ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis.
ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis.
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DOI：
10.1038/s41598-018-30159-5
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发表时间：
2018-08-20
影响因子：
4.6
通讯作者：
Amalfitano A
中科院分区：
文献类型：
--
作者：
Pepelyayeva Y;Rastall DPW;Aldhamen YA;O'Connell P;Raehtz S;Alyaqoub FS;Blake MK;Raedy AM;Angarita AM;Abbas AM;Pereira-Hicks CN;Roosa SG;McCabe L;Amalfitano A
强直性脊柱炎（AS）是一种典型的血清阴性自身免疫性疾病，影响着全世界数百万人。通过 GWAS 研究，内质网氨肽酶 1 (ERAP1) 基因中的单核苷酸多态性与 AS 相关联，然而，ERAP1 如何促进 AS 发病的确切机制尚不清楚。我们进行了 µCT 成像和组织学分析来评估 ERAP1−/− 小鼠中轴骨骼的骨形态，并发现了这些小鼠 AS 的标志性骨骼特征，包括脊柱强直、骨质疏松和脊柱炎症。我们还证实了 ERAP1−/− 小鼠存在自发性肠道菌群失调，并且对右旋糖酐硫酸钠 (DSS) 诱导的结肠炎的易感性增加，但是通过交叉寄养实验从野生型小鼠转移健康微生物群并没有解决 ERAP1−/− 小鼠的骨骼表型。免疫学分析表明，虽然 ERAP1−/− 小鼠的外周 Foxp3+ Tregs 数量正常，但它们的“Tr1 样”调节性 T 细胞和耐受性树突细胞数量减少，而这对 Tr1 细胞分化很重要。总之，我们的数据表明 ERAP1−/− 小鼠可以作为研究强直性脊柱炎的肠道、骨骼和免疫学表现的发病机制的有用动物模型。
Ankylosing spondylitis (AS) is a prototypical sero-negative autoimmune disease that affects millions worldwide. Single nucleotide polymorphisms in the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene have been linked to AS via GWAS studies, however, the exact mechanism as to how ERAP1 contributes to pathogenesis of AS is not understood. We undertook µCT imaging and histologic analysis to evaluate bone morphology of the axial skeletons of ERAP1−/− mice and discovered the hallmark skeletal features of AS in these mice, including spinal ankylosis, osteoporosis, and spinal inflammation. We also confirmed the presence of spontaneous intestinal dysbiosis and increased susceptibility to Dextran Sodium Sulfate (DSS)-induced colitis in ERAP1−/− mice, however the transfer of healthy microbiota from wild type mice via cross-fostering experiments did not resolve the skeletal phenotypes of ERAP1−/− mice. Immunological analysis demonstrated that while ERAP1−/− mice had normal numbers of peripheral Foxp3+ Tregs, they had reduced numbers of both “Tr1-like” regulatory T cells and tolerogenic dendritic cells, which are important for Tr1 cell differentiation. Together, our data suggests that ERAP1−/− mice may serve as a useful animal model for studying pathogenesis of intestinal, skeletal, and immunological manifestations of Ankylosing Spondylitis.
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影响因子：
--
作者：
Chihara N;Madi A;Karwacz K;Awasthi A;Kuchroo VK
通讯作者：
Kuchroo VK
DOI：
10.1126/science.1198469
发表时间：
2011-01-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Atarashi K;Tanoue T;Shima T;Imaoka A;Kuwahara T;Momose Y;Cheng G;Yamasaki S;Saito T;Ohba Y;Taniguchi T;Takeda K;Hori S;Ivanov II;Umesaki Y;Itoh K;Honda K
通讯作者：
Honda K
影响因子：
4.9
作者：
Klingberg E;Lorentzon M;Mellström D;Geijer M;Göthlin J;Hilme E;Hedberg M;Carlsten H;Forsblad-d'Elia H
通讯作者：
Forsblad-d'Elia H
影响因子：
3.4
作者：
Bron, Johannes L.;de Vries, Mirjam K.;Snieders, Marieke N.;van der Horst-Bruinsma, Irene E.;Van Royen, Barend J.
通讯作者：
Van Royen, Barend J.
出生后立即进行交叉促进会引起由哺乳母亲塑造的永久性菌群转移。
影响因子：
15.5
作者：
Daft JG;Ptacek T;Kumar R;Morrow C;Lorenz RG
通讯作者：
Lorenz RG