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The antibody and cytokine profile in Musk-associated myasthenia gravis

Yıl 2017, Cilt: 7 Sayı: 14, 39 - 49, 14.12.2017

Öz

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness associated with acetylcholine receptor (AChR) or muscle-specific receptor tyrosine kinase (MuSK)-antibodies. MuSK-antibodies are predominantly of IgG4 isotype. MuSK associated experimental autoimmune myasthenia gravis (EAMG) model was established to investigate immunoglobulins (Ig) and cytokines related with MuSK associated MG (MuSK-MG).

Immunopathological findings of mice immunized with recombinant human MuSK protein and complete Freund’s adjuvant (CFA) (MuSK+CFA, n=8) or only CFA (CFA, n=8) were compared. Muscle weakness was assessed with clinical scoring, inverted screen and motor activity tests. Serum anti-MuSK Ig isotype and complement C3 levels were measured by ELISA, neuromuscular junction (NMJ) Ig, complement deposits, AChR, MuSK levels were measured by immunofluorescence staining and western blot. Levels of cytokines in sera and supernatants of MuSK-stimulated lymph node cells were measured with ELISA and multiplex assays.

Seven mice (87.5%) from MuSK+CFA group and no mice from CFA group showed muscle weakness. MuSK+CFA group showed increased anti-MuSK Ig isotype and C3 levels, NMJ Ig isotype, C3 and membrane attack complex (MAC) deposit counts, decreased NMJ AChR and comparable MuSK levels. IgG1 was the dominant anti-MuSK Ig isotype. MuSK+CFA group showed increased IL-4 levels in sera, increased IL-4, IL-10, IFN-γ levels in supernatants.




Similar to MuSK-MG patients, non-complement activating IgG1 was the dominant Ig isotype. Nevertheless, NMJ complement deposits suggests that complement-mediated membrane damage might participate in MuSK-MG pathogenesis. Increased IgG1, IL-4, IL-10 levels suggest that Th2-type T-helper cells are involved in MuSK immunity.

Kaynakça

  • 1]. Leite MI, Waters P, Vincent A. Diagnostic use of autoantibodies in myasthenia gravis. Autoimmunity 2011; 43(5-6):371-379. [2]. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A ve Vincent A. Autoantibodies to the receptor tyrosine kinase Musk in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Medicine 2001; 7:365-368. [3]. Guptill JT ve Sanders DB. Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Curr Opin in Neurol 2010; 23(5):530-535. [4]. Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77(20):1819-1826. [5]. Wu H, Lu Y, Shen C, Patel N, Gan L, Xiong WC, et al. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron 2012; 75(1):94-107. [6]. Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135(Pt 4):1081-1101. [7]. Viegas S, Jacobson L, Waters P, Cossins J, Jacob S, Leite MI, et al. Passive and active immunization models of Musk-Ab positive myasthenia: Electrophysiological evidence for pre and postsynaptic defects. Exp Neurol 2012; 234(2):506-512. [8]. Zhang G, Link H. Cytokines and the pathogenesis of myasthenia gravis. Muscle Nerve 1997; 20:543-551. [9]. Bai Y, Liu R, Huang D, La Cava A, Tang YY, Iwakura Y. CCL2 recruitment of IL-6-producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17-dependent B cell-mediated autoimmunity. Eur J Immunol 2008; 38(7):1877-1888. [10]. Richman DP, Nishi K, Ferns MJ, Schnier J, Pytel P, Maselli RA, Agius MA. Animal models of antimuscle-specific kinase myasthenia. Ann N Y Acad Sci 2012; 1274:140-147. [11]. Sundaram C, Meena AK, Uppin MS, Govindaraj P, Vanniarajan A, Thangaraj K, et al. Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin. J Clin Neurosci 2011; 18(4):535-538. [12]. Cavalcante P, Bernasconi P, Mantegazza R. Autoimmune mechanisms in myasthenia gravis. Curr Opin Neurol 2012; 25(5):621-629. [13]. Gilhus NE. Myasthenia and the neuromuscular junction. Curr Opin Neurol 2012 Oct; 25(5): 523-9. [14]. Cossins J, Belaya K, Zoltowska K, Koneczny I, Maxwell S, Jacobson L, et al. The search for new antigenic targets in myasthenia gravis. Ann N Y Acad Sci 2012; 1275:123-128. [15]. Evoli A, Padua L. Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase. Autoimmun Rev 2013; 12(9):931-935. [16]. Kumar V, Kaminski HJ. Treatment of myasthenia gravis. Curr Neurol Neurosci Rep 2011; 11(1): 89-96. [17]. Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve 2011; 44(1):36-40. [18]. Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, et al. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5. Neurology 2006; 66(11):1772-1774. [19]. Plomp JJ, Huijbers MG, van der Maarel SM, Verschuuren JJ. Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Ann N Y Acad Sci 2012; 1275:114-122. [20]. Xu K, Jha S, Hoch W, Dryer SE. Delayed synapsing muscles are more severely affected in an experimental model of MuSK-induced myasthenia gravis. Neuroscience 2006; 143(3):655-659. [21]. Shigemoto K, Kubo S, Jie C, Hato N, Abe Y, Ueda N, et al. Myasthenia gravis experimentally induced with muscle-specific kinase. Ann N Y Acad Sci 2008; 1132:93-98. [22]. Cole RN, Reddel SW, Gervásio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 2008; 63(6):782-789. [23]. Cole RN, Ghazanfari N, Ngo ST, Gervásio OL, Reddel SW, Phillips WD. Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice. J Physiol 2010; 588(Pt 17): 3217-3229. [24]. Punga AR, Lin S, Oliveri F, Meinen S, Rüegg MA. Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice. Exp Neurol 2011; 230(2):207-217. [25]. Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77(20):1819-1826. [26]. Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Hotta H, et al. Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis. Am J Pathol 2012; 180(2):798-810. [27]. Richman DP, Nishi K, Morell SW, Chang JM, Ferns MJ, Wollmann RL, et al. Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes. Arch Neurol 2012; 69(4):453-460. Deneysel Tıp Araştırma Enstitüsü dergisidir49 [28]. Mori S, Yamada S, Kubo S, Chen J, Matsuda S, Shudou M, et al. Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis. J Neuroimmunol 2012; 244(1-2):1-7. [29]. Viegas S, Jacobson L, Waters P, Cossins J, Jacob S, Leite MI, et al. Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Exp Neurol 2012; 234(2):506-512. [30]. Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135(Pt 4):1081-1101. [31]. Mori S, Shigemoto K. Mechanisms associated with the pathogenicity of antibodies against muscle-specific kinase in myasthenia gravis. Autoimmun Rev 2013; 12(9):912-917. [32]. Klein-Schneegans AS, Kuntz L, Fonteneau P, Loor F. Serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA in C57BL/6 mice and their congenics at the lpr (lymphoproliferation) locus. J Autoimmun 1989; 2(6):869-875. [33]. Tüzün E, Scott BG, Yang H, Wu B, Goluszko E, Guigneaux M, et al. Circulating immune complexes augment severity of antibody-mediated myasthenia gravis in hypogammaglobulinemic RIIIS/J mice. J Immunol 2004; 172(9):5743-5752. [34]. Deng C, Goluszko E, Tüzün E, Yang H, Christadoss P. Resistance to experimental autoimmune myasthenia gravis in IL-6-deficient mice is associated with reduced germinal center formation and C3 production. J Immunol 2002; 169(2):1077-1083. [35]. Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008; 131(Pt 7):1940-1052. [36]. Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57(2):289-293. [37]. Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, et al. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 1988; 334(6179):255-258. [38]. Sano K, Haneda K, Tamura G, Shirato K. Ovalbumin (OVA) and Mycobacterium tuberculosis bacilli cooperatively polarize anti-OVA T-helper (Th) cells toward a Th1-dominant phenotype and ameliorate murine tracheal eosinophilia. Am J Respir Cell Mol Biol 1999; 20(6):1260-1267. [39]. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002; 196(12):1645-1651. [40]. Billiau A, Matthys P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol 2001; 70(6):849-860. [41]. Wang ZY, Okita DK, Howard JF Jr, Conti-Fine BM. Th1 cells of myasthenia gravis patients recognize multiple epitopes on the muscle acetylcholine receptor alpha subunit. Ann N Y Acad Sci 1998; 841:329-333. [42]. Wang W, Ostlie NS, Conti-Fine BM, Milani M. The susceptibility to experimental myasthenia gravis of STAT6-/- and STAT4-/- BALB/c mice suggests a pathogenic role of Th1 cells. J Immunol 2004; 172(1):97-103. [43]. Tüzün E, Allman W, Ulusoy C, Yang H, Christadoss P. Novel animal models of acetylcholine receptor antibody-related myasthenia

Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili

Yıl 2017, Cilt: 7 Sayı: 14, 39 - 49, 14.12.2017

Öz

Myasthenia gravis (MG) asetilkolin reseptörü (AChR) veya “muscle-specific receptor tyrosine kinase” (MuSK) antikoruyla ilişkili, kas zaafıyla karakterize otoimmün bir hastalıktır. MuSK antikorları ağırlıkla IgG4 izotipindendir. MuSK ilişkili MG (MuSK-MG) gelişimini etkileyen immünglobülin (Ig) ve sitokinleri araştırmak amacıyla MuSK ilişkili deneysel otoimmün MG (MuSK-DOMG) modeli C57BL/6 farelerinde oluşturulmuştur.

Rekombinan insan MuSK proteini ve “complete Freund’s adjuvant” (CFA) (MuSK+CFA, n=8) ile immünize farelerin immünopatolojik bulguları sadece CFA ile immünize (CFA, n=8) kontrol farelerle karşılaştırılmıştır. Kas zaafı, klinik skorlama, asma ve motor aktivite testleriyle değerlendirilmiştir. Serum anti-MuSK Ig izotip ve kompleman C3 seviyeleri ELISA ile, nöromüsküler bileşke (NMB)’deki Ig ve kompleman depozitleri immünofloresan boyamayla, kas AChR ve MuSK miktarları immünfloresan boyama ve western blot ile değerlendirilmiştir. Serum ve lenf ganglionu hücrelerinin kültür üst sıvılarında sitokin düzeyleri ELISA ve çoklu boncuk yöntemiyle ölçülmüştür.

MuSK+CFA grubunda 7 farede (%87.5) kas zaafı gözlenirken, CFA grubunda yoktu. CFA grubuna göre, MuSK+CFA’da serum anti-MuSK Ig izotip ve C3 seviyeleri, NMB Ig izotip, C3, membran atak kompleksi (MAK) depozit sayıları yüksek, NMB’deki AChR düzeyleri düşükken MuSK benzerdi. IgG1 baskın anti-MuSK Ig izotipiydi. MuSK+CFA grubunda serumda IL-4, kültür üst sıvılarında IL-4, IL-10, IFN-γ düzeyleri artmıştı.




MuSK-MG’ye benzer şekilde MuSK-DOMG de komplemanı aktive etmeyen Ig izotipi IgG1 baskındır. NMB’de kompleman depozitlerinin görülmesi MuSK-MG patogenezinde kompleman aracılı membran hasarında rol oynar. IgG1, IL-4, IL-10 düzeylerindeki artış MuSK immünitesinde Th2 tipi yardımcı T lenfositlerini düşündürmektedir.

Kaynakça

  • 1]. Leite MI, Waters P, Vincent A. Diagnostic use of autoantibodies in myasthenia gravis. Autoimmunity 2011; 43(5-6):371-379. [2]. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A ve Vincent A. Autoantibodies to the receptor tyrosine kinase Musk in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Medicine 2001; 7:365-368. [3]. Guptill JT ve Sanders DB. Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Curr Opin in Neurol 2010; 23(5):530-535. [4]. Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77(20):1819-1826. [5]. Wu H, Lu Y, Shen C, Patel N, Gan L, Xiong WC, et al. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron 2012; 75(1):94-107. [6]. Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135(Pt 4):1081-1101. [7]. Viegas S, Jacobson L, Waters P, Cossins J, Jacob S, Leite MI, et al. Passive and active immunization models of Musk-Ab positive myasthenia: Electrophysiological evidence for pre and postsynaptic defects. Exp Neurol 2012; 234(2):506-512. [8]. Zhang G, Link H. Cytokines and the pathogenesis of myasthenia gravis. Muscle Nerve 1997; 20:543-551. [9]. Bai Y, Liu R, Huang D, La Cava A, Tang YY, Iwakura Y. CCL2 recruitment of IL-6-producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17-dependent B cell-mediated autoimmunity. Eur J Immunol 2008; 38(7):1877-1888. [10]. Richman DP, Nishi K, Ferns MJ, Schnier J, Pytel P, Maselli RA, Agius MA. Animal models of antimuscle-specific kinase myasthenia. Ann N Y Acad Sci 2012; 1274:140-147. [11]. Sundaram C, Meena AK, Uppin MS, Govindaraj P, Vanniarajan A, Thangaraj K, et al. Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin. J Clin Neurosci 2011; 18(4):535-538. [12]. Cavalcante P, Bernasconi P, Mantegazza R. Autoimmune mechanisms in myasthenia gravis. Curr Opin Neurol 2012; 25(5):621-629. [13]. Gilhus NE. Myasthenia and the neuromuscular junction. Curr Opin Neurol 2012 Oct; 25(5): 523-9. [14]. Cossins J, Belaya K, Zoltowska K, Koneczny I, Maxwell S, Jacobson L, et al. The search for new antigenic targets in myasthenia gravis. Ann N Y Acad Sci 2012; 1275:123-128. [15]. Evoli A, Padua L. Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase. Autoimmun Rev 2013; 12(9):931-935. [16]. Kumar V, Kaminski HJ. Treatment of myasthenia gravis. Curr Neurol Neurosci Rep 2011; 11(1): 89-96. [17]. Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve 2011; 44(1):36-40. [18]. Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, et al. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5. Neurology 2006; 66(11):1772-1774. [19]. Plomp JJ, Huijbers MG, van der Maarel SM, Verschuuren JJ. Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Ann N Y Acad Sci 2012; 1275:114-122. [20]. Xu K, Jha S, Hoch W, Dryer SE. Delayed synapsing muscles are more severely affected in an experimental model of MuSK-induced myasthenia gravis. Neuroscience 2006; 143(3):655-659. [21]. Shigemoto K, Kubo S, Jie C, Hato N, Abe Y, Ueda N, et al. Myasthenia gravis experimentally induced with muscle-specific kinase. Ann N Y Acad Sci 2008; 1132:93-98. [22]. Cole RN, Reddel SW, Gervásio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 2008; 63(6):782-789. [23]. Cole RN, Ghazanfari N, Ngo ST, Gervásio OL, Reddel SW, Phillips WD. Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice. J Physiol 2010; 588(Pt 17): 3217-3229. [24]. Punga AR, Lin S, Oliveri F, Meinen S, Rüegg MA. Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice. Exp Neurol 2011; 230(2):207-217. [25]. Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77(20):1819-1826. [26]. Mori S, Kubo S, Akiyoshi T, Yamada S, Miyazaki T, Hotta H, et al. Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis. Am J Pathol 2012; 180(2):798-810. [27]. Richman DP, Nishi K, Morell SW, Chang JM, Ferns MJ, Wollmann RL, et al. Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes. Arch Neurol 2012; 69(4):453-460. Deneysel Tıp Araştırma Enstitüsü dergisidir49 [28]. Mori S, Yamada S, Kubo S, Chen J, Matsuda S, Shudou M, et al. Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis. J Neuroimmunol 2012; 244(1-2):1-7. [29]. Viegas S, Jacobson L, Waters P, Cossins J, Jacob S, Leite MI, et al. Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Exp Neurol 2012; 234(2):506-512. [30]. Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135(Pt 4):1081-1101. [31]. Mori S, Shigemoto K. Mechanisms associated with the pathogenicity of antibodies against muscle-specific kinase in myasthenia gravis. Autoimmun Rev 2013; 12(9):912-917. [32]. Klein-Schneegans AS, Kuntz L, Fonteneau P, Loor F. Serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA in C57BL/6 mice and their congenics at the lpr (lymphoproliferation) locus. J Autoimmun 1989; 2(6):869-875. [33]. Tüzün E, Scott BG, Yang H, Wu B, Goluszko E, Guigneaux M, et al. Circulating immune complexes augment severity of antibody-mediated myasthenia gravis in hypogammaglobulinemic RIIIS/J mice. J Immunol 2004; 172(9):5743-5752. [34]. Deng C, Goluszko E, Tüzün E, Yang H, Christadoss P. Resistance to experimental autoimmune myasthenia gravis in IL-6-deficient mice is associated with reduced germinal center formation and C3 production. J Immunol 2002; 169(2):1077-1083. [35]. Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008; 131(Pt 7):1940-1052. [36]. Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57(2):289-293. [37]. Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, et al. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 1988; 334(6179):255-258. [38]. Sano K, Haneda K, Tamura G, Shirato K. Ovalbumin (OVA) and Mycobacterium tuberculosis bacilli cooperatively polarize anti-OVA T-helper (Th) cells toward a Th1-dominant phenotype and ameliorate murine tracheal eosinophilia. Am J Respir Cell Mol Biol 1999; 20(6):1260-1267. [39]. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002; 196(12):1645-1651. [40]. Billiau A, Matthys P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol 2001; 70(6):849-860. [41]. Wang ZY, Okita DK, Howard JF Jr, Conti-Fine BM. Th1 cells of myasthenia gravis patients recognize multiple epitopes on the muscle acetylcholine receptor alpha subunit. Ann N Y Acad Sci 1998; 841:329-333. [42]. Wang W, Ostlie NS, Conti-Fine BM, Milani M. The susceptibility to experimental myasthenia gravis of STAT6-/- and STAT4-/- BALB/c mice suggests a pathogenic role of Th1 cells. J Immunol 2004; 172(1):97-103. [43]. Tüzün E, Allman W, Ulusoy C, Yang H, Christadoss P. Novel animal models of acetylcholine receptor antibody-related myasthenia
Toplam 1 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Sağlık Kurumları Yönetimi
Bölüm Makale
Yazarlar

Erdem Tüzün

Yayımlanma Tarihi 14 Aralık 2017
Yayımlandığı Sayı Yıl 2017 Cilt: 7 Sayı: 14

Kaynak Göster

APA Tüzün, E. (2017). Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili. Deneysel Tıp Araştırma Enstitüsü Dergisi, 7(14), 39-49.
AMA Tüzün E. Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili. Deneysel Tıp Araştırma Enstitüsü Dergisi. Aralık 2017;7(14):39-49.
Chicago Tüzün, Erdem. “Musk-ilişkili Myasthenia gravis’te Antikor Ve Sitokin Profili”. Deneysel Tıp Araştırma Enstitüsü Dergisi 7, sy. 14 (Aralık 2017): 39-49.
EndNote Tüzün E (01 Aralık 2017) Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili. Deneysel Tıp Araştırma Enstitüsü Dergisi 7 14 39–49.
IEEE E. Tüzün, “Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili”, Deneysel Tıp Araştırma Enstitüsü Dergisi, c. 7, sy. 14, ss. 39–49, 2017.
ISNAD Tüzün, Erdem. “Musk-ilişkili Myasthenia gravis’te Antikor Ve Sitokin Profili”. Deneysel Tıp Araştırma Enstitüsü Dergisi 7/14 (Aralık 2017), 39-49.
JAMA Tüzün E. Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili. Deneysel Tıp Araştırma Enstitüsü Dergisi. 2017;7:39–49.
MLA Tüzün, Erdem. “Musk-ilişkili Myasthenia gravis’te Antikor Ve Sitokin Profili”. Deneysel Tıp Araştırma Enstitüsü Dergisi, c. 7, sy. 14, 2017, ss. 39-49.
Vancouver Tüzün E. Musk-ilişkili myasthenia gravis’te antikor ve sitokin profili. Deneysel Tıp Araştırma Enstitüsü Dergisi. 2017;7(14):39-4.