Inmunosenescencia y autoinmunidad: Mecanismos e implicaciones patológicas

Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther. 2023;8(1):200.

Montoya G. Immunosenescence. In: Autoimmunity: From Bench to Bedside Anaya JM, Shoenfeld Y, Villaraga A, Roger L, Cervera R. Bogotá: Universidad del Rosario; 2013. p. 185–201.

Ramos-Casals M, Brito-Zerón P, Kostov B, Sisó-Almirall A, Bosch X, Buss D, et al. Google-driven search for big data in autoimmune geoepidemiology: Analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun Rev. 2015;14(8):670–9.

Zheng Y, Liu Q, Goronzy JJ, Weyand CM. Immune aging – A mechanism in autoimmune disease. Semin Immunol. 2023;69:101814.

Lindstrom TM, Robinson WH. Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc. 2010;58(8):1565–75.

Goronzy JJ, Weyand CM. Immune aging and autoimmunity. Cellular and Molecular Life Sciences. 2012;69(10):1615–23.

Liu Q, Zheng Y, Goronzy JJ, Weyand CM. T cell aging as a risk factor for autoimmunity. J Autoimmun. 2023;137:102947.

Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19(1):10–9.

Ucar D, Márquez EJ, Chung CH, Marches R, Rossi RJ, Uyar A, et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. Journal of Experimental Medicine. 2017;214(10):3123–44.

Fulop T, Witkowski JM, Pawelec G, Alan C, Larbi A. On the Immunological Theory of Aging. In 2014. p. 163–76.

Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front Immunol. 2018;9.

Elyahu Y, Monsonego A. Thymus involution sets the clock of the aging T-cell landscape: Implications for declined immunity and tissue repair. Ageing Res Rev. 2021;65:101231.

Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nat Immunol. 2021;22(6):687–98.

Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med. 2006;12(10):1133–8.

Sanderson SL, Simon AK. In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell. 2017;16(6):1234–43.

Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, et al. The Loss of Telomerase Activity in Highly Differentiated CD8+CD28− CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation. The Journal of Immunology. 2007;178(12):7710–9.

Kell L, Simon AK, Alsaleh G, Cox LS. The central role of DNA damage in immunosenescence. Frontiers in Aging. 2023;4.

Desdín-Micó G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E, Gabandé-Rodríguez E, et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science (1979). 2020;368(6497):1371–6.

Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, et al. Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging. 2019;11(21):9234–63.

Desdín-Micó G, Soto-Heredero G, Mittelbrunn M. Mitochondrial activity in T cells. Mitochondrion. 2018;41:51–7.

Quinn KM, Palchaudhuri R, Palmer CS, La Gruta NL. The clock is ticking: the impact of ageing on T cell metabolism. Clin Transl Immunology. 2019;8(11).

Soto-Heredero G, Gómez de las Heras MM, Gabandé-Rodríguez E, Oller J, Mittelbrunn M. Glycolysis – a key player in the inflammatory response. FEBS J. 2020;287(16):3350–69.

Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, et al. Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction. The Journal of Immunology. 2015;195(6):2624–32.

Sen P, Shah PP, Nativio R, Berger SL. Epigenetic Mechanisms of Longevity and Aging. Cell. 2016;166(4):822–39.

Hu B, Jadhav RR, Gustafson CE, Le Saux S, Ye Z, Li X, et al. Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells. Front Immunol. 2020;11.

Ucar D, Márquez EJ, Chung CH, Marches R, Rossi RJ, Uyar A, et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. Journal of Experimental Medicine. 2017;214(10):3123–44.

Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, et al. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol. 2017;2(8).

Zhang Y, Wilson R, Heiss J, Breitling LP, Saum KU, Schöttker B, et al. DNA methylation signatures in peripheral blood strongly predict all-cause mortality. Nat Commun. 2017;8(1):14617.

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Mol Cell. 2013;49(2):359–67.

Wilson CB, Makar KW, Shnyreva M, Fitzpatrick DR. DNA methylation and the expanding epigenetics of T cell lineage commitment. Semin Immunol. 2005;17(2):105–19.

Cheung P, Vallania F, Warsinske HC, Donato M, Schaffert S, Chang SE, et al. Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell. 2018;173(6):1385-1397. e14.

Liggett LA, Sankaran VG. Unraveling Hematopoiesis through the Lens of Genomics. Cell. 2020;182(6):1384–400.

Bogeska R, Mikecin AM, Kaschutnig P, Fawaz M, Büchler-Schäff M, Le D, et al. Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell. 2022;29(8):1273-1284.e8.

Caruso C, Ligotti ME, Accardi G, Aiello A, Candore G. An immunologist’s guide to immunosenescence and its treatment. Expert Rev Clin Immunol. 2022;18(9):961–81.

Cancro MP. Age-Associated B Cells. Annu Rev Immunol. 2020;38(1):315–40.

Zhou D, Borsa M, Simon AK. Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells. Aging Cell. 2021;20(2).

Frasca D, Diaz A, Romero M, Garcia D, Blomberg BB. B Cell Immunosenescence. Annu Rev Cell Dev Biol. 2020;36(1):551–74.

Hao Y, O’Neill P, Naradikian MS, Scholz JL, Cancro MP. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood. 2011;118(5):1294–304.

Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, et al. Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front Immunol. 2019;10:2247.

Xu W, Larbi A. Markers of T Cell Senescence in Humans. Int J Mol Sci. 2017;18(8):1742.

Teissier T, Boulanger E, Cox LS. Interconnections between Inflammageing and Immunosenescence during Ageing. Cells. 2022;11(3):359.

Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2011;10(3):330–5.

Bulati M, Caruso C, Colonna-Romano G. From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing.” Ageing Res Rev. 2017;36:125–36.

Brauning A, Rae M, Zhu G, Fulton E, Admasu TD, Stolzing A, et al. Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions. Cells. 2022;11(6):1017.

Fulop T, Larbi A, Pawelec G, Khalil A, Cohen AA, Hirokawa K, et al. Immunology of Aging: the Birth of Inflammaging. Clin Rev Allergy Immunol. 2021;64(2):109–22.

Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90.

Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol. 2018;8.

Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. The Lancet. 2023;402(10416):2019–33.

Bauer ME. Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression. Immunity & Ageing. 2020;17(1):6.

Thewissen M, Somers V, Venken K, Linsen L, Van Paassen P, Geusens P, et al. Analyses of immunosenescent markers in patients with autoimmune disease. Clinical Immunology. 2007;123(2):209–18.

Thewissen M, Linsen L, Somers V. Premature Immunosenescence in Rheumatoid Arthritis and Multiple Sclerosis Patients. Ann N Y Acad Sci. 2005;1051(1):255–62.

Chalan P, van den Berg A, Kroesen BJ, Brouwer L, Boots A. Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging. Curr Aging Sci. 2015;8(2):131–46.

Barbé-Tuana F, Funchal G, Schmitz CRR, Maurmann RM, Bauer ME. The interplay between immunosenescence and age-related diseases. Semin Immunopathol. 2020;42(5):545–57.

Schönland SO, Lopez C, Widmann T, Zimmer J, Bryl E, Goronzy JJ, et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proceedings of the National Academy of Sciences. 2003;100(23):13471–6.

Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, af Klint E, et al. Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007;9(5):R87.

Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 1997;40(6):1106–14.

Pieper J, Johansson S, Snir O, Linton L, Rieck M, Buckner JH, et al. Peripheral and Site-Specific CD scp> 4 + CD 28 null T Cells from Rheumatoid Arthritis Patients Show Distinct Characteristics. Scand J Immunol. 2014;79(2):149–55.

Liu Y, Chen Y, Richardson B. Decreased DNA methyltransferase levels contribute to abnormal gene expression in “senescent” CD4(+)CD28(-) T cells. Clin Immunol. 2009;132(2):257–65.

Gerli R, Schillaci G, Giordano A, Bocci EB, Bistoni O, Vaudo G, et al. CD4+CD28− T Lymphocytes Contribute to Early Atherosclerotic Damage in Rheumatoid Arthritis Patients. Circulation. 2004;109(22):2744–8.

Scarsi M, Zigliogli T, Airó P. Decreased Circulating CD28-negative T Cells in Patients with Rheumatoid Arthritis Treated with Abatacept Are Correlated with Clinical Response. J Rheumatol. 2010;37(5):911–6.

Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708–12.

Li Z yu, Cai ML, Qin Y, Chen Z. Age/autoimmunity-associated B cells in inflammatory arthritis: An emerging therapeutic target. Front Immunol. 2023;14.

Qin Y, Cai ML, Jin HZ, Huang W, Zhu C, Bozec A, et al. Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways. Ann Rheum Dis. 2022;81(11):1504–14.

Fessler J, Raicht A, Husic R, Ficjan A, Schwarz C, Duftner C, et al. Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis. Front Immunol. 2017;8.

Del Rey MJ, Valín Á, Usategui A, Ergueta S, Martín E, Municio C, et al. Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Immunity & Ageing. 2019;16(1):29.

Shibatomi K, Ida H, Yamasaki S, Nakashima T, Origuchi T, Kawakami A, et al. A novel role for interleukin-18 in human natural killer cell death: high serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases. Arthritis Rheum. 2001;44(4):884–92.

Sagiv A, Krizhanovsky V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology. 2013;14(6):617–28.

Steer SE, Williams FMK, Kato B, Gardner JP, Norman PJ, Hall MA, et al. Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration. Ann Rheum Dis. 2006;66(4):476–80.

Costenbader KH, Prescott J, Zee RY, De Vivo I. Immunosenescence and rheumatoid arthritis: Does telomere shortening predict impending disease? Autoimmun Rev. 2011;10(9):569–73.

Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proceedings of the National Academy of Sciences. 2000;97(16):9203–8.

Li Y, Shen Y, Hohensinner P, Ju J, Wen Z, Goodman SB, et al. Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity. 2016;45(4):903–16.

Da Sylva TR, Connor A, Mburu Y, Keystone E, Wu GE. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2005;7(4):R844-51.

Hajizadeh S, DeGroot J, TeKoppele JM, Tarkowski A, Collins LV. Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis. Arthritis Res Ther. 2003;5(5):R234.

Tsokos GC. Systemic Lupus Erythematosus. New England Journal of Medicine. 2011;365(22):2110–21.

Suárez-Fueyo A, Bradley SJ, Tsokos GC. T cells in Systemic Lupus Erythematosus. Curr Opin Immunol. 2016;43:32–8.

Kurien BT, Scofield RH. Lipid peroxidation in systemic lupus erythematosus. Indian J Exp Biol. 2006;44(5):349–56.

Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46(1):175–90.

Kahlenberg JM, Kaplan MJ. The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? Curr Opin Rheumatol. 2014;26(5):475–81.

Li KJ, Wu CH, Hsieh SC, Lu MC, Tsai CY, Yu CL. Deranged bioenergetics and defective redox capacity in T lymphocytes and neutrophils are related to cellular dysfunction and increased oxidative stress in patients with active systemic lupus erythematosus. Clin Dev Immunol. 2012;2012:548516.

Su YJ, Cheng TT, Chen CJ, Chang WN, Tsai NW, Kung CT, et al. Investigation of the caspase-dependent mitochondrial apoptotic pathway in mononuclear cells of patients with systemic lupus erythematosus. J Transl Med. 2014;12(1):303.

Lee HT, Lin CS, Chen WS, Liao HT, Tsai CY, Wei YH. Leukocyte Mitochondrial DNA Alteration in Systemic Lupus Erythematosus and Its Relevance to the Susceptibility to Lupus Nephritis. Int J Mol Sci. 2012;13(7):8853–68.

Tsai CY. Oxidative DNA and mitochondrial DNA change in patients with SLE. Frontiers in Bioscience. 2017;22(3):4497.

Beier F, Balabanov S, Amberger CC, Hartmann U, Manger K, Dietz K, et al. Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow- FISH. Lupus. 2007;16(12):955–62.

Wu CH, Hsieh SC, Li KJ, Lu MC, Yu CL. Premature telomere shortening in polymorphonuclear neutrophils from patients with systemic lupus erythematosus is related to the lupus disease activity. Lupus. 2007;16(4):265–72.

Kurosaka D, Yasuda J, Yoshida K, Yoneda A, Yasuda C, Kingetsu I, et al. Abnormal telomerase activity and telomere length in T and B cells from patients with systemic lupus erythematosus. J Rheumatol. 2006;33(6):1102–7.

López P, Rodríguez-Carrio J, Martínez-Zapico A, Caminal-Montero L, Suarez A. Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. J Leukoc Biol. 2016;99(3):405–12.

Rekik R, Smiti Khanfir M, Larbi T, Zamali I, Beldi-Ferchiou A, Kammoun O, et al. Impaired TGF-β signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22. Cytokine. 2018;108:182–9.

van den Hoogen L, Sims G, van Roon J, Fritsch- Stork R. Aging and Systemic Lupus Erythematosus - Immunosenescence and Beyond. Curr Aging Sci. 2015;8(2):158–77.

Ruan P, Wang S, Yang M, Wu H. The ABC-associated immunosenescence and lifestyle interventions in autoimmune disease. Rheumatology and Immunology Research. 2022;3(3):128–35.

Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol. 2021;17(2):98–108.

Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022;605(7909):349– 56.

Lundberg IE, Fujimoto M, Vencovsky J, Aggarwal R, Holmqvist M, Christopher-Stine L, et al. Idiopathic inflammatory myopathies. Nat Rev Dis Primers. 2021;7(1):86.

Strioga M, Pasukoniene V, Characiejus D. CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology. 2011;134(1):17–32.

McLeish E, Slater N, Sooda A, Wilson A, Coudert JD, Lloyd TE, et al. Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity. Best Pract Res Clin Rheumatol. 2022;36(2):101761.

Fasth AER, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, et al. T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells. The Journal of Immunology. 2009;183(7):4792–9.

Knauss S, Preusse C, Allenbach Y, Leonard-Louis S, Touat M, Fischer N, et al. PD1 pathway in immune-mediated myopathies. Neurol Neuroimmunol Neuroinflamm. 2019;6(3).

Nelke C, Kleefeld F, Preusse C, Ruck T, Stenzel W. Inclusion body myositis and associated diseases: an argument for shared immune pathologies. Acta Neuropathol Commun. 2022;10(1):84.

Greenberg SA, Pinkus JL, Kong SW, Baecher-Allan C, Amato AA, Dorfman DM. Highly differentiated cytotoxic T cells in inclusion body myositis. Brain. 2019;142(9):2590–604.

Goyal NA, Coulis G, Duarte J, Farahat PK, Mannaa AH, Cauchii J, et al. Immunophenotyping of Inclusion Body Myositis Blood T and NK Cells. Neurology. 2022;98(13):e1374–83.

Vallejo AN, Mueller RG, Hamel DL, Way A, Dvergsten JA, Griffin P, et al. Expansions of NK-like αβT cells with chronologic aging: Novel lymphocyte effectors that compensate for functional deficits of conventional NK cells and T cells. Ageing Res Rev. 2011;10(3):354–61.

Greenberg SA. Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol. 2019;15(5):257–72.

Lindgren U, Roos S, Hedberg Oldfors C, Moslemi AR, Lindberg C, Oldfors A. Mitochondrial pathology in inclusion body myositis. Neuromuscular Disorders. 2015;25(4):281–8.

Morosetti R, Broccolini A, Sancricca C, Gliubizzi C, Gidaro T, Tonali PA, et al. Increased aging in primary muscle cultures of sporadic inclusion-body myositis. Neurobiol Aging. 2010;31(7):1205–14.

De Rossi M, Bernasconi P, Baggi F, de Waal Malefyt R, Mantegazza R. Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. Int Immunol. 2000;12(9):1329–35.

Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol. 2019;15(7):753– 64.

Volkmann ER, Andréasson K, Smith V. Systemic sclerosis. The Lancet. 2023;401(10373):304–18.

Martyanov V, Whitfield ML, Varga J. Senescence Signature in Skin Biopsies From Systemic Sclerosis Patients Treated With Senolytic Therapy: Potential Predictor of Clinical Response? Arthritis & Rheumatology. 2019;71(10):1766–7.

Dumit VI, Küttner V, Käppler J, Piera-Velazquez S, Jimenez SA, Bruckner-Tuderman L, et al. Altered MCM Protein Levels and Autophagic Flux in Aged and Systemic Sclerosis Dermal Fibroblasts. Journal of Investigative Dermatology. 2014;134(9):2321– 30.

Shen CY, Li KJ, Lai PH, Yu CL, Hsieh SC. Anti-CENP-B and anti-TOPO-1-containing sera from systemic sclerosis-related diseases with Raynaud’s phenomenon induce vascular endothelial cell senescence not via classical p53-p21 pathway. Clin Rheumatol. 2018;37(3):749–56.

Romano E, Rosa I, Fioretto BS, Manetti M. The contribution of endothelial cells to tissue fibrosis. Curr Opin Rheumatol. 2024;36(1):52–60.

Di Benedetto P, Ruscitti P, Berardicurti O, Vomero M, Navarini L, Dolo V, et al. Endothelial-to-mesenchymal transition in systemic sclerosis. Clin Exp Immunol. 2021;205(1):12–27.

Manetti M, Romano E, Rosa I, Guiducci S, Bellando-Randone S, De Paulis A, et al. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann Rheum Dis. 2017;76(5):924–34.

Chiu YH, Spierings J, van Laar JM, de Vries-Bouwstra JK, van Dijk M, Goldschmeding R. Association of endothelial to mesenchymal transition and cellular senescence with fibrosis in skin biopsies of systemic sclerosis patients: a cross-sectional study. Clin Exp Rheumatol. 2023;41(8):1612-1617

Usategui A, Municio C, Arias-Salgado EG, Martín M, Fernández-Varas B, Del Rey MJ, et al. Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis. Immun Ageing. 2022;19(1):7.

Tsou P, Talia NN, Pinney AJ, Kendzicky A, Piera-Velazquez S, Jimenez SA, et al. Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts. Arthritis Rheum. 2012;64(6):1978–89.

Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini G, et al. Oxidative stress in scleroderma: Maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum. 2001;44(11):2653–64.

Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8(1):14532.

Coppé JP, Desprez PY, Krtolica A, Campisi J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Review of Pathology: Mechanisms of Disease. 2010;5(1):99– 118.

Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310–21.

Carvalheiro T, Zimmermann M, Radstake TRDJ, Marut W. Novel insights into dendritic cells in the pathogenesis of systemic sclerosis. Clin Exp Immunol. 2020;201(1):25–33.

Liu Q, Zaba LC, Satpathy AT, Longmire M, Zhang W, Li K, et al. Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis. Nat Commun. 2020;11(1):5843.

Impellizzieri D, Egholm C, Valaperti A, Distler O, Boyman O. Patients with systemic sclerosis show phenotypic and functional defects in neutrophils. Allergy. 2022;77(4):1274–84.

Benyamine A, Magalon J, Sabatier F, Lyonnet L, Robert S, Dumoulin C, et al. Natural Killer Cells Exhibit a Peculiar Phenotypic Profile in Systemic Sclerosis and Are Potent Inducers of Endothelial Microparticles Release. Front Immunol. 2018;9:1665.

Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: Expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–27.

Mavropoulos A, Simopoulou T, Varna A, Liaskos C, Katsiari CG, Bogdanos DP, et al. Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis. Arthritis & Rheumatology. 2016;68(2):494–504.

Dumoitier N, Chaigne B, Régent A, Lofek S, Mhibik M, Dorfmüller P, et al. Scleroderma Peripheral B Lymphocytes Secrete Interleukin-6 and Transforming Growth Factor β and Activate Fibroblasts. Arthritis & Rheumatology. 2017;69(5):1078–89.

Paleja B, Low AHL, Kumar P, Saidin S, Lajam A, Nur Hazirah S, et al. Systemic Sclerosis Perturbs the Architecture of the Immunome. Front Immunol. 2020;11:1602.

Radstakes TRDJ, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, et al. The Pronounced Th17 Profile in Systemic Sclerosis (SSc) Together with Intracellular Expression of TGFβ and IFNγ Distinguishes SSc Phenotypes. PLoS One. 2009;4(6):e5903.

Maehara T, Kaneko N, Perugino CA, Mattoo H, Kers , Jesper, Allard-Chamard H, et al. Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. Journal of Clinical Investigation. 2020;130(5):2451–64.

Reiff A, Krogstad P, Moore S, Shaham B, Parkman R, Kitchen C, et al. Study of thymic size and function in children and adolescents with treatment refractory systemic sclerosis eligible for immunoablative therapy. Clinical Immunology. 2009;133(3):295–302.

Meunier M, Bazeli R, Feydy A, Drape JL, Kahan A, Allanore Y. Incomplete thymic involution in systemic sclerosis and rheumatoid arthritis. Joint Bone Spine. 2013;80(1):48–51.

Ferri C, Colaci M, Battolla L, Giuggioli D, Sebastiani M. Thymus alterations and systemic sclerosis. Rheumatology. 2006;45(1):72–5.

Servaas NH, Zaaraoui-Boutahar F, Wichers CGK, Ottria A, Chouri E, Affandi AJ, et al. Longitudinal analysis of T-cell receptor repertoires reveals persistence of antigen-driven CD4+ and CD8+ T-cell clusters in systemic sclerosis. J Autoimmun. 2021;117:102574.

Sakkas LI, Xu B, Artlett CM, Lu S, Jimenez SA, Platsoucas CD. Oligoclonal T Cell Expansion in the Skin of Patients with Systemic Sclerosis. The Journal of Immunology. 2002;168(7):3649–59.

Arruda LCM, Malmegrim KCR, Lima-Júnior JR, Clave E, Dias JBE, Moraes DA, et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2018;2(2):126–41.

Farge D, Arruda LCM, Brigant F, Clave E, Douay C, Marjanovic Z, et al. Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. J Hematol Oncol. 2017;10(1):21.

Zhou X, Trinh-Minh T, Tran-Manh C, Gießl A, Bergmann C, Györfi A, et al. Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis. Arthritis & Rheumatology. 2022;74(5):871–81.

Ryu C, Walia A, Ortiz V, Perry C, Woo S, Reeves BC, et al. Bioactive Plasma Mitochondrial DNA Is Associated With Disease Progression in Scleroderma Associated Interstitial Lung Disease. Arthritis & Rheumatology. 2020;72(11):1905–15.

Park JA, Lee J, Kim HR, Fujii H, Weyand CM, Goronzy JJ, et al. AB0050 Immunosenescence of T and B cells in systemic sclerosis. Ann Rheum Dis. 2013;71(Suppl 3):640.10-640.

Adler BL, Boin F, Wolters PJ, Bingham CO, Shah AA, Greider C, et al. Autoantibodies targeting telomere-associated proteins in systemic sclerosis. Ann Rheum Dis. 2021;80(7):912–9.

Lakota K, Varga J. Linking autoimmunity, short telomeres and lung fibrosis in SSc. Nat Rev Rheumatol. 2021;17(9):511–2.

Lee SH, Lee JH, Lee HY, Min KJ. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019;52(1):24–34.

Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017;18(4):447–76.

Akamata K, Wei J, Bhattacharyya M, Cheresh P, Bonner MY, Arbiser JL, et al. SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget. 2016;7(43):69321–36.

Manetti M, Rosa I, Fioretto BS, Matucci-Cerinic M, Romano E. Decreased Serum Levels of SIRT1 and SIRT3 Correlate with Severity of Skin and Lung Fibrosis and Peripheral Microvasculopathy in Systemic Sclerosis. J Clin Med. 2022;11(5):1362.

Brito-Zerón P, Baldini C, Bootsma H, Bowman SJ, Jonsson R, Mariette X, et al. Sjögren syndrome. Nat Rev Dis Primers. 2016;2(1):16047.

Mihai A, Caruntu C, Jurcut C, Blajut FC, Casian M, Opris-Belinski D, et al. The Spectrum of Extraglandular Manifestations in Primary Sjögren’s Syndrome. J Pers Med. 2023;13(6):961.

Kurosawa M, Shikama Y, Furukawa M, Arakaki R, Ishimaru N, Matsushita K. Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sjögren’s Syndrome Model Mice. Int J Mol Sci. 2021;22(5):2302.

Smoleńska Ż, Pawłowska J, Zdrojewski Z, Daca A, Bryl E. Increased percentage of CD8+CD28− T cells correlates with clinical activity in primary Sjögren’s syndrome. Cell Immunol. 2012;278(1– 2):143–51.

Fessler J, Fasching P, Raicht A, Hammerl S, Weber J, Lackner A, et al. Lymphopenia in primary Sjögren’s syndrome is associated with premature aging of naïve CD4+ T cells. Rheumatology. 2021;60(2):588–97.

Wang X, Bootsma H, Terpstra J, Vissink A, van der Vegt B, Spijkervet FKL, et al. Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren’s syndrome. Rheumatology. 2020;59(10):3003–13.

Zong Y, Yang Y, Zhao J, Li L, Luo D, Hu J, et al. Characterisation of macrophage infiltration and polarisation based on integrated transcriptomic and histological analyses in Primary Sjögren’s syndrome. Front Immunol. 2023;14:1292146.

Pringle S, Wang X, Verstappen GMPJ, Terpstra JH, Zhang CK, He A, et al. Salivary Gland Stem Cells Age Prematurely in Primary Sjögren’s Syndrome. Arthritis & Rheumatology. 2019;71(1):133–42.

Peng X, Wu Y, Brouwer U, van Vliet T, Wang B, Demaria M, et al. Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche. Cell Death Dis. 2020;11(10):854.

Kawashima M, Kawakita T, Maida Y, Kamoi M, Ogawa Y, Shimmura S, et al. Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjögren syndrome and non-Sjögren syndrome dry eye patients. Mol Vis. 2011;17:1397–404.

Lu C, Pi X, Xu W, Qing P, Tang H, Li Y, et al. Clinical significance of T cell receptor repertoire in primary Sjogren’s syndrome. EBioMedicine. 2022;84:104252.

Zheng Q, Huang J, Wang G. Mitochondria, Telomeres and Telomerase Subunits. Front Cell Dev Biol. 2019;7.

Javorova P, Fessler J, Rammerstorfer C, Zeiler M, Muralikrishnan AS, Lackner A, et al. POS0294 MITOCHONDRIAL DYSFUNCTION AND SENESCENCE OF NAÏVE T CELLS IN SJÖGREN´S SYNDROME. In: Scientific Abstracts. BMJ Publishing Group Ltd and European League Against Rheumatism; 2023. p. 389.1-389.

Yoon J, Lee M, Ali AA, Oh YR, Choi YS, Kim S, et al. Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjӧgren’s syndrome. Mol Ther Nucleic Acids. 2022;30:257–69.

Shi H, Zheng L, Zhang P, Yu C. miR-146a and miR- 155 expression in PBMC s from patients with Sjögren’s syndrome. Journal of Oral Pathology & Medicine. 2014;43(10):792–7.

Weyand CM, Goronzy JJ. Mediumand Large-Vessel Vasculitis. New England Journal of Medicine. 2003;349(2):160–9.

Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127–34.

Maciejewski-Duval A, Comarmond C, Leroyer A, Zaidan M, Le Joncour A, Desbois AC, et al. mTOR pathway activation in large vessel vasculitis. J Autoimmun. 2018;94:99–109.

Arriola Apelo SI, Lamming DW. Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island. J Gerontol A Biol Sci Med Sci. 2016;71(7):841–9.

Ianni A, Kumari P, Tarighi S, Argento FR, Fini E, Emmi G, et al. An Insight into Giant Cell Arteritis Pathogenesis: Evidence for Oxidative Stress and SIRT1 Downregulation. Antioxidants. 2021;10(6):885.

Jiemy WF, van Sleen Y, Graver JC, Pringle S, Brouwer E, van der Geest KSM, et al. Indication of Activated Senescence Pathways in the Temporal Arteries of Patients With Giant Cell Arteritis. Arthritis & Rheumatology. 2023;75(10):1812–8.

Antonio AA, Santos RN, Abariga SA. Tocilizumab for giant cell arteritis. Cochrane Database of Systematic Reviews. 2022;2022(5).

Cid MC, Unizony SH, Blockmans D, Brouwer E, Dagna L, Dasgupta B, et al. Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(5):653–61.

Kurata A, Saito A, Hashimoto H, Fujita K, Ohno S ichiro, Kamma H, et al. Difference in immunohistochemical characteristics between Takayasu arteritis and giant cell arteritis: It may be better to distinguish them in the same age. Mod Rheumatol. 2019;29(6):992–1001.

Dejaco C, Duftner C, Al-Massad J, Wagner AD, Park JK, Fessler J, et al. NKG 2 D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica. Ann Rheum Dis. 2013;72(11):1852–9.

Jin K, Wen Z, Wu B, Zhang H, Qiu J, Wang Y, et al. NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis. Journal of Clinical Investigation. 2021;131(1).

Watanabe R, Hashimoto M. Pathogenic role of monocytes/macrophages in large vessel vasculitis. Front Immunol. 2022;13.

Watanabe R, Maeda T, Zhang H, Berry GJ, Zeisbrich M, Brockett R, et al. MMP (Matrix Metalloprotease)-9–Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res. 2018;123(6):700–15.

Coit P, De Lott LB, Nan B, Elner VM, Sawalha AH. DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis. Ann Rheum Dis. 2016;75(6):1196–202.

Croci S, Zerbini A, Boiardi L, Muratore F, Bisagni A, Nicoli D, et al. MicroRNA markers of inflammation and remodelling in temporal arteries from patients with giant cell arteritis. Ann Rheum Dis. 2016;75(8):1527–33.

Kim C, Hu B, Jadhav RR, Jin J, Zhang H, Cavanagh MM, et al. Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells. Cell Rep. 2018;25(8):2148-2162.e5.

Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11.

Moosig F, Csernok E, Wang G, Gross WL. Costimulatory molecules in Wegener’s granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells. Clin Exp Immunol. 2001;114(1):113–8.

Kerstein A, Schüler S, Cabral-Marques O, Fazio J, Häsler R, Müller A, et al. Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis. J Autoimmun. 2017;78:79–91.

Lamprecht P. CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener’s granulomatosis. Thorax. 2001;56(10):751–7.

Vogt S, Iking-Konert C, Hug F, Andrassy K, Hänsch GM. Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener’s granulomatosis. Kidney Int. 2003;63(6):2144–51.

Eriksson P, Sandell C, Backteman K, Ernerudh J. Expansions of CD4+CD28– and CD8+CD28– T cells in Granulomatosis with Polyangiitis and Microscopic Polyangiitis Are Associated with Cytomegalovirus Infection But Not with Disease Activity. J Rheumatol. 2012;39(9):1840–3.

Anaya JM, Lozada-Martinez ID, Torres I, Shoenfeld Y. Autoimmunity in centenarians. A paradox. J Transl Autoimmun. 2024;8:100237.

Anaya JM, Monsalve DM, Rojas M, Rodríguez Y, Montoya-García N, Mancera-Navarro LM, et al. Latent rheumatic, thyroid and phospholipid autoimmunity in hospitalized patients with COVID-19. J Transl Autoimmun. 2021;4:100091.

Meroni PL, Mari D, Monti D, Coppola R, Capri M, Salvioli S, et al. Anti-beta 2 glycoprotein I antibodies in centenarians. Exp Gerontol. 2004;39(10):1459–65.

Avrameas S, Alexopoulos H, Moutsopoulos HM. Natural Autoantibodies: An Undersugn Hero of the Immune System and Autoimmune Disorders—A Point of View. Front Immunol. 2018;9:1320.

Ahuja SK, Manoharan MS, Lee GC, McKinnon LR, Meunier JA, Steri M, et al. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Nat Commun. 2023;14(1):3286.

Zhou L, Ge M, Zhang Y, Wu X, Leng M, Gan C, et al. Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells. Front Pharmacol. 2022;13:877709.

Frankowska N, Bryl E, Fulop T, Witkowski JM. Longevity, Centenarians and Modified Cellular Proteodynamics. Int J Mol Sci. 2023;24(3):2888.

Santos-Lozano A, Santamarina A, Pareja-Galeano H, Sanchis-Gomar F, Fiuza-Luces C, Cristi-Montero C, et al. The genetics of exceptional longevity: Insights from centenarians. Maturitas. 2016;90:49–57.