IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages.
IL7Rα contributes to experimental autoimmune encephalomyelitis through altered T cell responses and nonhematopoietic cell lineages.
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DOI：
10.4049/jimmunol.1203214
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Bethea JR
中科院分区：
文献类型：
--
作者：
Ashbaugh JJ;Brambilla R;Karmally SA;Cabello C;Malek TR;Bethea JR
白介素7Rα基因突变已被确定为多发性硬化症(MS)的危险因素，MS是一种以炎症、脱髓鞘和轴突损伤为特征的神经退行性自身免疫性疾病。IL7Rα在淋巴细胞发育和动态平衡中的作用已得到很好的证实，但它在疾病中的作用在很大程度上还没有得到充分的研究。在这里，我们使用实验性自身免疫性脑脊髓炎(EAE)的MS模型来表明，当IL7RTgIL7Rα的表达主要限于IL7RTgIL7R−/−小鼠的胸腺组织时，会产生一种不那么严重的疾病。与野生型(WT)小鼠相比，IL7RTgIL7R−/−小鼠表现出与抑制效应反应相关的瘫痪和髓鞘损伤的减轻，即肿瘤坏死因子的产生减少。此外，用中和抗IL7Rα抗体治疗WT病小鼠，也能显著改善EAE。此外，通过骨髓移植产生嵌合小鼠，以限制IL7Rα的表达，使其表达于造血系或非造血系细胞。仅在造血细胞上缺乏IL7Rα的小鼠发生严重的EAE，表明IL7Rα在非造血室的表达有助于疾病的发生。此外，在中枢神经系统内源性星形胶质细胞和少突胶质细胞上发现了新的IL7Rα表达。仅在非造血细胞上缺乏IL7Rα的嵌合小鼠也会发生严重的EAE，这进一步支持了IL7Rα在T细胞效应功能中的作用。相反，在两个隔间都缺乏IL7Rα的小鼠显著免受疾病的侵袭。综上所述，这些数据表明，多种细胞类型利用IL7Rα信号通路在EAE的发生发展中发挥作用，抑制这一途径应被认为是治疗MS的新途径。
A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. Here we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTgIL7R−/− mice. Compared to wild type (WT) mice, IL7RTgIL7R−/− mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7Rα antibody also resulted in significant improvement of EAE. Additionally, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic or non-hematopoietic origin. Mice lacking IL7Rα only on hematopoietic cells develop severe EAE, suggesting that IL7Rα expression in the non-hematopoietic compartment contributes to disease. Moreover, novel IL7Rα expression was identified on astrocytes and oligodendrocytes endogenous to the central nervous system. Chimeric mice that lack IL7Rα only on non-hematopoietic cells also develop severe EAE, which further supports the role of IL7Rα in T cell effector function. Conversely, mice that lack IL7Rα throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types utilize IL7Rα signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS.
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影响因子：
3.7
作者：
Comabella M;Craig DW;Camiña-Tato M;Morcillo C;Lopez C;Navarro A;Rio J;BiomarkerMS Study Group;Montalban X;Martin R
通讯作者：
Martin R
影响因子：
14.5
作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
Bethea, John R.
影响因子：
3.3
作者：
Kremlev, Sergey G.;Gaurnier-Hausser, Anita L.;Tuszynski, George
通讯作者：
Tuszynski, George
影响因子：
4.2
作者：
ISSAZADEH, S;MUSTAFA, M;OLSSON, T
通讯作者：
OLSSON, T
影响因子：
--
作者：
HAIRE, M;FRASER, KB;MILLAR, JHD
通讯作者：
MILLAR, JHD