Analysis of cytokines in patients with optic neuritis associated with neuromyelitis optic spectrum disorder before and after glucocorticoid pulse therapy_Chinese Journal of Ocular Fundus Diseases

Authors：

Shao Yonghui ¹ , Zhang Jing ² , Guo Sitong ¹ , Liu Yi ¹ ,  Jiang Libin ¹

1. Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing 100730, China;
2. Department of Ophthalmology, Beijing Puren Hospital, Beijing 100062, China;

Corresponding author：

Jiang Libin, Email: jlbjlb@sina.com

Keywords：

Neuromyelitis optica; Optic neuritis; Glucocorticoid pulse therapy; Cytokines

DOI：

10.3760/cma.j.cn511434-20221111-00602

Video：

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Objective To observe the changes of serum cytokines in patients with neuromyelitis optic neuromyelitis optic spectrum disorder (NMOSD) associated optic neuritis (NMOSD-ON) before and after intravenous methylprednisolone pulse (IVMP) treatment. Methods A prospective clinical study. From November 2020 to December 2021, 24 NMOSD-ON patients who visited the Neuro-Ophthalmology Clinic of Beijing Tongren Hospital Affiliated to Capital Medical University were included. Among them, 9 patients were male; 15 patients were female. According to the detection results of aquaporin 4 (AQP4) immunoglobulin G (IgG) antibody (AQP4-IgG) in peripheral blood, the patients were divided into AQP4-lgG positive group and AQP4-lgG negative group, which were 10 and 14 cases respectively. Twenty healthy volunteers were selected as control group. Age (F=0.639) and sex (χ²=2.373) composition ratio of the three groups were compared, the difference were not statistically significant (P=0.504, 0.333). All patients were treated with 500 mg/d or 1 000 mg/d IVMP. Peripheral venous blood of all subjects, and quantitatively analyze interferon-gamma (IFN-γ), interleukin (IL)- 4, IL-31, IL-33, IL-17A, IL-6, IL-21, IL-23, IL-10, tumor necrosis factor (TNF)-α level in serum with Luminex FLEX MAP 3D liquid-phase suspension chip detection system were collected. The differences among groups were analyzed by one-way ANOVA and Kruskal Wallis H test. Results Before IVMP treatment, serum IL-17A concentrations in AQP4-lgG positive group, AQP4-lgG negative group and control group were 2.39, 2.17 and 1.97 pg/ml, respectively. TNF-α concentrations were 5.60, 4.17 and 5.89 pg/ml, respectively. Compared with control group, serum IL-17A concentration in AQP4-IgG positive group was increased, while TNF-α concentration in AQP4-IgG negative group was decreased, with statistical significance (H=12.720, 10.900; P=0.040, 0.039). The levels of IL-17A, IL-6 and other cytokines did not change significantly. After IVMP treatment, serum IL-6 in AQP4-lgG positive group and AQP4-lgG negative group were 0.72 pg/ml and 0.73 pg/ml, respectively. TNF-α concentrations were 4.17 pg/ml and 3.88 pg/ml, respectively. IFN-γ concentrations were 2.15 pg/ml and 2.55 pg/ml, respectively. Compared with before treatment, serum levels of IL-6, TNF-α and IFN-γ in AQP4-lgG positive patients were significantly decreased, with statistical significance (Z=－2.668, －2.547, －2.201; P=0.008, 0.011, 0.028). Serum levels of IL-6 and TNF-α were significantly decreased in AQP4-lgG negative patients, and the difference was statistically significant (Z=－2.501, －1.978; P=0.012, 0.048). Conclusion Glucocorticoid may play a therapeutic role by affecting the levels of serum IL-6, TNF-α, IFN-γ in patients with NMOSD-ON.

Citation： Shao Yonghui, Zhang Jing, Guo Sitong, Liu Yi, Jiang Libin. Analysis of cytokines in patients with optic neuritis associated with neuromyelitis optic spectrum disorder before and after glucocorticoid pulse therapy. Chinese Journal of Ocular Fundus Diseases, 2022, 38(12): 974-980. doi: 10.3760/cma.j.cn511434-20221111-00602 Copy

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13.	Strachan MW, Reynolds RM, Frier BM, et al. The relationship between type 2 diabetes and dementia[J]. Br Med Bull, 2008, 88(1): 131-146. DOI: 10.1093/bmb/ldn042.
14.	Wang KC, Tsai CP, Lee CL, et al. Elevated plasma high-mobility group box 1 protein is a potential marker for neuromyelitis optica[J]. Neuroscience, 2012, 226: 510-516. DOI: 10.1016/j.neuroscience.2012.08.041.
15.	Kalluri SR, Rothhammer V, Staszewski O, et al. Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica[J/OL]. PLoS One, 2011, 6(1): e16083 [2011-01-14]. https://pubmed.ncbi.nlm.nih.gov/21264240/. DOI: 10.1371/journal.pone.0016083.
16.	Röcken M, Racke M, Shevach EM. IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease[J]. Immunol Today, 1996, 17(5): 225-231. DOI: 10.1016/0167-5699(96)80556-1.
17.	Tran GT, Hodgkinson SJ, Carter NM, et al. IL-5 promotes induction of antigen- specific CD4⁺CD25⁺ T regulatory cells that suppress autoimmunity[J]. Blood, 2012, 119(19): 4441-4450. DOI: 10.1182/blood-2011-12-396101.
18.	Vocca L, Di Sano C, Uasuf CG, et al. IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases[J]. Immunobiology, 2015, 220(8): 954-963. DOI: 10.1016/j.imbio.2015.02.005.
19.	Zhang Y, Yao XY, Gao MC, et al. Th2 axis-related cytokines in patients with neuromyelitis optica spectrum disorders[J]. CNS Neurosci Ther, 2018, 24(1): 64-69. DOI: 10.1111/cns.12774.
20.	Chihara N, Aranami T, Sato W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica[J]. Proc Natl Acad Sci USA, 2011, 108(9): 3701-3706. DOI: 10.1073/pnas.1017385108.
21.	Kong BS, Kim Y, Kim GY, et al. Increased frequency of IL-6-producing nonclassical monocytes in neuromyelitis optica spectrum disorder[J]. J Neuroinflammation, 2017, 14(1): 191. DOI: 10.1186/s12974-017-0961-z.
22.	Wei Y, Chang H, Li X, et al. Cytokines and tissue damage biomarkers in first-onset neuromyelitis optica spectrum disorders: significance of interleukin-6[J]. Neuroimmunomodulation, 2018, 25(4): 215-224. DOI: 10.1159/000494976.
23.	Knier B, Rothhammer V, Heink S, et al. Neutralizing IL-17 protects the optic nerve from autoimmune pathology and prevents retinal nerve fiber layer atrophy during experimental autoimmune encephalomyelitis[J]. J Autoimmun, 2015, 56: 34-44. DOI: 10.1016/j.jaut.2014.09.003.
24.	Kurebayashi Y, Nagai S, Ikejiri A, et al. Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells[J]. Genes Cells, 2013, 18(4): 247-265. DOI: 10.1111/gtc.12039.
25.	Hou MM, Li YF, He LL, et al. Proportions of Th17 cells and Th17-related cytokines in neuromyelitis optica spectrum disorders patients: a meta-analysis[J/OL]. Int Immunopharmacol, 2019, 75: 105793[2019-08-08]. https://pubmed.ncbi.nlm.nih.gov/31401379/. DOI: 10.1016/j.intimp.2019.105793.
26.	Kang H, Li H, Ai N, et al. Markedly elevated serum level of T-helper cell 17-related cytokines/chemokines in acute myelin oligodendrocyte glycoprotein antibody-associated optic neuritis[J/OL]. Front Neurol, 2020, 11: 589288[2020-11-13]. https://pubmed.ncbi.nlm.nih.gov/33281728/. DOI: 10.3389/fneur.2020.589288.
27.	Banuelos J, Lu NZ. A gradient of glucocorticoid sensitivity among helper T cell cytokines[J]. Cytokine Growth Factor Rev, 2016, 31: 27-35. DOI: 10.1016/j.cytogfr.2016.05.002.
28.	Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α blockers[J]. Curr Neurol Neurosci Rep, 2017, 17(4): 36. DOI: 10.1007/s11910-017-0742-1.
29.	Li YJ, Zhang F, Qi Y, et al. Association of circulating follicular helper T cells with disease course of NMO spectrum disorders[J]. J Neuroimmunol, 2015, 278: 239-246. DOI: 10.1016/j.jneuroim.2014.11.011.
30.	Pentón-Rol G, Cervantes-Llanos M, Martínez-Sánchez G, et al. TNF-alpha and IL-10 downregulation and marked oxidative stress in neuromyelitis optica[J]. J Inflamm (Lond), 2009, 6: 18. DOI: 10.1186/1476-9255-6-18.
31.	Saadoun S, Waters P, MacDonald C, et al. Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain[J]. Ann Neurol, 2012, 71(3): 323-333. DOI: 10.1002/ana.22686.

1. Toosy AT, Mason DF, Miller DH. Optic neuritis[J]. Lancet Neurol, 2014, 13(1): 83-99. DOI: 10.1016/S1474-4422(13)70259-X.
2. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin- 4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan[J]. Brain, 2012, 135(Pt 6): 1834-1849. DOI: 10.1093/brain/aws109.
3. Jarius S, Paul F, Weinshenker BG, et al. Neuromyelitis optica[J]. Nat Rev Dis Primers, 2020, 6(1): 85. DOI: 10.1038/s41572-020-0214-9.
4. Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, et al. The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives[J]. Int J Mol Sci, 2016, 17(3): 273. DOI: 10.3390/ijms17030273.
5. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study[J]. JAMA Neurol, 2014, 71(3): 276-283. DOI: 10.1001/jamaneurol.2013.5857.
6. Spadaro M, Gerdes LA, Mayer MC, et al. Histopathology and clinical course of MOG-antibody-associated encephalomyelitis[J]. Ann Clin Transl Neurol, 2015, 2(3): 295-301. DOI: 10.1002/acn3.164.
7. Mitsdoerffer M, Kuchroo V, Korn T. Immunology of neuromyelitis optica: a T cell-B cell collaboration[J]. Ann N Y Acad Sci, 2013, 1283: 57-66. DOI: 10.1111/nyas.12118.
8. Brummelman J, Pilipow K, Lugli E. The single-cell phenotypic identity of human CD8⁺ and CD4⁺ T cells[J]. Int Rev Cell Mol Biol, 2018, 341: 63-124. DOI: 10.1016/bs.ircmb.2018.05.007.
9. Taves MD, Ashwell JD. Glucocorticoids in T cell development, differentiation and function[J]. Nat Rev Immunol, 2021, 21(4): 233-243. DOI: 10.1038/s41577-020-00464-0.
10. 中华医学会眼科学分会神经眼科学组. 视神经炎诊断和治疗专家共识(2014年)[J]. 中华眼科杂志, 2014, 50(6): 459-463. DOI: 10.3760/cma.j.issn.0412-4081.2014.06.013.Neuro-ophthalmology Group, Ophthalmological Branch, Chinese Medical Association. Expert consensus on diagnosis and treatment of optic neuritis (2014)[J]. Chin J Ophthalmol, 2014, 50(6): 459-463. DOI: 10.3760/cma.j.issn.0412-4081.2014.06.013.
11. 中华医学会眼科学分会神经眼科学组. 中国脱髓鞘性视神经炎诊断和治疗循证指南(2021年)[J]. 中华眼科杂志, 2021, 57(3): 171-186. DOI: 10.3760/cma.j.cn112142-20201124-00769.Neuro-ophthalmology Group, Ophthalmology Branch, Chinese Medical Association. Evidence-based guidelines for diagnosis and treatment of demyelinating optic neuritis in China (2021)[J]. Chin J Ophthalmol, 2021, 57(3): 171-186. DOI: 10.3760/cma.j.cn112142-20201124-00769.
12. Sparrow JM, Taylor H, Qureshi K, et al. The cataract national dataset electronic multi-centre audit of 55, 567 operations: risk indicators for monocular visual acuity outcomes[J]. Eye (Lond), 2012, 26: 821-826. DOI: 10.1038/eye.2012.51.
13. Strachan MW, Reynolds RM, Frier BM, et al. The relationship between type 2 diabetes and dementia[J]. Br Med Bull, 2008, 88(1): 131-146. DOI: 10.1093/bmb/ldn042.
14. Wang KC, Tsai CP, Lee CL, et al. Elevated plasma high-mobility group box 1 protein is a potential marker for neuromyelitis optica[J]. Neuroscience, 2012, 226: 510-516. DOI: 10.1016/j.neuroscience.2012.08.041.
15. Kalluri SR, Rothhammer V, Staszewski O, et al. Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica[J/OL]. PLoS One, 2011, 6(1): e16083 [2011-01-14]. https://pubmed.ncbi.nlm.nih.gov/21264240/. DOI: 10.1371/journal.pone.0016083.
16. Röcken M, Racke M, Shevach EM. IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease[J]. Immunol Today, 1996, 17(5): 225-231. DOI: 10.1016/0167-5699(96)80556-1.
17. Tran GT, Hodgkinson SJ, Carter NM, et al. IL-5 promotes induction of antigen- specific CD4⁺CD25⁺ T regulatory cells that suppress autoimmunity[J]. Blood, 2012, 119(19): 4441-4450. DOI: 10.1182/blood-2011-12-396101.
18. Vocca L, Di Sano C, Uasuf CG, et al. IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases[J]. Immunobiology, 2015, 220(8): 954-963. DOI: 10.1016/j.imbio.2015.02.005.
19. Zhang Y, Yao XY, Gao MC, et al. Th2 axis-related cytokines in patients with neuromyelitis optica spectrum disorders[J]. CNS Neurosci Ther, 2018, 24(1): 64-69. DOI: 10.1111/cns.12774.
20. Chihara N, Aranami T, Sato W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica[J]. Proc Natl Acad Sci USA, 2011, 108(9): 3701-3706. DOI: 10.1073/pnas.1017385108.
21. Kong BS, Kim Y, Kim GY, et al. Increased frequency of IL-6-producing nonclassical monocytes in neuromyelitis optica spectrum disorder[J]. J Neuroinflammation, 2017, 14(1): 191. DOI: 10.1186/s12974-017-0961-z.
22. Wei Y, Chang H, Li X, et al. Cytokines and tissue damage biomarkers in first-onset neuromyelitis optica spectrum disorders: significance of interleukin-6[J]. Neuroimmunomodulation, 2018, 25(4): 215-224. DOI: 10.1159/000494976.
23. Knier B, Rothhammer V, Heink S, et al. Neutralizing IL-17 protects the optic nerve from autoimmune pathology and prevents retinal nerve fiber layer atrophy during experimental autoimmune encephalomyelitis[J]. J Autoimmun, 2015, 56: 34-44. DOI: 10.1016/j.jaut.2014.09.003.
24. Kurebayashi Y, Nagai S, Ikejiri A, et al. Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells[J]. Genes Cells, 2013, 18(4): 247-265. DOI: 10.1111/gtc.12039.
25. Hou MM, Li YF, He LL, et al. Proportions of Th17 cells and Th17-related cytokines in neuromyelitis optica spectrum disorders patients: a meta-analysis[J/OL]. Int Immunopharmacol, 2019, 75: 105793[2019-08-08]. https://pubmed.ncbi.nlm.nih.gov/31401379/. DOI: 10.1016/j.intimp.2019.105793.
26. Kang H, Li H, Ai N, et al. Markedly elevated serum level of T-helper cell 17-related cytokines/chemokines in acute myelin oligodendrocyte glycoprotein antibody-associated optic neuritis[J/OL]. Front Neurol, 2020, 11: 589288[2020-11-13]. https://pubmed.ncbi.nlm.nih.gov/33281728/. DOI: 10.3389/fneur.2020.589288.
27. Banuelos J, Lu NZ. A gradient of glucocorticoid sensitivity among helper T cell cytokines[J]. Cytokine Growth Factor Rev, 2016, 31: 27-35. DOI: 10.1016/j.cytogfr.2016.05.002.
28. Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α blockers[J]. Curr Neurol Neurosci Rep, 2017, 17(4): 36. DOI: 10.1007/s11910-017-0742-1.
29. Li YJ, Zhang F, Qi Y, et al. Association of circulating follicular helper T cells with disease course of NMO spectrum disorders[J]. J Neuroimmunol, 2015, 278: 239-246. DOI: 10.1016/j.jneuroim.2014.11.011.
30. Pentón-Rol G, Cervantes-Llanos M, Martínez-Sánchez G, et al. TNF-alpha and IL-10 downregulation and marked oxidative stress in neuromyelitis optica[J]. J Inflamm (Lond), 2009, 6: 18. DOI: 10.1186/1476-9255-6-18.
31. Saadoun S, Waters P, MacDonald C, et al. Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain[J]. Ann Neurol, 2012, 71(3): 323-333. DOI: 10.1002/ana.22686.

Chinese Journal of Ocular Fundus Diseases

Analysis of cytokines in patients with optic neuritis associated with neuromyelitis optic spectrum disorder before and after glucocorticoid pulse therapy

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