Skip to main content

Advertisement

SpringerLink
Log in

The role of NK cells in rheumatoid arthritis

  • Review
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Natural killer (NK) cells are part of the innate immune system which not only provides a primary response to pathogenic conditions but can also play an important regulatory role in immune responses. Furthermore, these cells can influence immune responses by affecting other involved cells. Human NK cells can be classified as CD56dim and CD56bright; the former demonstrates mostly cytotoxic effects, while the latter comprises mostly tolerant or regulatory NK cells. These cells participate in the immunopathogenesis of rheumatoid arthritis (RA) and their role remains still unclear.

Methods

We searched PubMed/MEDLINE and Scopus databases to review and analyze relevant literature on the impact of NK cells in the pathogenesis of RA.

Results

Although the percentage of NK cells increases in peripheral blood of RA patients compared to healthy individuals, the cytotoxic function of these cells is impaired. It is demonstrated by reduced “perforin+ NK cells” and decreased per-cell lytic function. These cytotoxic NK cells may control the pathogenic bone absorptive function of osteoclasts by directly targeting these cells.

Conclusion

Collectively, the evidence collected in the current review emphasizes the possible protective role of CD56dim NK cells in the pathogenesis of RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2019;15(1):9–17. https://doi.org/10.1038/s41584-018-0109-2.

    Article  CAS  PubMed  Google Scholar 

  2. Holers VM, Demoruelle MK, Kuhn KA, Buckner JH, Robinson WH, Okamoto Y, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol. 2018;14(9):542–57. https://doi.org/10.1038/s41584-018-0070-0.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jeong HJ, Sohn IW, Kim D, Cho SK, Park SB, Sung IH, et al. Impact of midfoot and Hindfoot involvement on functional disability in Korean patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2017;18(1):365. https://doi.org/10.1186/s12891-017-1726-7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ball EM, Bell AL. Lupus arthritis–do we have a clinically useful classification? Rheumatology. 2012;51(5):771–9. https://doi.org/10.1093/rheumatology/ker381.

    Article  PubMed  Google Scholar 

  5. Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular manifestations in rheumatoid arthritis. Maedica. 2010;5(4):286–91.

    PubMed  PubMed Central  Google Scholar 

  6. Prete M, Racanelli V, Digiglio L, Vacca A, Dammacco F, Perosa F. Extra-articular manifestations of rheumatoid arthritis: an update. Autoimmun Rev. 2011;11(2):123–31. https://doi.org/10.1016/j.autrev.2011.09.001.

    Article  PubMed  Google Scholar 

  7. Fu B, Tian Z, Wei H. Subsets of human natural killer cells and their regulatory effects. Immunology. 2014;141(4):483–9. https://doi.org/10.1111/imm.12224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mandal A, Viswanathan C. Natural killer cells: In health and disease. Hematol Oncol Stem Cell Ther. 2015;8(2):47–55. https://doi.org/10.1016/j.hemonc.2014.11.006.

    Article  PubMed  Google Scholar 

  9. Karmakar S, Kay J, Gravallese EM. Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention. Rheum Dis Clin North Am. 2010;36(2):385–404. https://doi.org/10.1016/j.rdc.2010.03.003.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64. https://doi.org/10.1038/nrrheum.2012.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Braun T, Zwerina J. Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis Res Ther. 2011;13(4):235. https://doi.org/10.1186/ar3380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(9):1068–76. https://doi.org/10.1093/rheumatology/kel045.

    Article  CAS  Google Scholar 

  13. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(Suppl 5):v3-11. https://doi.org/10.1093/rheumatology/kes113.

    Article  CAS  Google Scholar 

  14. Mellado M, Martínez-Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM. T cell migration in rheumatoid arthritis. Front Immunol. 2015;6:384. https://doi.org/10.3389/fimmu.2015.00384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204(12):2803–12. https://doi.org/10.1084/jem.20071397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kosmaczewska A, Swierkot J, Ciszak L, Wiland P. The role of Th1, Th17, and Treg cells in the pathogenesis of rheumatoid arthritis including anti-inflammatory action of Th1 cytokines. Postepy Hig Med Dosw(Online). 2011;65:397–403.

    Article  Google Scholar 

  17. Colin EM, Asmawidjaja PS, van Hamburg JP, Mus AM, van Driel M, Hazes JM, et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis Rheum. 2010;62(1):132–42. https://doi.org/10.1002/art.25043.

    Article  CAS  PubMed  Google Scholar 

  18. Kunwar S, Dahal K, Sharma S. Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36(8):1065–75. https://doi.org/10.1007/s00296-016-3480-9.

    Article  CAS  PubMed  Google Scholar 

  19. Wei M, Duan D. Efficacy and safety of monoclonal antibodies targeting interleukin-17 pathway for inflammatory arthritis: a meta-analysis of randomized controlled clinical trials. Drug Des Dev Ther. 2016;10:2771–7. https://doi.org/10.2147/dddt.s91374.

    Article  CAS  Google Scholar 

  20. Lee YH, Bae SC. Associations between circulating IL-17 levels and rheumatoid arthritis and between IL-17 gene polymorphisms and disease susceptibility: a meta-analysis. Postgrad Med J. 2017;93(1102):465–71. https://doi.org/10.1136/postgradmedj-2016-134637.

    Article  CAS  PubMed  Google Scholar 

  21. Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med. 2007;204(1):41–7. https://doi.org/10.1084/jem.20062259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lai Kwan Lam Q, King Hung Ko O, Zheng BJ, Lu L. Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proceed Natl Acad Sci USA. 2008;105(39):14993–8. https://doi.org/10.1073/pnas.0806044105.

    Article  Google Scholar 

  23. Li J, Hsu HC, Mountz JD. The dynamic duo-inflammatory M1 macrophages and Th17 cells in rheumatic diseases. J Ortho Rheumatol. 2013;1(1):4. https://doi.org/10.13188/2334-2846.1000002.

    Article  Google Scholar 

  24. Agalioti T, Villablanca EJ, Huber S, Gagliani N. T(H)17 cell plasticity: The role of dendritic cells and molecular mechanisms. J Autoimmun. 2018;87:50–60. https://doi.org/10.1016/j.jaut.2017.12.003.

    Article  CAS  PubMed  Google Scholar 

  25. Sun W, Zhang H, Wang H, Chiu YG, Wang M, Ritchlin CT, et al. Targeting notch-activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis. J Bone Mineral Res Off J Am Soc Bone Miner Res. 2017;32(7):1469–80. https://doi.org/10.1002/jbmr.3117.

    Article  CAS  Google Scholar 

  26. Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009;126(4):458–65. https://doi.org/10.1111/j.1365-2567.2008.03027.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yamin R, Berhani O, Peleg H, Aamar S, Stein N, Gamliel M, et al. High percentages and activity of synovial fluid NK cells present in patients with advanced stage active rheumatoid arthritis. Sci Rep. 2019;9(1):1351. https://doi.org/10.1038/s41598-018-37448-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wythe SE, Nicolaidou V, Horwood NJ. Cells of the immune system orchestrate changes in bone cell function. Calcif Tissue Int. 2014;94(1):98–111. https://doi.org/10.1007/s00223-013-9764-0.

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka Y, Maruo A, Fujii K, Nomi M, Nakamura T, Eto S, et al. Intercellular adhesion molecule 1 discriminates functionally different populations of human osteoblasts: characteristic involvement of cell cycle regulators. J Bone Mineral Res Off J Am Soc Bone Miner Res. 2000;15(10):1912–23. https://doi.org/10.1359/jbmr.2000.15.10.1912.

    Article  CAS  Google Scholar 

  30. Feng S, Madsen SH, Viller NN, Neutzsky-Wulff AV, Geisler C, Karlsson L, et al. Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro. Immunology. 2015;145(3):367–79. https://doi.org/10.1111/imm.12449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kurachi T, Morita I, Murota S. Involvement of adhesion molecules LFA-1 and ICAM-1 in osteoclast development. Biochem Biophys Acta. 1993;1178(3):259–66. https://doi.org/10.1016/0167-4889(93)90202-z.

    Article  CAS  PubMed  Google Scholar 

  32. Kakehi S, Nakahama K, Morita I. Expression and possible role of PVR/CD155/Necl-5 in osteoclastogenesis. Mol Cell Biochem. 2007;301(1–2):209–17. https://doi.org/10.1007/s11010-007-9413-x.

    Article  CAS  PubMed  Google Scholar 

  33. Colucci S, Brunetti G, Cantatore FP, Oranger A, Mori G, Pignataro P, et al. The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis. Apoptosis Int J Program Cell Death. 2007;12(9):1623–32. https://doi.org/10.1007/s10495-007-0095-3.

    Article  CAS  Google Scholar 

  34. Kovacić N, Lukić IK, Grcević D, Katavić V, Croucher P, Marusić A. The Fas/Fas ligand system inhibits differentiation of murine osteoblasts but has a limited role in osteoblast and osteoclast apoptosis. J Immunol. 2007. https://doi.org/10.4049/jimmunol.178.6.3379.

    Article  PubMed  Google Scholar 

  35. Song K, Chen Y, Göke R, Wilmen A, Seidel C, Göke A, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med. 2000;191(7):1095–104. https://doi.org/10.1084/jem.191.7.1095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408(6812):600–5. https://doi.org/10.1038/35046102.

    Article  CAS  PubMed  Google Scholar 

  37. McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, et al. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996;2(2):175–82. https://doi.org/10.1038/nm0296-175.

    Article  CAS  PubMed  Google Scholar 

  38. Thurkow EW, van der Heijden IM, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, et al. Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis. J Pathol. 1997;181(4):444–50. https://doi.org/10.1002/(sici)1096-9896(199704)181:4%3c444::aid-path778%3e3.0.co;2-o.

    Article  CAS  PubMed  Google Scholar 

  39. Andersson AK, Feldmann M, Brennan FM. Neutralizing IL-21 and IL-15 inhibits pro-inflammatory cytokine production in rheumatoid arthritis. Scand J Immunol. 2008;68(1):103–11. https://doi.org/10.1111/j.1365-3083.2008.02118.x.

    Article  CAS  PubMed  Google Scholar 

  40. Ogata Y, Kukita A, Kukita T, Komine M, Miyahara A, Miyazaki S, et al. A novel role of IL 15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol. 1999;162(5):2754–60.

    CAS  PubMed  Google Scholar 

  41. Söderström K, Stein E, Colmenero P, Purath U, Müller-Ladner U, de Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci USA. 2010;107(29):13028–33. https://doi.org/10.1073/pnas.1000546107.

    Article  PubMed  Google Scholar 

  42. Takeda H, Kikuchi T, Soboku K, Okabe I, Mizutani H, Mitani A, et al. Effect of IL-15 and natural killer cells on osteoclasts and osteoblasts in a mouse coculture. Inflammation. 2014;37(3):657–69. https://doi.org/10.1007/s10753-013-9782-0.

    Article  CAS  PubMed  Google Scholar 

  43. Pridgeon C, Lennon GP, Pazmany L, Thompson RN, Christmas SE, Moots RJ. Natural killer cells in the synovial fluid of rheumatoid arthritis patients exhibit a CD56bright, CD94bright, CD158negative phenotype. Rheumatology (Oxford). 2003;42(7):870–8. https://doi.org/10.1093/rheumatology/keg240.

    Article  CAS  Google Scholar 

  44. de Matos CT, Berg L, Michaëlsson J, Felländer-Tsai L, Kärre K, Söderström K. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology. 2007;122(2):291–301. https://doi.org/10.1111/j.1365-2567.2007.02638.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Milush JM, López-Vergès S, York VA, Deeks SG, Martin JN, Hecht FM, et al. CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology. 2013;10:158. https://doi.org/10.1186/1742-4690-10-158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Voiculescu C, Avramescu C, Balasoiu M, Turculeanu A, Radu E. Changes of blood CD16/CD56 (NK) and HLA-DR/CD3-positive lymphocyte amounts in HIV-infected children, as related to clinical progression and p24-antigen/p24-antibody presence. FEMS Immunol Med Microbiol. 1994;9(3):217–21. https://doi.org/10.1111/j.1574-695X.1994.tb00496.x.

    Article  CAS  PubMed  Google Scholar 

  47. Hu PF, Hultin LE, Hultin P, Hausner MA, Hirji K, Jewett A, et al. Natural killer cell immunodeficiency in HIV disease is manifest by profoundly decreased numbers of CD16+CD56+ cells and expansion of a population of CD16dimCD56- cells with low lytic activity. J Acquir Immun Def Syndr Human Retrovirol Off Pub Int Retrovirol Assoc. 1995;10(3):331–40.

    CAS  Google Scholar 

  48. Gonzalez VD, Falconer K, Björkström NK, Blom KG, Weiland O, Ljunggren HG, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol. 2009. https://doi.org/10.4049/jimmunol.0901437.

    Article  PubMed  Google Scholar 

  49. Björkström NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med. 2011;208(1):13–21. https://doi.org/10.1084/jem.20100762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Antonioli CM, Airò P. Dermatomyositis associated with lymphoproliferative disorder of NK cells and occult small cell lung carcinoma. Clin Rheumatol. 2004;23(3):239–41. https://doi.org/10.1007/s10067-003-0814-2.

    Article  PubMed  Google Scholar 

  51. Nguyen S, Morel V, Le Garff-Tavernier M, Bolgert F, Leblond V, Debré P, et al. Persistence of CD16+/CD56-/2B4+ natural killer cells: a highly dysfunctional NK subset expanded in ocular myasthenia gravis. J Neuroimmunol. 2006;179(1–2):117–25. https://doi.org/10.1016/j.jneuroim.2006.05.028.

    Article  CAS  PubMed  Google Scholar 

  52. Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood. 2005;106(10):3366–9. https://doi.org/10.1182/blood-2005-03-1100.

    Article  CAS  PubMed  Google Scholar 

  53. Barker E, Martinson J, Brooks C, Landay A, Deeks S. Dysfunctional natural killer cells, in vivo, are governed by HIV viremia regardless of whether the infected individual is on antiretroviral therapy. AIDS (London, England). 2007;21(17):2363–5. https://doi.org/10.1097/QAD.0b013e3282f1d658.

    Article  Google Scholar 

  54. Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer-cell subsets associated with high levels of HIV-1 viremia. Blood. 2009;114(18):3822–30. https://doi.org/10.1182/blood-2009-06-226332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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. https://doi.org/10.1002/1529-0131(200104)44:4%3c884::aid-anr145%3e3.0.co;2-4.

    Article  CAS  PubMed  Google Scholar 

  56. Dalbeth N, Callan MF. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum. 2002;46(7):1763–72. https://doi.org/10.1002/art.10410.

    Article  PubMed  Google Scholar 

  57. Dalbeth N, Gundle R, Davies RJ, Lee YC, McMichael AJ, Callan MF. CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a reciprocal program of activation. J Immunol. 2004. https://doi.org/10.4049/jimmunol.173.10.6418.

    Article  PubMed  Google Scholar 

  58. Shegarfi H, Naddafi F, Mirshafiey A. Natural killer cells and their role in rheumatoid arthritis: friend or foe? The Sci World J. 2012. https://doi.org/10.1100/2012/491974.

    Article  Google Scholar 

  59. Aramaki T, Ida H, Izumi Y, Fujikawa K, Huang M, Arima K, et al. A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. Mod Rheumatol. 2009;19(3):245–52. https://doi.org/10.1007/s10165-009-0160-6.

    Article  PubMed  Google Scholar 

  60. Fathollahi A, Aslani S, Mostafaei S, Rezaei N, Mahmoudi M. The role of killer-cell immunoglobulin-like receptor (KIR) genes in susceptibility to inflammatory bowel disease: systematic review and meta-analysis. Inflamm Res Off J Euro Histamine Res Soc. 2018;67(9):727–36. https://doi.org/10.1007/s00011-018-1162-7.

    Article  CAS  Google Scholar 

  61. Horton NC, Mathew PA. NKp44 and natural cytotoxicity receptors as damage-associated molecular pattern recognition receptors. Front Immunol. 2015;6:31. https://doi.org/10.3389/fimmu.2015.00031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gunturi A, Berg RE, Forman J. The role of CD94/NKG2 in innate and adaptive immunity. Immunol Res. 2004;30(1):29–34. https://doi.org/10.1385/ir:30:1:029.

    Article  CAS  PubMed  Google Scholar 

  63. Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res. 2015;3(6):575–82. https://doi.org/10.1158/2326-6066.cir-15-0098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Meyaard L. LAIR and collagens in immune regulation. Immunol Lett. 2010;128(1):26–8. https://doi.org/10.1016/j.imlet.2009.09.014.

    Article  CAS  PubMed  Google Scholar 

  65. Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 2013;121(18):3599–608. https://doi.org/10.1182/blood-2012-04-425397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10. https://doi.org/10.1038/ni1582.

    Article  CAS  PubMed  Google Scholar 

  67. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735–47. https://doi.org/10.1038/nri911.

    Article  CAS  PubMed  Google Scholar 

  68. Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol. 2017;8:1124. https://doi.org/10.3389/fimmu.2017.01124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fauriat C, Long EO, Ljunggren HG, Bryceson YT. Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood. 2010;115(11):2167–76. https://doi.org/10.1182/blood-2009-08-238469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Della Chiesa M, Marcenaro E, Sivori S, Carlomagno S, Pesce S, Moretta A. Human NK cell response to pathogens. Semin Immunol. 2014;26(2):152–60. https://doi.org/10.1016/j.smim.2014.02.001.

    Article  CAS  PubMed  Google Scholar 

  71. Crouse J, Xu HC, Lang PA, Oxenius A. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol. 2015;36(1):49–58. https://doi.org/10.1016/j.it.2014.11.001.

    Article  CAS  PubMed  Google Scholar 

  72. Lee SH, Kim KS, Fodil-Cornu N, Vidal SM, Biron CA. Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. J Exp Med. 2009;206(10):2235–51. https://doi.org/10.1084/jem.20082387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL, et al. Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe. 2009;6(6):503–12. https://doi.org/10.1016/j.chom.2009.11.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cook KD, Kline HC, Whitmire JK. NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection. J Leukoc Biol. 2015;98(2):153–62. https://doi.org/10.1189/jlb.4HI1214-594R.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Parisi L, Bassani B, Tremolati M, Gini E, Farronato G, Bruno A. Natural killer cells in the orchestration of chronic inflammatory diseases. J Immunol Res. 2017;2017:4218254. https://doi.org/10.1155/2017/4218254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Freudenberg J, Gregersen P, Li W. Enrichment of genetic variants for rheumatoid arthritis within T-cell and NK-cell enhancer regions. Mol Med (Cambridge, Mass). 2015;21(1):180–4. https://doi.org/10.2119/molmed.2014.00252.

    Article  CAS  Google Scholar 

  77. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42. https://doi.org/10.1038/nature01658.

    Article  CAS  PubMed  Google Scholar 

  78. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4(8):638–49. https://doi.org/10.1038/nrg1122.

    Article  CAS  PubMed  Google Scholar 

  79. Firestein GS, Xu WD, Townsend K, Broide D, Alvaro-Gracia J, Glasebrook A, et al. Cytokines in chronic inflammatory arthritis I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988. https://doi.org/10.1084/jem.168.5.1573.

    Article  PubMed  Google Scholar 

  80. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 1990;345(6274):442–4. https://doi.org/10.1038/345442a0.

    Article  CAS  PubMed  Google Scholar 

  81. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998;95(7):3597–602. https://doi.org/10.1073/pnas.95.7.3597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Shigeyama Y, Pap T, Kunzler P, Simmen BR, Gay RE, Gay S. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 2000;43(11):2523–30. https://doi.org/10.1002/1529-0131(200011)43:11%3c2523::aid-anr20%3e3.0.co;2-z.

    Article  CAS  PubMed  Google Scholar 

  83. Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Investig. 2003;111(6):821–31. https://doi.org/10.1172/jci16069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li P, Schwarz EM, O’Keefe RJ, Ma L, Boyce BF, Xing L. RANK signaling is not required for TNFalpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Mineral Res Off J Am Soc Bone Mineral Res. 2004;19(2):207–13. https://doi.org/10.1359/jbmr.0301233.

    Article  CAS  Google Scholar 

  85. Zwerina J, Hayer S, Tohidast-Akrad M, Bergmeister H, Redlich K, Feige U, et al. Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum. 2004;50(1):277–90. https://doi.org/10.1002/art.11487.

    Article  CAS  PubMed  Google Scholar 

  86. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Investig. 2005;115(2):282–90. https://doi.org/10.1172/jci23394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19. https://doi.org/10.1016/s0092-8674(00)80209-3.

    Article  CAS  PubMed  Google Scholar 

  88. Geusens P. The role of RANK ligand/osteoprotegerin in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2012;4(4):225–33. https://doi.org/10.1177/1759720x12438080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Remuzgo-Martínez S, Genre F, López-Mejías R, Ubilla B, Mijares V, Pina T, et al. Expression of osteoprotegerin and its ligands, RANKL and TRAIL, in rheumatoid arthritis. Sci Rep. 2016;6:29713. https://doi.org/10.1038/srep29713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chalan P, Bijzet J, Kroesen BJ, Boots AM, Brouwer E. Altered natural killer cell subsets in seropositive arthralgia and early rheumatoid arthritis are associated with autoantibody status. J Rheumatol. 2016;43(6):1008–16. https://doi.org/10.3899/jrheum.150644.

    Article  PubMed  Google Scholar 

  91. Lurati A, Bertani L, Marrazza M, Re KA, Bompane D, Scarpellini M. NK cell count as predictor of clinical response in patients with rheumatoid arthritis treated with rituximab. Biol Targets Ther. 2012;6:83–7. https://doi.org/10.2147/btt.s29079.

    Article  CAS  Google Scholar 

  92. Daïen CI, Gailhac S, Audo R, Mura T, Hahne M, Combe B, et al. High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis. Rheumatology (Oxford). 2015;54(4):601–8. https://doi.org/10.1093/rheumatology/keu363.

    Article  CAS  Google Scholar 

  93. Zhu J, Jia E, Zhou Y, Xu J, Feng Z, Wang H, et al. Interleukin-22 secreted by NKp44+ natural killer cells promotes proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Medicine. 2015;94(52): e2137. https://doi.org/10.1097/md.0000000000002137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Thanapati S, Ganu M, Giri P, Kulkarni S, Sharma M, Babar P, et al. Impaired NK cell functionality and increased TNF-α production as biomarkers of chronic chikungunya arthritis and rheumatoid arthritis. Hum Immunol. 2017;78(4):370–4. https://doi.org/10.1016/j.humimm.2017.02.006.

    Article  CAS  PubMed  Google Scholar 

  95. Nazari M, Mahmoudi M, Rahmani F, Akhlaghi M, Beigy M, Azarian M, et al. Association of killer cell immunoglobulin- like receptor genes in iranian patients with rheumatoid arthritis. PLoS ONE. 2015;10(12): e0143757. https://doi.org/10.1371/journal.pone.0143757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yusa S, Catina TL, Campbell KS. KIR2DL5 can inhibit human NK cell activation via recruitment of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2). J Immunol. 2004. https://doi.org/10.4049/jimmunol.172.12.7385.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Anwar Fathollahi and Leila Nejatbakhsh Samimi contributed equally.

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Anwar Fathollahi

  2. Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Kargar Ave., Tehran, Iran

    Leila Nejatbakhsh Samimi, Maassoumeh Akhlaghi, Ahmadreza Jamshidi, Mahdi Mahmoudi & Elham Farhadi

  3. Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Maassoumeh Akhlaghi, Mahdi Mahmoudi & Elham Farhadi

Authors
  1. Anwar Fathollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leila Nejatbakhsh Samimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maassoumeh Akhlaghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ahmadreza Jamshidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahdi Mahmoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elham Farhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AF, LN, and MA contributed to the acquisition and interpretation of data and drafting the article. AJ, MM*, and EF* contributed to the interpretation of data, conception and design of the study, and critical revision of the article for important intellectual content. All authors contributed to the revision of the manuscript, read, and gave final approval for the submitted version of the article.

Corresponding author

Correspondence to Elham Farhadi.

Ethics declarations

Conflict of interest

The authors declared that they have no conflict of interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fathollahi, A., Samimi, L.N., Akhlaghi, M. et al. The role of NK cells in rheumatoid arthritis. Inflamm. Res. 70, 1063–1073 (2021). https://doi.org/10.1007/s00011-021-01504-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-021-01504-8

Keywords

Search

Navigation