Miller Patrick G, Bonn Michael B, Franklin Craig L, Ericsson Aaron C, McKarns Susan C
Laboratory of TGF-β Biology, Epigenetics, and Cytokine Regulation, Center for Cellular and Molecular Immunology, Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212;
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65201; and.
J Immunol. 2015 Nov 15;195(10):4668-84. doi: 10.4049/jimmunol.1501664. Epub 2015 Oct 16.
TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein-specific 2D2 TCR transgenic mice. Disease in TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein-specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to TNFR2(-/-) 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.
肿瘤坏死因子-α拮抗剂对患有炎症性自身免疫性疾病（如克罗恩病、类风湿性关节炎和强直性脊柱炎）的患者有益。然而，肿瘤坏死因子拮抗作用却出人意料地加剧了中枢神经系统自身免疫，包括多发性硬化症和视神经脊髓炎。其潜在机制仍然不明。我们证明，在髓鞘少突胶质细胞糖蛋白特异性2D2 TCR转基因小鼠中，TNFR2缺陷会导致雌性偏向的自发性自身免疫性中枢神经系统脱髓鞘。TNFR2(-/-) 2D2小鼠的疾病与T细胞和B细胞的中枢神经系统浸润以及髓鞘少突胶质细胞糖蛋白特异性IL-17、IFN-γ和IgG2b的产生增加有关。相对于TNFR2(-/-) 2D2小鼠，TNF(-/-) 2D2小鼠疾病的减轻确定了TNFR1和TNFR2的不同作用。口服抗生素治疗消除了TNFR2(-/-) 2D2小鼠的自发性自身免疫，提示肠道微生物群的作用。粪便16S rRNA的Illumina测序确定了雄性TNFR2(-/-) 2D2中与疾病保护相关的独特微生物群谱。嗜黏蛋白阿克曼氏菌、萨特氏菌属、颤螺菌属、嗜酸拟杆菌和厌氧支原体在雄性TNFR2(-/-) 2D2小鼠中选择性地更为丰富。相比之下，拟杆菌属、均匀拟杆菌和副拟杆菌在受影响的雌性TNFR2(-/-) 2D2小鼠中更为丰富，表明其在疾病病因中的作用。总体而言，TNFR2阻断似乎破坏了共生细菌与宿主的免疫共生关系，从而在基因易感小鼠中揭示自身免疫性脱髓鞘。在这种模式下，微生物可能影响个体对抗肿瘤坏死因子治疗的反应。该模型为针对宿主免疫-微生物群的中枢神经系统脱髓鞘自身免疫性疾病的预防和治疗措施提供了基础。
