Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4.
Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4.
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DOI：
10.1016/j.cellimm.2018.05.003
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发表时间：
2018-09
影响因子：
4.3
通讯作者：
Forsthuber TG
中科院分区：
文献类型：
--
作者：
Nalawade SA;Ji N;Raphael I;Pratt A 3rd;Kraig E;Forsthuber TG
人类自身免疫性疾病相关的HLA等位基因HLA-DR 2b（DRB 1 *1501）和HLA-DR 4（DRB 1 *0401）分别与多发性硬化症（MS）和类风湿性关节炎（RA）的易感性增加密切相关。潜在的机制尚未完全了解，但这些MHC等位基因可能通过中枢耐受性形成致病性T细胞的库。转录因子自身免疫调节因子（AIRE）通过异位表达组织特异性抗原（TSA）促进中枢T细胞耐受。人类的Aire缺乏会导致1型自身免疫性多内分泌病综合征（APS 1），Aire敲除小鼠（Aire−/−）会出现以多器官淋巴细胞浸润为特征的自发性自身免疫性病理。在这里，我们问是否受损的TSAs基因表达的情况下，Aire促进自发的MS或RA样自身免疫性病理的背景下，人类HLA等位基因在HLA-DR 2b或HLA-DR 4转基因（tg）小鼠。结果表明，Aire缺陷型HLA-DR 2b或HLA-DR 4 tg小鼠胸腺中TSAs基因表达的降低对应于唾液腺、肝脏和胰腺中的轻度自发性炎性浸润。此外，Aire缺乏适度增强HLA-DR tg小鼠的实验性自身免疫性脑脊髓炎（EAE），但动物没有表现出自发性神经炎症或关节炎的迹象。在CD 4 + T细胞数量、T细胞受体（TCR）分布、调节性T细胞（Treg）或抗原诱导的细胞因子产生方面未观察到显著变化。通过在Aire缺陷型HLA-DR tg小鼠中用抗CTLA-4或抗CD 25 mAb治疗来消除Treg功能不会引发EAE或其他自身免疫病理学。我们的研究结果表明，在自身免疫性疾病相关的人类HLA等位基因的背景下，Aire在维持免疫耐受中的作用是多余的。
The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire−/−) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates. Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice. The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4+ T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.
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DOI：
10.1084/jem.183.6.2635
发表时间：
1996-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ito K;Bian HJ;Molina M;Han J;Magram J;Saar E;Belunis C;Bolin DR;Arceo R;Campbell R;Falcioni F;Vidović D;Hammer J;Nagy ZA
通讯作者：
Nagy ZA
DOI：
10.1084/jem.20050693
发表时间：
2005-09-19
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Jiang W;Anderson MS;Bronson R;Mathis D;Benoist C
通讯作者：
Benoist C
DOI：
10.1126/science.1159407
发表时间：
2008-08-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gardner JM;Devoss JJ;Friedman RS;Wong DJ;Tan YX;Zhou X;Johannes KP;Su MA;Chang HY;Krummel MF;Anderson MS
通讯作者：
Anderson MS
影响因子：
4.9
作者：
García-Lozano JR;Torres-Agrela B;Montes-Cano MA;Ortiz-Fernández L;Conde-Jaldón M;Teruel M;García A;Núñez-Roldán A;Martín J;González-Escribano MF
通讯作者：
González-Escribano MF
影响因子：
30.5
作者：
Aschenbrenner, Katharina;D'Cruz, Louise M.;Klein, Ludger
通讯作者：
Klein, Ludger