English
French
T Helper 17-Like Regulatory T Cells in Equine Synovial Fluid Are Associated With Disease Severity of Naturally Occurring Posttraumatic Osteoarthritis.
Abstract: Infiltration of cluster of differentiation (CD) 3 (CD3) T cells into the synovium and synovial fluid occurs in most patients with posttraumatic osteoarthritis. During disease progression, proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells infiltrate the joint in response to inflammation. This study aimed to characterize the dynamics of regulatory T and T helper 17 cell populations in synovial fluid from equine clinical patients with posttraumatic osteoarthritis to determine whether phenotype and function are associated with potential immunotherapeutic targets. An imbalance of the ratio of regulatory T cells and T helper 17 cells would be associated with disease progression in posttraumatic osteoarthritis, suggesting opportunities for immunomodulatory therapy. Descriptive laboratory study. Synovial fluid was aspirated from the joints of equine clinical patients undergoing arthroscopic surgery for posttraumatic osteoarthritis resulting from intra-articular fragmentation. Joints were classified as having mild or moderate posttraumatic osteoarthritis. Synovial fluid was also obtained from nonoperated horses with normal cartilage. Peripheral blood was obtained from horses with normal cartilage and those with mild and moderate posttraumatic osteoarthritis. Synovial fluid and peripheral blood cells were analyzed by flow cytometry, and native synovial fluid was analyzed by enzyme-linked immunosorbent assay. CD3 T cells represented 81% of lymphocytes in synovial fluid, which increased in animals with moderate posttraumatic osteoarthritis to 88.3% ( = .02). CD14 macrophages were doubled in those with moderate posttraumatic osteoarthritis compared with mild posttraumatic osteoarthritis and controls ( < .001). Less than 5% of CD3 T cells found within the joint were forkhead box P3 protein (Foxp3) regulatory T cells, but a 4- to 8-times higher percentage of nonoperated and mild posttraumatic osteoarthritis joint regulatory T cells secreted interleukin (IL)-10 than peripheral blood Tregs ( < .005). T regulatory-1 cells that secreted IL-10 but did not express Foxp3 accounted for approximately 5% of CD3 T cells in all joints. T helper 17 cells and Th17-like regulatory T cells were increased in those with moderate posttraumatic osteoarthritis ( < .0001) compared with mild and nonoperated patients. IL-10, IL-17A, IL-6, chemokine (C-C motif) ligand (CCL) 2 (CCL2), and CCL5 concentrations detected by enzyme-linked immunosorbent assay in synovial fluid were not different between groups. An imbalance of the ratio of regulatory T cells and T helper 17 cells and an increase in T helper 17 cell-like regulatory T cells in synovial fluid from joints with more severe disease provide novel insights into immunological mechanisms that are associated with posttraumatic osteoarthritis progression and pathogenesis. Early and targeted use of immunotherapeutics in the mitigation of posttraumatic osteoarthritis may improve patient clinical outcomes.
Publication Date: 2023-02-16 PubMed ID: 36794851PubMed Central: PMC10375548DOI: 10.1177/03635465231153588Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research investigates the dynamic relationship between Regulatory T cells and T Helper 17 cells in the synovial fluid of horses with posttraumatic osteoarthritis. The study discovered an imbalance in these cell populations associated with the severity of the disease, suggesting potential future targets for immunotherapy.
Research Methodology
- The research team carried out a descriptive laboratory study where they aspirated synovial fluid from the joints of horses with posttraumatic osteoarthritis. These horses were undergoing arthroscopic surgery due to intra-articular fragmentation.
- The team classified the joints as either having mild or moderate posttraumatic osteoarthritis. They also obtained synovial fluid from non-operated horses with normal cartilage.
- Peripheral blood was drawn from horses with normal cartilage and those with mild and moderate posttraumatic osteoarthritis.
- The researchers analysed the synovial fluid and peripheral blood cells using flow cytometry. They also conducted enzyme-linked immunosorbent assay (ELISA) tests on the native synovial fluid.
Research Findings
- The study revealed that 81% of lymphocytes in synovial fluid were CD3 T cells. This percentage increased to 88.3% in animals with moderate posttraumatic osteoarthritis.
- The population of CD14 macrophages doubled in horses with moderate posttraumatic osteoarthritis compared to those with mild osteoarthritis and controls.
- Less than 5% of CD3 T cells found within the joint were forkhead box P3 protein (Foxp3) regulatory T cells. However, regulatory T cells from the joints of non-operated and mildly affected horses secreted 4 to 8 times more interleukin (IL)-10 than the peripheral blood Tregs.
- T regulatory-1 cells that secreted IL-10 but did not express Foxp3 represented around 5% of CD3 T cells in all joints.
- T helper 17 cells and Th17-like regulatory T cells increased in horses with moderate posttraumatic osteoarthritis compared with mild and non-operated patients.
- Analysis of the synovial fluid following ELISA testing revealed no significant difference in the concentrations of IL-10, IL-17A, IL-6, and chemokine (C-C motif) ligand (CCL) 2 (CCL2) and CCL5 between groups.
Conclusion
- The researchers concluded that there was an imbalance in the ratio between regulatory T cells and T helper 17 cells in synovial fluid. Additionally, an increase was noted in T helper 17-like regulatory T cells in joints with more severe manifestations of the disease.
- This discovery could provide novel insights into the immunological mechanisms associated with the progression and pathogenesis of posttraumatic osteoarthritis.
- The application of targeted immunotherapeutics early in the course of posttraumatic osteoarthritis may result in improved patient clinical outcomes.
Cite This Article
APA
Keller LE, Tait Wojno ED, Begum L, Fortier LA.
(2023).
T Helper 17-Like Regulatory T Cells in Equine Synovial Fluid Are Associated With Disease Severity of Naturally Occurring Posttraumatic Osteoarthritis.
Am J Sports Med, 51(4), 1047-1058.
https://doi.org/10.1177/03635465231153588 Publication
Researcher Affiliations
- Cornell University, College of Veterinary Medicine, Department of Clinical Sciences, Ithaca, New York, USA.
- University of Washington, Department of Immunology, Seattle, Washington, USA.
- Cornell University, College of Veterinary Medicine, Department of Clinical Sciences, Ithaca, New York, USA.
- Cornell University, College of Veterinary Medicine, Department of Clinical Sciences, Ithaca, New York, USA.
MeSH Terms
- Animals
- Disease Progression
- Forkhead Transcription Factors
- Horses
- Interleukin-10
- Osteoarthritis / etiology
- Patient Acuity
- Synovial Fluid
- T-Lymphocytes, Regulatory
- Th17 Cells
Grant Funding
- R01 AI130379 / NIAID NIH HHS
- R01 AI132708 / NIAID NIH HHS
- R01 AR071394 / NIAMS NIH HHS
References
This article includes 56 references
- Abdelaziz MH, Abdelwahab SF, Wan J, Cai W, Huixuan W, Jianjun C, Kumar KD, Vasudevan A, Sadek A, Su Z, Wang S, Xu H. Alternatively activated macrophages; a double-edged sword in allergic asthma.. J Transl Med 2020 Feb 5;18(1):58.
- Behrendt P, Preusse-Prange A, Klu00fcter T, Haake M, Rolauffs B, Grodzinsky AJ, Lippross S, Kurz B. IL-10 reduces apoptosis and extracellular matrix degradation after injurious compression of mature articular cartilage.. Osteoarthritis Cartilage 2016 Nov;24(11):1981-1988.
- Benderdour M, Tardif G, Pelletier JP, Di Battista JA, Reboul P, Ranger P, Martel-Pelletier J. Interleukin 17 (IL-17) induces collagenase-3 production in human osteoarthritic chondrocytes via AP-1 dependent activation: differential activation of AP-1 members by IL-17 and IL-1beta.. J Rheumatol 2002 Jun;29(6):1262-72.
- Bigoni M, Sacerdote P, Turati M, Franchi S, Gandolla M, Gaddi D, Moretti S, Munegato D, Augusti CA, Bresciani E, Omeljaniuk RJ, Locatelli V, Torsello A. Acute and late changes in intraarticular cytokine levels following anterior cruciate ligament injury.. J Orthop Res 2013 Feb;31(2):315-21.
- Boyce MK, Trumble TN, Carlson CS, Groschen DM, Merritt KA, Brown MP. Non-terminal animal model of post-traumatic osteoarthritis induced by acute joint injury.. Osteoarthritis Cartilage 2013 May;21(5):746-55.
- Cho J, Kuswanto W, Benoist C, Mathis D. T cell receptor specificity drives accumulation of a reparative population of regulatory T cells within acutely injured skeletal muscle.. Proc Natl Acad Sci U S A 2019 Dec 26;116(52):26727-26733.
- Delco ML, Kennedy JG, Bonassar LJ, Fortier LA. Post-traumatic osteoarthritis of the ankle: A distinct clinical entity requiring new research approaches.. J Orthop Res 2017 Mar;35(3):440-453.
- Deligne C, Casulli S, Pigenet A, Bougault C, Campillo-Gimenez L, Nourissat G, Berenbaum F, Elbim C, Houard X. Differential expression of interleukin-17 and interleukin-22 in inflamed and non-inflamed synovium from osteoarthritis patients.. Osteoarthritis Cartilage 2015 Nov;23(11):1843-52.
- Evans-Pickett A, Longobardi L, Spang JT, Creighton RA, Kamath G, Davis-Wilson HC, Loeser R, Blackburn JT, Pietrosimone B. Synovial fluid concentrations of matrix Metalloproteinase-3 and Interluekin-6 following anterior cruciate ligament injury associate with gait biomechanics 6 months following reconstruction.. Osteoarthritis Cartilage 2021 Jul;29(7):1006-1019.
- Faust HJ, Zhang H, Han J, Wolf MT, Jeon OH, Sadtler K, Peu00f1a AN, Chung L, Maestas DR Jr, Tam AJ, Pardoll DM, Campisi J, Housseau F, Zhou D, Bingham CO 3rd, Elisseeff JH. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.. J Clin Invest 2020 Oct 1;130(10):5493-5507.
- Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.. Nat Med 2009 Aug;15(8):930-9.
- Garcia-Montoya L, Marzo-Ortega H. The role of secukinumab in the treatment of psoriatic arthritis and ankylosing spondylitis.. Ther Adv Musculoskelet Dis 2018 Sep;10(9):169-180.
- Gu00f3mez-Aristizu00e1bal A, Gandhi R, Mahomed NN, Marshall KW, Viswanathan S. Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study.. Arthritis Res Ther 2019 Jan 18;21(1):26.
- Gregori S, Goudy KS, Roncarolo MG. The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells.. Front Immunol 2012;3:30.
- Haller JM, McFadden M, Kubiak EN, Higgins TF. Inflammatory cytokine response following acute tibial plateau fracture.. J Bone Joint Surg Am 2015 Mar 18;97(6):478-83.
- Haubruck P, Colbath AC, Liu Y, Stoner S, Shu C, Little CB. Flow Cytometry Analysis of Immune Cell Subsets within the Murine Spleen, Bone Marrow, Lymph Nodes and Synovial Tissue in an Osteoarthritis Model.. J Vis Exp 2020 Apr 24;(158).
- Henderson LA, Hoyt KJ, Lee PY, Rao DA, Jonsson AH, Nguyen JP, Rutherford K, Julu00e9 AM, Charbonnier LM, Case S, Chang MH, Cohen EM, Dedeoglu F, Fuhlbrigge RC, Halyabar O, Hazen MM, Janssen E, Kim S, Lo J, Lo MS, Meidan E, Son MBF, Sundel RP, Stoll ML, Nusbaum C, Lederer JA, Chatila TA, Nigrovic PA. Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis.. JCI Insight 2020 Mar 26;5(6).
- Huang Y, Fan Y, Liu Y, Xie W, Zhang Z. Efficacy and safety of secukinumab in active rheumatoid arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis of phase III randomized controlled trials.. Clin Rheumatol 2019 Oct;38(10):2765-2776.
- Jung MK, Kwak JE, Shin EC. IL-17A-Producing Foxp3(+) Regulatory T Cells and Human Diseases.. Immune Netw 2017 Oct;17(5):276-286.
- Kabithe E, Hillegas J, Stokol T, Moore J, Wagner B. Monoclonal antibodies to equine CD14.. Vet Immunol Immunopathol 2010 Nov 15;138(1-2):149-53.
- Kingery MT, Anil U, Berlinberg EJ, Clair AJ, Kenny L, Strauss EJ. Changes in the Synovial Fluid Cytokine Profile of the Knee Between an Acute Anterior Cruciate Ligament Injury and Surgical Reconstruction.. Am J Sports Med 2022 Feb;50(2):451-460.
- Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity.. Semin Immunol 2013 Nov 15;25(4):305-12.
- Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis.. Nat Med 2014 Jan;20(1):62-8.
- Kraus VB, Huebner JL, DeGroot J, Bendele A. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the guinea pig.. Osteoarthritis Cartilage 2010 Oct;18 Suppl 3(Suppl 3):S35-52.
- Kriegova E, Manukyan G, Mikulkova Z, Gabcova G, Kudelka M, Gajdos P, Gallo J. Gender-related differences observed among immune cells in synovial fluid in knee osteoarthritis.. Osteoarthritis Cartilage 2018 Sep;26(9):1247-1256.
- de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, Zuurmond AM, Schoones J, Toes RE, Huizinga TW, Kloppenburg M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.. Osteoarthritis Cartilage 2012 Dec;20(12):1484-99.
- Li S, Wan J, Anderson W, Sun H, Zhang H, Peng X, Yu Z, Wang T, Yan X, Smith W. Downregulation of IL-10 secretion by Treg cells in osteoarthritis is associated with a reduction in Tim-3 expression.. Biomed Pharmacother 2016 Apr;79:159-65.
- Liu Y, Peng H, Meng Z, Wei M. Correlation of IL-17 Level in Synovia and Severity of Knee Osteoarthritis.. Med Sci Monit 2015 Jun 15;21:1732-6.
- Lundy SK, Sarkar S, Tesmer LA, Fox DA. Cells of the synovium in rheumatoid arthritis. T lymphocytes.. Arthritis Res Ther 2007;9(1):202.
- Marinoni B, Ceribelli A, Massarotti MS, Selmi C. The Th17 axis in psoriatic disease: pathogenetic and therapeutic implications.. Auto Immun Highlights 2014 Jun;5(1):9-19.
- Menarim BC, Gillis KH, Oliver A, Ngo Y, Werre SR, Barrett SH, Rodgerson DH, Dahlgren LA. Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints.. Front Vet Sci 2020;7:568756.
- Miragaia RJ, Gomes T, Chomka A, Jardine L, Riedel A, Hegazy AN, Whibley N, Tucci A, Chen X, Lindeman I, Emerton G, Krausgruber T, Shields J, Haniffa M, Powrie F, Teichmann SA. Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation.. Immunity 2019 Feb 19;50(2):493-504.e7.
- Moran EM, Mullan R, McCormick J, Connolly M, Sullivan O, Fitzgerald O, Bresnihan B, Veale DJ, Fearon U. Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.. Arthritis Res Ther 2009;11(4):R113.
- Okeke EB, Uzonna JE. The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells.. Front Immunol 2019;10:680.
- Ozkan H, Di Francesco M, Willcockson H, Valdu00e9s-Fernu00e1ndez J, Di Francesco V, Granero-Moltu00f3 F, Pru00f3sper F, Decuzzi P, Longobardi L. Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis.. Drug Deliv Transl Res 2023 Feb;13(2):689-701.
- Pandolfi JB, Ferraro AA, Sananez I, Gancedo MC, Baz P, Billordo LA, Fainboim L, Arruvito L. ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity.. J Immunol 2016 Apr 15;196(8):3287-96.
- Panduro M, Benoist C, Mathis D. Tissue Tregs.. Annu Rev Immunol 2016 May 20;34:609-33.
- Perkins GA, Goodman LB, Wimer C, Freer H, Babasyan S, Wagner B. Maternal T-lymphocytes in equine colostrum express a primarily inflammatory phenotype.. Vet Immunol Immunopathol 2014 Oct 15;161(3-4):141-50.
- Robert M, Miossec P. IL-17 in Rheumatoid Arthritis and Precision Medicine: From Synovitis Expression to Circulating Bioactive Levels.. Front Med (Lausanne) 2018;5:364.
- Rodru00edguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents.. Clin Exp Immunol 2016 Sep;185(3):281-91.
- Rosshirt N, Trauth R, Platzer H, Tripel E, Nees TA, Lorenz HM, Tretter T, Moradi B. Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis.. Arthritis Res Ther 2021 Jan 22;23(1):37.
- Sandquist I, Kolls J. Update on regulation and effector functions of Th17 cells.. F1000Res 2018;7:205.
- Sharabi A, Tsokos MG, Ding Y, Malek TR, Klatzmann D, Tsokos GC. Regulatory T cells in the treatment of disease.. Nat Rev Drug Discov 2018 Nov;17(11):823-844.
- Shevyrev D, Tereshchenko V. Treg Heterogeneity, Function, and Homeostasis.. Front Immunol 2019;10:3100.
- Snelling SJ, Bas S, Puskas GJ, Dakin SG, Suva D, Finckh A, Gabay C, Hoffmeyer P, Carr AJ, Lu00fcbbeke A. Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype.. PLoS One 2017;12(4):e0175109.
- Sullivan B, Stone AV, Conley CEW, Hunt ER, Lattermann C, Jacobs CA. Human synovial fluid interleukin-6, but not type II collagen breakdown, positively correlated with pain after anterior cruciate ligament injury and reconstruction.. J Orthop Res 2023 Feb;41(2):300-306.
- Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease.. Immunol Rev 2008 Jun;223:87-113.
- Teunis T, Beekhuizen M, Van Osch GV, Schuurman AH, Creemers LB, van Minnen LP. Soluble mediators in posttraumatic wrist and primary knee osteoarthritis.. Arch Bone Jt Surg 2014 Sep;2(3):146-50.
- Tumas DB, Hines MT, Perryman LE, Davis WC, McGuire TC. Corticosteroid immunosuppression and monoclonal antibody-mediated CD5+ T lymphocyte depletion in normal and equine infectious anaemia virus-carrier horses.. J Gen Virol 1994 May;75 ( Pt 5):959-68.
- Wagner B, Freer H. Development of a bead-based multiplex assay for simultaneous quantification of cytokines in horses.. Vet Immunol Immunopathol 2009 Feb 15;127(3-4):242-8.
- Wagner B, Hillegas JM, Brinker DR, Horohov DW, Antczak DF. Characterization of monoclonal antibodies to equine interleukin-10 and detection of T regulatory 1 cells in horses.. Vet Immunol Immunopathol 2008 Mar 15;122(1-2):57-64.
- Wang T, Sun X, Zhao J, Zhang J, Zhu H, Li C, Gao N, Jia Y, Xu D, Huang FP, Li N, Lu L, Li ZG. Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood.. Ann Rheum Dis 2015 Jun;74(6):1293-301.
- Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis.. Rheumatol Int 2012 Apr;32(4):887-93.
- McIlwraith CW, Fortier LA, Frisbie DD, Nixon AJ. Equine Models of Articular Cartilage Repair.. Cartilage 2011 Oct;2(4):317-26.
- Zhang X, Mao Z, Yu C. Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 receptor antagonist and interleukin-10.. J Orthop Res 2004 Jul;22(4):742-50.
- Zhu Z, Li J, Ruan G, Wang G, Huang C, Ding C. Investigational drugs for the treatment of osteoarthritis, an update on recent developments.. Expert Opin Investig Drugs 2018 Nov;27(11):881-900.
Citations
This article has been cited 0 times.Secure Payments
