Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides
Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides
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DOI：
10.3389/fimmu.2019.03088
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发表时间：
2020-01-17
影响因子：
7.3
通讯作者：
Belogurov, Alexey, Jr.
中科院分区：
文献类型：
--
作者：
Mamedov, Azad;Vorobyeva, Nadezhda;Belogurov, Alexey, Jr.
多发性硬化症（MS）的发展的风险是已知的增加，在个人轴承不同的II类人类白细胞抗原（HLA）的变体，而其中一些可能有保护作用。在这里，我们分析了一个高度多态性HLA-DRB 1基因座的分布在超过1000复发缓解型MS患者和俄罗斯种族的健康人。携带HLA-DRB 1 *15和HLA-DRB 1 *03等位基因与MS风险相关，而携带HLA-DRB 1 *01和HLA-DRB 1 *11则具有保护作用。基因型分析显示的风险和抗性等位基因的补偿效应的反式。我们已经确定了以前未知的MBP 153 -161肽位于MBP蛋白和MBP 90 -98肽，结合重组HLA-DRB 1 *01：01蛋白的亲和力可比的经典抗原肽306-318从血凝素（HA）的流感病毒证明HLA-DRB 1 *01：01的能力，目前新发现的MBP 153 -161和MBP 90 -98肽。MBP和HA肽与HLA-DM催化的HLA-DRB 1 *01：01结合的动力学参数的测量显示，与HA肽相比，MBP 153 -161和MBP 90 -98肽的CLIP交换速率显著更低。嵌合MBP-HA肽的结合分析表明，所观察到的MBP 153 -161、MBP 90 -98和HA肽表位之间的差异是由MBP肽的C-末端部分中缺少锚残基引起的，这导致与HA（308-316）肽相比，MBP 153 -161和MBP 90 -98肽对HLA-DRB 1 *01：01的P6/7和P9口袋的适度占据。这导致P1和P4对接失败以及快速肽解离和空HLA-DM-HLA-DR复合物的释放。我们想提出，HLA-DRB 1 *01等位基因的保护特性可能与HLA-DRB 1 *01：01在抗原性外源肽和内源性MBP衍生肽之间进行动力学区分的能力直接相关。
Risk of the development of multiple sclerosis (MS) is known to be increased in individuals bearing distinct class II human leukocyte antigen (HLA) variants, whereas some of them may have a protective effect. Here we analyzed distribution of a highly polymorphous HLA-DRB1 locus in more than one thousand relapsing-remitting MS patients and healthy individuals of Russian ethnicity. Carriage of HLA-DRB1*15 and HLA-DRB1*03 alleles was associated with MS risk, whereas carriage of HLA-DRB1*01 and HLA-DRB1*11 was found to be protective. Analysis of genotypes revealed the compensatory effect of risk and resistance alleles in trans. We have identified previously unknown MBP153-161 peptide located at the C-terminus of MBP protein and MBP90-98 peptide that bound to recombinant HLA-DRB1*01:01 protein with affinity comparable to that of classical antigenic peptide 306-318 from the hemagglutinin (HA) of the influenza virus demonstrating the ability of HLA-DRB1*01:01 to present newly identified MBP153-161 and MBP90-98 peptides. Measurements of kinetic parameters of MBP and HA peptides binding to HLA-DRB1*01:01 catalyzed by HLA-DM revealed a significantly lower rate of CLIP exchange for MBP153-161 and MBP90-98 peptides as opposed to HA peptide. Analysis of the binding of chimeric MBP-HA peptides demonstrated that the observed difference between MBP153-161, MBP90-98, and HA peptide epitopes is caused by the lack of anchor residues in the C-terminal part of the MBP peptides resulting in a moderate occupation of P6/7 and P9 pockets of HLA-DRB1*01:01 by MBP153-161 and MBP90-98 peptides in contrast to HA(308-316) peptide. This leads to the P1 and P4 docking failure and rapid peptide dissociation and release of empty HLA-DM-HLA-DR complex. We would like to propose that protective properties of the HLA-DRB1*01 allele could be directly linked to the ability of HLA-DRB1*01:01 to kinetically discriminate between antigenic exogenous peptides and endogenous MBP derived peptides.