Van Praet Jens T, Donovan Erin, Vanassche Inge, Drennan Michael B, Windels Fien, Dendooven Amélie, Allais Liesbeth, Cuvelier Claude A, van de Loo Fons, Norris Paula S, Kruglov Andrey A, Nedospasov Sergei A, Rabot Sylvie, Tito Raul, Raes Jeroen, Gaboriau-Routhiau Valerie, Cerf-Bensussan Nadine, Van de Wiele Tom, Eberl Gérard, Ware Carl F, Elewaut Dirk
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
Department of Pathology, University Medical Center, Utrecht, the Netherlands.
EMBO J. 2015 Feb 12;34(4):466-74. doi: 10.15252/embj.201489966. Epub 2015 Jan 19.
Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance against nuclear self-constituents remain largely unresolved. Using mice deficient in lymphotoxin and Hox11, we report that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies. Interestingly, we find this phenotype is not caused by a defect in central tolerance. Rather, cell-specific deletion and in vivo lymphotoxin blockade link these systemic autoimmune responses to the formation of gut-associated lymphoid tissue in the neonatal period of life. We further demonstrate antinuclear antibody production is influenced by the presence of commensal gut flora, in particular increased colonization with segmented filamentous bacteria, and IL-17 receptor signaling. Together, these data indicate that neonatal colonization of gut microbiota influences generalized autoimmunity in adult life.
抗核抗体是包括系统性红斑狼疮和系统性硬化症在内的全身性自身免疫性疾病的一个标志性特征。然而，针对核自身成分的免疫耐受丧失背后的机制在很大程度上仍未得到解决。利用缺乏淋巴毒素和Hox11的小鼠，我们报告称，约25%缺乏次级淋巴器官的小鼠会自发产生特异性抗核抗体。有趣的是，我们发现这种表型并非由中枢免疫耐受缺陷引起。相反，细胞特异性缺失和体内淋巴毒素阻断将这些全身性自身免疫反应与生命早期肠道相关淋巴组织的形成联系起来。我们进一步证明，抗核抗体的产生受共生肠道菌群的影响，特别是分节丝状菌的定植增加以及白细胞介素-17受体信号传导的影响。总之，这些数据表明肠道微生物群的新生儿定植会影响成年后的全身性自身免疫。
