HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis.
HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis.
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DOI：
10.4049/jimmunol.1303118
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Vandenbark AA
中科院分区：
文献类型：
--
作者：
Meza-Romero R;Benedek G;Yu X;Mooney JL;Dahan R;Duvshani N;Bucala R;Offner H;Reiter Y;Burrows GG;Vandenbark AA
CD 74是MHC II类不变链的细胞表面形式，是作为巨噬细胞迁移抑制因子（MIF）结合复合物的一部分参与各种免疫介导的疾病的关键炎症因子。然而，在这种情况下，对CD 74的天然调节因子知之甚少。为了研究HLA-DR分子在调节CD 74中的作用，我们利用了HLA-DRα1结构域，该结构域显示与CD 11b+单核细胞上的CD 74结合并下调CD 74。我们发现DRα1可直接抑制MIF与CD 74的结合，并阻断其在实验性自身免疫性脑脊髓炎（EAE）小鼠脊髓中的下游炎症作用。DRα1结构域的效力可被胰蛋白酶消化破坏，但可通过添加提供DRα1中不存在的二级结构的肽延伸（MOG-35-55肽）来增强。这些数据表明DRα1-MOG上的构象敏感决定子负责与CD 74的最佳结合和MIF效应的拮抗作用，从而减少轴突损伤并逆转EAE的持续临床和组织学体征。这些结果证明了DRα1对MIF的天然拮抗剂活性，其被MOG肽延伸强烈增强，从而产生了一种新的治疗剂DRα1-MOG-35-55，其在EAE模型的局限性内可能具有治疗自身免疫性疾病如多发性硬化症的潜力。
CD74, the cell surface form of the MHC class II invariant chain, is a key inflammatory factor that is involved in various immune mediated diseases as part of the Macrophage Migration Inhibitory Factor (MIF) binding complex. However, little is known about the natural regulators of CD74 in this context. In order to study the role of the HLA-DR molecule in regulating CD74, we utilized the HLA-DRα1 domain, which was shown to bind to and downregulate CD74 on CD11b+ monocytes. We found that DRα1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Potency of the DRα1 domain could be destroyed by trypsin digestion but enhanced by addition of a peptide extension (MOG-35–55 peptide) that provided secondary structure not present in DRα1. These data suggest a conformationally-sensitive determinant on DRα1-MOG that is responsible for optimal binding to CD74 and antagonism of MIF effects, resulting in reduced axonal damage and reversal of ongoing clinical and histological signs of EAE. These results demonstrate natural antagonist activity of DRα1 for MIF that was strongly potentiated by the MOG peptide extension, resulting in a novel therapeutic, DRα1-MOG-35–55,that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis.
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影响因子：
3.7
作者：
Koch N;Zacharias M;König A;Temme S;Neumann J;Springer S
通讯作者：
Springer S
影响因子：
3.6
作者：
Benedek, Gil;Zhu, Wenbin;Offner, Halina
通讯作者：
Offner, Halina
DOI：
10.1073/pnas.95.19.11383
发表时间：
1998-09-15
影响因子：
11.1
作者：
Calandra, T;Spiegel, LA;Bucala, R
通讯作者：
Bucala, R
DOI：
10.1073/pnas.0306885101
发表时间：
2004-03-23
影响因子：
11.1
作者：
Kim, CY;Quarsten, H;Sollid, LM
通讯作者：
Sollid, LM
影响因子：
4.8
作者：
Carven, GJ;Chitta, S;Stern, LJ
通讯作者：
Stern, LJ