients with an inadequate response to anti-TNFalpha therapy. Ann. Rheum. Dis. 78, abstr. OP0224 (2019).

    Google Scholar 

  104. Orr, C. et al. Synovial tissue research: a state-of-the-art review. Nat. Rev. Rheumatol. 13, 463–475 (2017).

    PubMed  Google Scholar 

  105. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Chakarov, S. et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363, eaau0964 (2019).

    CAS  PubMed  Google Scholar 

  107. Molawi, K. & Sieweke, M. H. Monocytes compensate Kupffer cell loss during bacterial infection. Immunity 42, 10–12 (2015).

    CAS  PubMed  Google Scholar 

  108. Murray, P. J. Immune regulation by monocytes. Semin. Immunol. 35, 12–18 (2018).

    CAS  PubMed  Google Scholar 

  109. Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).

    CAS  PubMed  Google Scholar 

  110. Udalova, I. A., Mantovani, A. & Feldmann, M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 472–485 (2016).

    CAS  PubMed  Google Scholar 

  111. Herenius, M. M. et al. Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab. Ann. Rheum. Dis. 70, 1160–1162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670–675 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kuo, D. et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci. Transl. Med. 11, eaau8587 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kang, Y. M. et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J. Exp. Med. 195, 1325–1336 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    CAS  PubMed  Google Scholar 

  116. Bocharnikov, A. V. et al. PD-1hiCXCR5 T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 4, e130062 (2019).

    PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang, S. et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nat. Commun. 9, 1758 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. Wu, B. et al. Succinyl-CoA ligase deficiency in pro-inflammatory and tissue-invasive T cells. Cell Metab. (in the press).

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Acknowledgements

This work was supported by the National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068 and P01 HL129941 to C.M.W.; and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191 and IO1 BX001669 to J.J.G.) and the Encrantz Family Discovery Fund.

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Weyand, C.M., Goronzy, J.J. The immunology of rheumatoid arthritis. Nat Immunol 22, 10–18 (2021). https://doi.org/10.1038/s41590-020-00816-x

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