Güneş ESENDAĞLI, Erdem KARABULUT, Can Ebru BEKİRCAN KURT, Sevim EERDEM ÖZDAMAR, Sevgen ÖNDER, Lala MEHDIKHANOVA, Aslı TUNCER, Gürcan TUNALI, Mustafa YILMAZ

NK and Th17 Cells in The Thymus of Myasthenia Gravis Patients

Objective: As a classical autoimmune disorder, anti-acetylcholine receptor antibody positive myasthenia gravis has an unconventional pathophysiology that involves thymus, the central organ for immune tolerance induction. Both natural cells and type 17 helper T (Th17) cells possess capacity to influence autoimmune inflammation. This study aims to determine the presence of Th17 and natural killer cells in the thymus from myasthenia gravis patients. Materials and Methods: Thymectomy materials of myasthenia gravis patients and non-myasthenic controls were assessed by CD56, CD16, CD2, CD3, NKG2D, NKp46 and IL-23R flow cytometry and IL-23R, IL-21R, and ROR-γ immunohistochemistry. Results: Even though natural killer cell infiltration was limited, the majority of these cells displayed activation markers NKG2D and NKp46. Expectedly, the amount of CD2+ lymphocytic cells were higher than CD3+ thymocytes in which a considerable percentage was carrying the receptor for IL-23 (IL-23R). In addition to IL-23R, IL21R, and ROR-γ were also detected in myasthenic thymus as a marker related to Th17 cells. These Th17-related markers were reduced in thymoma compared to that of detected in thymic hyperplasia or the myasthenic thymus with normal histopathology. Conclusion: Both natural killer cells and Th17 cells are found in the myasthenic thymus indicating a possible cross-regulation between these cell types that may influence the course of autoimmune reactions.

PDF

___

[1] Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001; 357: 2122-2128.
[2] Berrih-Aknin S, Le Panse R. Myasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun. 2014; 52: 90-100.
[3] Berrih-Aknin S, Morel E, Raimond F, et al. The role of the thymus in myasthenia gravis: immunohistological and immunological studies in 115 cases. Ann N Y Acad Sci. 1987; 505: 50-70.
[4] Schluep M, Willcox N, Vincent A, et al. Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol. 1987; 22: 212-222.
[5] Strobel P, Rosenwald A, Beyersdorf N, et al. Selective loss of regulatory T cells in thymomas. Ann Neurol. 2004; 56: 901-904.
[6] Kadota Y, Okumura M, Miyoshi S, et al. Altered T cell development in human thymoma is related to impairment of MHC class II transactivator expression induced by interferon-gamma (IFN-gamma). Clin Exp İmmunol. 2000; 121: 59-68.
[7] Baecher-Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev. 2006; 212: 203-216.
[8] Wang HB, Shi FD, Li H, et al. Role for interferon-gamma in rat strains with different susceptibility to experimental autoimmune myasthenia gravis. Clin Immunol. 2000; 95: 156-162.
[9] Balandina A, Lecart S, Dartevelle P, et al. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005; 105: 735-741.
[10] Luther C, Poeschel S, Varga M, et al. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J Neuroimmunol. 2005; 164: 124-128.
[11] Fattorossi A, Battaglia A, Buzzonetti A, et al. Thymopoiesis, regulatory T cells, and TCRVbeta expression in thymoma with and without myasthenia gravis, and modulatory effects of steroid therapy. J Clin Immunol. 2008; 28: 194-206.
[12] Mu L, Sun B, Kong Q, et al. Disequilibrium of T helper type 1, 2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis. Immunology. 2009; 128: e826-836.
[13] Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008; 28: 454-467.
[14] Shi FD, Wang HB, Li H, et al. Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol. 2000; 1(3): 245-51.
[15] Hao J, Liu R, Piao W, et al. Central nervous system (CNS)- resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. J Exp Med. 2010; 207(9):1907-21.
[16] Wu W, Shi S, Ljunggren HG, et al. NK cells inhibit T-betdeficient, autoreactive Th17 cells. Scand J Immunol. 2012; 76(6): 559-66.
[17] Fu B, Li X, Sun R, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. PNAS. 2013; 110(3): E231-40.
[18] Suzuki Y, Onodera H, Tago H, et al. Altered populations of natural killer cell and natural killer T cell subclasses in myasthenia gravis. J Neuroimmunol. 2005; 167(1-2): 186- 9.
[19] Kott E, Hahn T, Huberman M, et al. Interferon system and natural killer cell activity in myasthenia gravis. Q J Med. 1990; 76(281): 951-60.
[20] Spits H, Lanier LL, Phillips JH. Development of human T and natural killer cells. Blood. 1995; 85(10): 2654-70.
[21] Dave VP. Hierarchical role of CD3 chains in thymocyte development. Immunol Rev. 2009; 232(1): 22-33.
[22] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008; 8: 337-348.
[23] Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448: 484-487.
[24] Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007; 448: 480-483.
[25] Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL21 and IL-23 pathways. Nat Immunol. 2007; 8: 967-974.
[26] Chien PJ, Yeh JH, Chiu HC, et al. Inhibition of peripheral blood natural killer cell cytotoxicity in patients with myasthenia gravis treated with plasmapheresis. Eur J Neurol. 2011; 18(11): 1350-7.
[27] Jeager BN, Vivier E. Natural killer cell tolerance: control by self or self-control? Cold Spring Harb Perspect Biol. 2012; 4(3). pii: a007229.
[28] Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol. 2014; 26(2): 138-44.
[29] Luckheeram RV, Zhou R, Verma AD, et al. CD4+T cells: Differentiation and functions. Clin Dev Immunol. 2012; 2012: 925135.
[30] Wang Z, Wang W, Chen Y, et al. T helper type 17 cells expand in patients with myasthenia-associated thymoma. Scand J Immunol. 2012; 76: 54-61.
[31] Tan ZY, Bealgey KW, Fang Y, et al. Interleukin-23: immunological roles and clinical implications. Int J Biochem Cell Biol. 2009; 41: 733-735.
[32] Eberl G, Marmon S, Sunshine MJ, et al. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004; 5: 64-73.
[33]Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front Immunol. 2016; 7: 128.
[34] Cordiglieri C, Marolda R, Franzi S, et al. Innate immunity in myasthenia gravis thymus: pathogenic effects of Toll-like receptor 4 signaling on autoimmunity. J Autoimmun. 2014; 52: 74-89.
[35] Roche JC, Capablo JL, Larrad L, et al. Increased serum interleukin-17 levels in patients with myasthenia gravis. Muscle Nerve. 2011; 44: 278-280.
[36] Fan X, Zhang H, Cheng Y, et al. Double Roles of Macrophages in Human Neuroimmune Diseases and Their Animal Models. Mediators Inflamm. 2016; 2016:8489251.