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image of The TIM-3/Gal-9 Pathway: A Promising Therapeutic Target for Regulation of Immune Checkpoint in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune ailment that is marked by persistent synovial joint inflammation, which causes joint destruction and other systemic consequences. The immune system is equipped with a wide range of effector mechanisms that are capable of inflicting severe harm on pathogens that invade it, as well as inflicting severe harm on the body itself. The immune system must carefully regulate itself to avoid such damage to host tissues and restore equilibrium following an inflammatory response. In the peripheral immune system, the immune cell responses are regulated by a balance of positive and negative signals that are sent to effector cells to adjust them to their environment. The identification of immunological checkpoints has opened up new avenues for studying and perhaps modifying immune responses in the context of RA pathogenesis. T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a member of the TIM family, has emerged as a major regulator in immune checkpoint pathways, with several studies on its various functions in immunological homeostasis and autoimmune disorders. This review narrates the critical function of TIM-3 in the control of immunological checkpoints in rheumatoid arthritis also the potential role of TIM-3/GAL-9 signalling as a therapeutic target for the development of a new class of immunotherapeutic agents for the treatment of RA.

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2025-03-20
2025-09-06

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References

  1. Bolon B. Cellular and molecular mechanisms of autoimmune disease. Toxicol. Pathol. 2012 40 2 216 229 10.1177/0192623311428481 22105648
    [Google Scholar]
  2. Menichelli D. Cormaci V.M. Marucci S. Franchino G. Del Sole F. Capozza A. Fallarino A. Valeriani E. Violi F. Pignatelli P. Pastori D. Risk of venous thromboembolism in autoimmune diseases: A comprehensive review. Autoimmun. Rev. 2023 22 11 103447 10.1016/j.autrev.2023.103447 37714419
    [Google Scholar]
  3. Mechelli R. Romano S. Romano C. Morena E. Buscarinu M.C. Bigi R. Bellucci G. Reniè R. Pellicciari G. Salvetti M. Ristori G. Mait cells and microbiota in multiple sclerosis and other autoimmune diseases. Microorganisms 2021 9 6 1132 10.3390/microorganisms9061132 34074025
    [Google Scholar]
  4. Youssefi M. Tafaghodi M. Farsiani H. Ghazvini K. Keikha M. Helicobacter pylori infection and autoimmune diseases; Is there an association with systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis and autoimmune pancreatitis? A systematic review and meta-analysis study. J. Microbiol. Immunol. Infect. 2021 54 3 359 369 10.1016/j.jmii.2020.08.011 32891538
    [Google Scholar]
  5. Domingo S. Solé C. Moliné T. Ferrer B. Cortés-Hernández J. MicroRNAs in several cutaneous autoimmune diseases: Psoriasis, cutaneous lupus erythematosus and atopic dermatitis. Cells 2020 9 12 2656 10.3390/cells9122656 33321931
    [Google Scholar]
  6. Ferrari S.M. Fallahi P. Ruffilli I. Elia G. Ragusa F. Benvenga S. Antonelli A. The association of other autoimmune diseases in patients with Graves’ disease (with or without ophthalmopathy): Review of the literature and report of a large series. Autoimmun. Rev. 2019 18 3 287 292 10.1016/j.autrev.2018.10.001 30639646
    [Google Scholar]
  7. Yan J. Luo M. Chen Z. He B. The function and role of the Th17/Treg cell balance in inflammatory bowel disease. J. Immunol. Res. 2020 2020 1 8 10.1155/2020/8813558 33381606
    [Google Scholar]
  8. Radu A.F. Bungau S.G. Management of rheumatoid arthritis: An overview. Cells 2021 10 11 2857 10.3390/cells10112857 34831081
    [Google Scholar]
  9. Scherer H.U. Häupl T. Burmester G.R. The etiology of rheumatoid arthritis. J. Autoimmun. 2020 110 102400 10.1016/j.jaut.2019.102400 31980337
    [Google Scholar]
  10. Weyand C.M. Goronzy J.J. The immunology of rheumatoid arthritis. Nat. Immunol. 2021 22 1 10 18 10.1038/s41590‑020‑00816‑x 33257900
    [Google Scholar]
  11. Burmester G.R. Pope J.E. Novel treatment strategies in rheumatoid arthritis. Lancet 2017 389 10086 2338 2348 10.1016/S0140‑6736(17)31491‑5 28612748
    [Google Scholar]
  12. Chaudhari K. Rizvi S. Syed B.A. Rheumatoid arthritis: Current and future trends. Nat. Rev. Drug Discov. 2016 15 5 305 306 10.1038/nrd.2016.21 27080040
    [Google Scholar]
  13. Bullock J. Rizvi S.A.A. Saleh A.M. Ahmed S.S. Do D.P. Ansari R.A. Ahmed J. Rheumatoid arthritis: A brief overview of the treatment. Med. Princ. Pract. 2018 27 6 501 507 10.1159/000493390 30173215
    [Google Scholar]
  14. Scheinecker C. The Role of T Cells in Rheumatoid Arthritis. Rheumatoid Arthritis. Elsevier 2008 91 96 10.1016/B978‑032305475‑1.50018‑5
    [Google Scholar]
  15. Small A. Lowe K. Wechalekar M.D. Immune checkpoints in rheumatoid arthritis: Progress and promise. Front. Immunol. 2023 14 1285554 10.3389/fimmu.2023.1285554 38077329
    [Google Scholar]
  16. Carvalheiro H. da Silva J.A.P. Souto-Carneiro M.M. Potential roles for CD8+ T cells in rheumatoid arthritis. Autoimmun. Rev. 2013 12 3 401 409 10.1016/j.autrev.2012.07.011 22841983
    [Google Scholar]
  17. Van Der Vlist M Kuball J Radstake TRD Meyaard L Immune checkpoints and rheumatic diseases: What can cancer immunotherapy teach us? Nat. Rev. Rheumatol. 2016 12 10 593 604 10.1038/nrrheum.2016.131
    [Google Scholar]
  18. Jeurling S. Cappelli L.C. Treatment of immune checkpoint inhibitor-induced inflammatory arthritis. Curr. Opin. Rheumatol. 2020 32 3 315 320 10.1097/BOR.0000000000000701 32168068
    [Google Scholar]
  19. Lee J. Oh J-M. Hwang J.W. Ahn J.K. Bae E-K. Won J. Koh E-M. Cha H-S. Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis. Scand. J. Rheumatol. 2011 40 5 334 340 10.3109/03009742.2010.547871 21446887
    [Google Scholar]
  20. Liu Y. Shu Q. Gao L. Hou N. Zhao D. Liu X. Zhang X. Xu L. Yue X. Zhu F. Guo C. Liang X. Ma C. Increased Tim-3 expression on peripheral lymphocytes from patients with rheumatoid arthritis negatively correlates with disease activity. Clin. Immunol. 2010 137 2 288 295 10.1016/j.clim.2010.07.012 20805041
    [Google Scholar]
  21. Cooles F.A.H. Isaacs J.D. Anderson A.E. Treg cells in rheumatoid arthritis: An update. Curr. Rheumatol. Rep. 2013 15 9 352 10.1007/s11926‑013‑0352‑0 23888361
    [Google Scholar]
  22. O’Garra A. Robinson D. Development and function of T helper 1 cells. Adv. Immunol. 2004 83 133 162 10.1016/S0065‑2776(04)83004‑9 15135630
    [Google Scholar]
  23. Udagawa N. The mechanism of osteoclast differentiation from macrophages: Possible roles of T lymphocytes in osteoclastogenesis. J. Bone Miner. Metab. 2003 21 6 337 343 10.1007/s00774‑003‑0439‑1 14586789
    [Google Scholar]
  24. Mellado M. Martínez-Muñoz L. Cascio G. Lucas P. Pablos J.L. Rodríguez-Frade J.M. T cell migration in rheumatoid arthritis. Front. Immunol. 2015 6 384 10.3389/fimmu.2015.00384 26284069
    [Google Scholar]
  25. Cao D. Vollenhoven R. Klareskog L. Trollmo C. Malmström V. CD25brightCD4+regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res. Ther. 2004 6 4 R335 R346 10.1186/ar1192 15225369
    [Google Scholar]
  26. He Y. Cao J. Zhao C. Li X. Zhou C. Hirsch F. TIM-3, a promising target for cancer immunotherapy. OncoTargets Ther. 2018 11 7005 7009 10.2147/OTT.S170385 30410357
    [Google Scholar]
  27. Weyand C.M. Goronzy J.J. T-cell-targeted therapies in rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2006 2 4 201 210 10.1038/ncprheum0142 16932686
    [Google Scholar]
  28. Weyand C.M. Wu B. Goronzy J.J. The metabolic signature of T cells in rheumatoid arthritis. Curr. Opin. Rheumatol. 2020 32 2 159 167 10.1097/BOR.0000000000000683 31895885
    [Google Scholar]
  29. Broadley I. Pera A. Morrow G. Davies K.A. Kern F. Expansions of cytotoxic CD4+CD28− T cells drive excess cardiovascular mortality in rheumatoid arthritis and other chronic inflammatory conditions and are triggered by CMV infection. Front. Immunol. 2017 8 195 10.3389/fimmu.2017.00195 28303136
    [Google Scholar]
  30. Weyand C.M. Fulbright J.W. Goronzy J.J. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp. Gerontol. 2003 38 8 833 841 10.1016/S0531‑5565(03)00090‑1 12915205
    [Google Scholar]
  31. Lucas C. Perdriger A. Amé P. Definition of B cell helper T cells in rheumatoid arthritis and their behavior during treatment. Semin. Arthritis Rheum. 2020 50 5 867 872 10.1016/j.semarthrit.2020.06.021 32896702
    [Google Scholar]
  32. Kasakovski D. Xu L. Li Y. T cell senescence and CAR-T cell exhaustion in hematological malignancies. J. Hematol. Oncol. 2018 11 1 91 10.1186/s13045‑018‑0629‑x 29973238
    [Google Scholar]
  33. Fessler J. Husic R. Schwetz V. Lerchbaum E. Aberer F. Fasching P. Ficjan A. Obermayer-Pietsch B. Duftner C. Graninger W. Stradner M.H. Dejaco C. Senescent T-cells promote bone loss in rheumatoid arthritis. Front. Immunol. 2018 9 95 95 10.3389/fimmu.2018.00095 29472917
    [Google Scholar]
  34. Haque M. Fino K. Lei F. Xiong X. Song J. Utilizing regulatory T cells against rheumatoid arthritis. Front. Oncol. 2014 4 209 10.3389/fonc.2014.00209 25152867
    [Google Scholar]
  35. van Amelsfort J.M.R. Jacobs K.M.G. Bijlsma J.W.J. Lafeber F.P.J.G. Taams L.S. CD4+CD25+ regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004 50 9 2775 2785 10.1002/art.20499 15457445
    [Google Scholar]
  36. Möttönen M. Heikkinen J. Mustonen L. Isomäki P. Luukkainen R. Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Immunol. 2005 140 2 360 367 10.1111/j.1365‑2249.2005.02754.x 15807863
    [Google Scholar]
  37. Lawson C.A. Brown A.K. Bejarano V. Douglas S.H. Burgoyne C.H. Greenstein A.S. Boylston A.W. Emery P. Ponchel F. Isaacs J.D. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 2006 45 10 1210 1217 10.1093/rheumatology/kel089 16571607
    [Google Scholar]
  38. Moradi B. Schnatzer P. Hagmann S. Rosshirt N. Gotterbarm T. Kretzer J.P. Thomsen M. Lorenz H.M. Zeifang F. Tretter T. CD4+CD25+/highCD127low/- regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints—analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res. Ther. 2014 16 2 R97 10.1186/ar4545 24742142
    [Google Scholar]
  39. Jiang Q. Yang G. Liu Q. Wang S. Cui D. Function and role of regulatory T cells in rheumatoid arthritis. Front. Immunol. 2021 12 626193 10.3389/fimmu.2021.626193 33868244
    [Google Scholar]
  40. Behrens F. Himsel A. Rehart S. Stanczyk J. Beutel B. Zimmermann S.Y. Koehl U. Möller B. Gay S. Kaltwasser J.P. Pfeilschifter J.M. Radeke H.H. Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis. Ann. Rheum. Dis. 2007 66 9 1151 1156 10.1136/ard.2006.068320 17392348
    [Google Scholar]
  41. Li S. Yin H. Zhang K. Wang T. Yang Y. Liu X. Chang X. Zhang M. Yan X. Ren Y. Pan W. Zhang L. Effector T helper cell populations are elevated in the bone marrow of rheumatoid arthritis patients and correlate with disease severity. Sci. Rep. 2017 7 1 4776 10.1038/s41598‑017‑05014‑8 28684770
    [Google Scholar]
  42. Das M. Zhu C. Kuchroo V.K. Tim-3 and its role in regulating anti-tumor immunity. Immunol. Rev. 2017 276 1 97 111 10.1111/imr.12520 28258697
    [Google Scholar]
  43. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014 41 4 529 542 10.1016/j.immuni.2014.10.004 25367570
    [Google Scholar]
  44. Ma E.H. Bantug G. Griss T. Condotta S. Johnson R.M. Samborska B. Mainolfi N. Suri V. Guak H. Balmer M.L. Verway M.J. Raissi T.C. Tsui H. Boukhaled G. Henriques da Costa S. Frezza C. Krawczyk C.M. Friedman A. Manfredi M. Richer M.J. Hess C. Jones R.G. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2017 25 2 345 357 10.1016/j.cmet.2016.12.011 28111214
    [Google Scholar]
  45. Guo Y. Walsh A.M. Canavan M. Wechalekar M.D. Cole S. Yin X. Scott B. Loza M. Orr C. McGarry T. Bombardieri M. Humby F. Proudman S.M. Pitzalis C. Smith M.D. Friedman J.R. Anderson I. Madakamutil L. Veale D.J. Fearon U. Nagpal S. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS One 2018 13 2 e0192704 10.1371/journal.pone.0192704 29489833
    [Google Scholar]
  46. Paluch C. Santos A.M. Anzilotti C. Cornall R.J. Davis S.J. Immune checkpoints as therapeutic targets in autoimmunity. Front. Immunol. 2018 9 2306 10.3389/fimmu.2018.02306 30349540
    [Google Scholar]
  47. Zhang Y. Zheng J. Functions of immune checkpoint molecules beyond immune evasion. Adv. Exp. Med. Biol. 2020 1248 201 226 10.1007/978‑981‑15‑3266‑5_9 32185712
    [Google Scholar]
  48. Cutolo M. Sulli A. Paolino S. Pizzorni C. CTLA-4 blockade in the treatment of rheumatoid arthritis: An update. Expert Rev. Clin. Immunol. 2016 12 4 417 425 10.1586/1744666X.2016.1133295 26679631
    [Google Scholar]
  49. Gertel S. Polachek A. Elkayam O. Furer V. Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatment response in autoimmune diseases. Autoimmun. Rev. 2022 21 6 103085 10.1016/j.autrev.2022.103085 35341974
    [Google Scholar]
  50. Li S. Peng D. He Y. Zhang H. Sun H. Shan S. Song Y. Zhang S. Xiao H. Song H. Zhang M. Expression of TIM-3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis. Acta Pathol. Microbiol. Scand. Suppl. 2014 122 10 899 904 10.1111/apm.12228 24689929
    [Google Scholar]
  51. Chae S.C. Song J.H. Heo J.C. Lee Y.C. Kim J.W. Chung H.T. Molecular variations in the promoter and coding regions of human Tim-1 gene and their association in Koreans with asthma. Hum. Immunol. 2003 64 12 1177 1182 10.1016/j.humimm.2003.09.011 14630400
    [Google Scholar]
  52. Umetsu D.T. Umetsu S.E. Freeman G.J. DeKruyff R.H. TIM gene family and their role in atopic diseases. Curr. Top. Microbiol. Immunol. 2008 321 201 215 10.1007/978‑3‑540‑75203‑5_10 18727494
    [Google Scholar]
  53. McIntire J.J. Umetsu S.E. Macaubas C. Hoyte e.g. Cinnioglu C. Cavalli-Sforza L.L. Barsh G.S. Hallmayer J.F. Underhill P.A. Risch N.J. Freeman G.J. DeKruyff R.H. Umetsu D.T. Hepatitis A virus link to atopic disease. Nature 2003 425 6958 576 10.1038/425576a 14534576
    [Google Scholar]
  54. Kuchroo V.K. Umetsu D.T. DeKruyff R.H. Freeman G.J. The TIM gene family: Emerging roles in immunity and disease. Nat. Rev. Immunol. 2003 3 6 454 462 10.1038/nri1111 12776205
    [Google Scholar]
  55. Liu Y. Chen H. Chen Z. Qiu J. Pang H. Zhou Z. Novel roles of the tim family in immune regulation and autoimmune diseases. Front. Immunol. 2021 12 748787 10.3389/fimmu.2021.748787 34603337
    [Google Scholar]
  56. Kuchroo V.K. Dardalhon V. Xiao S. Anderson A.C. New roles for TIM family members in immune regulation. Nat. Rev. Immunol. 2008 8 8 577 580 10.1038/nri2366 18617884
    [Google Scholar]
  57. Jemielity S. Wang J.J. Chan Y.K. Ahmed A.A. Li W. Monahan S. Bu X. Farzan M. Freeman G.J. Umetsu D.T. DeKruyff R.H. Choe H. TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS Pathog. 2013 9 3 e1003232 10.1371/journal.ppat.1003232 23555248
    [Google Scholar]
  58. Monney L. Sabatos C.A. Gaglia J.L. Ryu A. Waldner H. Chernova T. Manning S. Greenfield E.A. Coyle A.J. Sobel R.A. Freeman G.J. Kuchroo V.K. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002 415 6871 536 541 10.1038/415536a 11823861
    [Google Scholar]
  59. Yeung M.Y. McGrath M. Najafian N. The emerging role of the TIM molecules in transplantation. Am. J. Transplant. 2011 11 10 2012 2019 10.1111/j.1600‑6143.2011.03727.x 21906254
    [Google Scholar]
  60. McIntire J.J. Umetsu S.E. Akbari O. Potter M. Kuchroo V.K. Barsh G.S. Freeman G.J. Umetsu D.T. DeKruyff R.H. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat. Immunol. 2001 2 12 1109 1116 10.1038/ni739 11725301
    [Google Scholar]
  61. Phong B.L. Avery L. Sumpter T.L. Gorman J.V. Watkins S.C. Colgan J.D. Kane L.P. Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation. J. Exp. Med. 2015 212 13 2289 2304 10.1084/jem.20150388 26598760
    [Google Scholar]
  62. Wada J. Kanwar Y.S. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J. Biol. Chem. 1997 272 9 6078 6086 10.1074/jbc.272.9.6078 9038233
    [Google Scholar]
  63. Zhao L. Cheng S. Fan L. Zhang B. Xu S. TIM-3: An update on immunotherapy. Int. Immunopharmacol. 2021 99 107933 10.1016/j.intimp.2021.107933 34224993
    [Google Scholar]
  64. Wolf Y Anderson AC Kuchroo VK TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol 2020 20 3 173 185 10.1038/s41577‑019‑0224‑6
    [Google Scholar]
  65. Kane L.P. Banerjee H. Immune regulation by Tim-3. F1000 Res. 2018 7 10.12688/F1000RESEARCH.13446.1/DOI
    [Google Scholar]
  66. Chiba S. Baghdadi M. Akiba H. Yoshiyama H. Kinoshita I. Dosaka-Akita H. Fujioka Y. Ohba Y. Gorman J.V. Colgan J.D. Hirashima M. Uede T. Takaoka A. Yagita H. Jinushi M. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 2012 13 9 832 842 10.1038/ni.2376 22842346
    [Google Scholar]
  67. Gandhi AK Kim WM Sun ZYJ Huang YH Bonsor DA Sundberg EJ High resolution X-ray and NMR structural study of human T-cell immunoglobulin and mucin domain containing protein-3. Sci Rep 2018 8 17512 10.1038/s41598‑018‑35754‑0
    [Google Scholar]
  68. Zhu C Sakuishi K Xiao S Sun Z Zaghouani S Gu G An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun. 2015 6 7657 10.1038/ncomms7072
    [Google Scholar]
  69. Anderson A.C. Anderson D.E. TIM-3 in autoimmunity. Curr. Opin. Immunol. 2006 18 6 665 669 10.1016/j.coi.2006.09.009 17011764
    [Google Scholar]
  70. Möller-Hackbarth K. Dewitz C. Schweigert O. Trad A. Garbers C. Rose-John S. Scheller J. A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J. Biol. Chem. 2013 288 48 34529 34544 10.1074/jbc.M113.488478 24121505
    [Google Scholar]
  71. Kikushige Y. TIM-3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways. Cancer Sci. 2021 112 9 3419 3426 10.1111/cas.15042 34159709
    [Google Scholar]
  72. Türeci Ö. Schmitt H. Fadle N. Pfreundschuh M. Sahin U. Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin’s disease. J. Biol. Chem. 1997 272 10 6416 6422 10.1074/jbc.272.10.6416 9045665
    [Google Scholar]
  73. Curtin J.F. Liu N. Candolfi M. Xiong W. Assi H. Yagiz K. Edwards M.R. Michelsen K.S. Kroeger K.M. Liu C. Muhammad A.K.M.G. Clark M.C. Arditi M. Comin-Anduix B. Ribas A. Lowenstein P.R. Castro M.G. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009 6 1 e1000010 10.1371/journal.pmed.1000010 19143470
    [Google Scholar]
  74. Laskari K. Sabu S. Distler O. Neidhart M. Karouzakis E. Huang X. POS0368 citrullination induces epigenetic memory of the innate immune system. Ann. Rheum. Dis. 2021 80 414 414 10.1136/annrheumdis‑2021‑eular.3302
    [Google Scholar]
  75. Li N. Wang Y. Forbes K. Vignali K.M. Heale B.S. Saftig P. Hartmann D. Black R.A. Rossi J.J. Blobel C.P. Dempsey P.J. Workman C.J. Vignali D.A.A. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J. 2007 26 2 494 504 10.1038/sj.emboj.7601520 17245433
    [Google Scholar]
  76. Breitkopf SB Yang X Begley MJ Kulkarni M Chiu YH Turke AB A cross-species study of PI3K protein-protein interactions reveals the direct interaction of P85 and SHP2. Sci Rep 2016 6 20471 10.1038/srep20471
    [Google Scholar]
  77. Skejoe C. Hansen A.S. Stengaard-Pedersen K. Junker P. Hoerslev-Pedersen K. Hetland M.L. Oestergaard M. Greisen S. Hvid M. Deleuran M. Deleuran B. T-cell immunoglobulin and mucin domain 3 is upregulated in rheumatoid arthritis, but insufficient in controlling inflammation. Am. J. Clin. Exp. Immunol. 2022 11 3 34 44 35874466
    [Google Scholar]
  78. Wang Y. Song L. Sun J. Sui Y. Li D. Li G. Liu J. Shu Q. Expression of Galectin-9 and correlation with disease activity and vascular endothelial growth factor in rheumatoid arthritis. Clin. Exp. Rheumatol. 2020 38 4 654 661 31820713
    [Google Scholar]
  79. Matsumoto H. Fujita Y. Asano T. Matsuoka N. Temmoku J. Sato S. Yashiro-Furuya M. Watanabe H. Migita K. T cell immunoglobulin and mucin domain-3 is associated with disease activity and progressive joint damage in rheumatoid arthritis patients. Medicine 2020 99 44 e22892 10.1097/MD.0000000000022892 33126340
    [Google Scholar]
  80. Han G. Chen G. Shen B. Li Y. Tim-3: An activation marker and activation limiter of innate immune cells. Front. Immunol. 2013 4 449 10.3389/fimmu.2013.00449 24339828
    [Google Scholar]
  81. Zhang Y. Ma C.J. Wang J.M. Ji X.J. Wu X.Y. Moorman J.P. Yao Z.Q. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. J. Leukoc. Biol. 2011 91 2 189 196 10.1189/jlb.1010591 21844165
    [Google Scholar]
  82. Chen H. Zha J. Tang R. Chen G. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3): Solving a key puzzle in autoimmune diseases. Int. Immunopharmacol. 2023 121 110418 10.1016/j.intimp.2023.110418 37290326
    [Google Scholar]
  83. Zhu C. Anderson A.C. Schubart A. Xiong H. Imitola J. Khoury S.J. Zheng X.X. Strom T.B. Kuchroo V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 2005 6 12 1245 1252 10.1038/ni1271 16286920
    [Google Scholar]
  84. Isshiki T. Akiba H. Nakayama M. Harada N. Okumura K. Homma S. Miyake S. Cutting edge: Anti–TIM-3 treatment exacerbates pulmonary inflammation and fibrosis in mice. J. Immunol. 2017 199 11 3733 3737 10.4049/jimmunol.1700059 29061768
    [Google Scholar]
  85. Bailly C. Thuru X. Quesnel B. Modulation of the Gal-9/TIM-3 immune checkpoint with α-Lactose. Does anomery of lactose matter? Cancers 2021 13 24 6365 10.3390/cancers13246365 34944985
    [Google Scholar]
  86. Cao E. Zang X. Ramagopal U.A. Mukhopadhaya A. Fedorov A. Fedorov E. Zencheck W.D. Lary J.W. Cole J.L. Deng H. Xiao H. DiLorenzo T.P. Allison J.P. Nathenson S.G. Almo S.C. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity 2007 26 3 311 321 10.1016/j.immuni.2007.01.016 17363302
    [Google Scholar]
  87. Christopher D Koehn Y.Y. Yu Y. Koehn C.D. Zhang Z. Su K. Galectins in the pathogenesis of rheumatoid arthritis. J. Clin. Cell. Immunol. 2013 4 5 1000164 10.4172/2155‑9899.1000164 24416634
    [Google Scholar]
  88. Kanzaki M. Wada J. Sugiyama K. Nakatsuka A. Teshigawara S. Murakami K. Inoue K. Terami T. Katayama A. Eguchi J. Akiba H. Yagita H. Makino H. Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. Endocrinology 2012 153 2 612 620 10.1210/en.2011‑1579 22186414
    [Google Scholar]
  89. Seki M. Oomizu S. Sakata K. Sakata A. Arikawa T. Watanabe K. Ito K. Takeshita K. Niki T. Saita N. Nishi N. Yamauchi A. Katoh S. Matsukawa A. Kuchroo V. Hirashima M. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin. Immunol. 2008 127 1 78 88 10.1016/j.clim.2008.01.006 18282810
    [Google Scholar]
  90. Pan H.F. Zhang N. Li W.X. Tao J.H. Ye D.Q. TIM-3 as a new therapeutic target in systemic lupus erythematosus. Mol. Biol. Rep. 2010 37 1 395 398 10.1007/s11033‑009‑9833‑7 19768575
    [Google Scholar]
  91. Wiersma V.R. Clarke A. Pouwels S.D. Perry E. Abdullah T.M. Kelly C. Soyza A.D. Hutchinson D. Eggleton P. Bremer E. Galectin-9 is a possible promoter of immunopathology in rheumatoid arthritis by activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes. Int. J. Mol. Sci. 2019 20 16 4046 10.3390/ijms20164046 31430907
    [Google Scholar]
  92. Wang Z. Chang C. Lu Q. Epigenetics of CD4+ T cells in autoimmune diseases. Curr. Opin. Rheumatol. 2017 29 4 361 368 10.1097/BOR.0000000000000393 28362657
    [Google Scholar]
  93. Catrina A.I. Joshua V. Klareskog L. Malmström V. Mechanisms involved in triggering rheumatoid arthritis. Immunol. Rev. 2016 269 1 162 174 10.1111/imr.12379 26683152
    [Google Scholar]
/content/journals/crr/10.2174/0115733971330865250312075719
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The TIM-3/Gal-9 Pathway: A Promising Therapeutic Target for Regulation of Immune Checkpoint in Rheumatoid Arthritis
Bentham Science Publishers ; https://doi.org/10.2174/0115733971330865250312075719
/content/journals/crr/10.2174/0115733971330865250312075719
/content/journals/crr/10.2174/0115733971330865250312075719
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  • Article Type:     Review Article
Keywords: autoimmune disease ; Rheumatoid arthritis ; T cells ; TIM-3 ; Gal-9 ; regulatory T cell ; immune checkpoint inhibitor ; immune checkpoint

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