Tao Yazhong, Zhang Xin, Zivadinov Robert, Dwyer Michael G, Kennedy Cheryl, Bergsland Niels, Ramasamy Deepa, Durfee Jacqueline, Hojnacki David, Hayward Brooke, Dangond Fernando, Weinstock-Guttman Bianca, Markovic-Plese Silva
Departments of Neurology (Y.T., X.Z., S.M.-P.) and Microbiology and Immunology (S.M.-P.), University of North Carolina at Chapel Hill; Buffalo Neuroimaging Analysis Center (R.Z., M.G.D., C.K., N.B., D.R., J.D.), Department of Neurology (R.Z., M.G.D., C.K., N.B., D.R., D.H., J.D., B.W.-G.), State University of New York at Buffalo; and EMD Serono, Inc. (B.H., F.D.), Rockland, MA.
Neurol Neuroimmunol Neuroinflamm. 2015 Nov 12;2(6):e176. doi: 10.1212/NXI.0000000000000176. eCollection 2015 Dec.
To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon β-1a (IFN-β-1a).
Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-β-1a for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively.
Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22-expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22-producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-β-1a induced reductions in transcription factor AHR, T-bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD4(+) cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR.
Findings indicate that IFN-β-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.
This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-β-1a treatment in patients with RRMS.
评估效应细胞和免疫标志物在中枢神经系统脱髓鞘病变形成中的潜在作用，以及它们受干扰素β-1a（IFN-β-1a）的调节情况。
23例复发缓解型多发性硬化症（RRMS）患者接受IFN-β-1a治疗6个月。将免疫标志物结果与脑MRI病变体积以及正常表观脑组织（NABT）体积相关联，NABT的体素级磁化传递率（VW-MTR）分别降低或升高，提示脱髓鞘和再髓鞘化。
与健康对照者相比，患者的Th22细胞转录因子芳烃受体（AHR）和白细胞介素（IL）-17F的基线表达以及表达IL-22的CD4(+)和CD8(+)细胞百分比显著更高；CD4(+)细胞中的IL-4更低。产生IL-22的CD8(+)细胞基线百分比与T₂病变体积呈正相关，而产生IL-17A的CD8(+)细胞百分比与T₂和T₁病变体积呈正相关。IFN-β-1a导致转录因子AHR、T-bet和视黄酸相关孤儿核激素受体C（RORc）基因表达降低，而它增加了CD4(+)细胞中GATA3的表达。治疗后，表达IL-22、IL-17A和IL-17F的T细胞百分比显著降低。表达IL-10的CD4(+)和CD8(+)细胞百分比增加与VW-MTR增加时更大的NABT体积相关，而表达IL-17F的CD4(+)细胞百分比降低与VW-MTR降低时NABT体积减小呈正相关。
研究结果表明，IFN-β-1a抑制Th22和Th17细胞反应，这与MRI检测到的脱髓鞘减少相关。
这项初步研究提供了III类证据，即RRMS患者接受IFN-β-1a治疗后，Th22和Th17反应降低与脱髓鞘减少相关。
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