Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice.
Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice.
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DOI：
10.4049/jimmunol.181.5.3202
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发表时间：
2008-09-01
期刊：
影响因子：
--
通讯作者：
Forsthuber TG
中科院分区：
文献类型：
--
作者：
Kawamura K;McLaughlin KA;Weissert R;Forsthuber TG
主要组织相容性复合体（MHC）基因与多发性硬化症（MS）的遗传相关性最强，但其潜在机制尚未得到解决。在这里，我们问MS相关的MHC II类分子，HLA-DRB 1 *1501，HLA-DRB 5 *0101，和HLA-DRB 1 *0401是否有助于自身免疫性中枢神经系统（CNS）脱髓鞘通过促进致病性T细胞对人髓鞘碱性蛋白（hMBP）的反应，使用三个转基因（Tg）小鼠系表达这些MHC分子。出乎意料的是，在所有Tg小鼠系中观察到T细胞对高亲和力MHC结合hMBP 82 -100表位的强烈耐受性。在HLA-DR Tg小鼠与MBP缺陷小鼠回交后，对hMBP 82 -100的T细胞耐受性被消除。相反，T细胞耐受性是不完全的低亲和力MHC结合hMBP表位。此外，hMBP 82 -100特异性“B型”T细胞在HLA-DRB 5 *0101 Tg小鼠中逃避耐受。重要的是，特异于低亲和力MHC结合hMBP表位的T细胞和hMBP 82 -100特异性“B型”T细胞具有高度致脑炎性。总的来说，结果显示MS相关的MHC II类分子在诱导T细胞对高亲和力MHC结合表位的耐受性方面是高度有效的，而对低亲和力MHC结合表位特异性的自身反应性T细胞和“B型”T细胞可以逃避T细胞耐受性的诱导并且可以促进MS。
Genes of the major histocompatibility complex (MHC) show the strongest genetic association with multiple sclerosis (MS) but the underlying mechanisms have remained unresolved. Here, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401 contribute to autoimmune central nervous system (CNS) demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon backcrossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific “type B” T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific “type B” T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and “type B” T cells can escape the induction of T cell tolerance and may promote MS.
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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.193.1.1
发表时间：
2001-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Anderton SM;Radu CG;Lowrey PA;Ward ES;Wraith DC
通讯作者：
Wraith DC
影响因子：
4.4
作者：
Karulin, AY;Hesse, MD;Lehmann, PV
通讯作者：
Lehmann, PV
影响因子：
4.4
作者：
Lovitch, SB;Walters, JJ;Unanue, ER
通讯作者：
Unanue, ER
影响因子：
4.4
作者：
Bielekova, B;Sung, MH;Martin, R
通讯作者：
Martin, R