Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides
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 thous...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.03088/full |
| _version_ | 1818526389529214976 |
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| author | Azad Mamedov Nadezhda Vorobyeva Ioanna Filimonova Maria Zakharova Maria Zakharova Ivan Kiselev Vitalina Bashinskaya Natalia Baulina Alexey Boyko Alexey Boyko Alexander Favorov Alexander Favorov Olga Kulakova Rustam Ziganshin Ivan Smirnov Ivan Smirnov Alina Poroshina Igor Shilovskiy Musa Khaitov Yuri Sykulev Olga Favorova Valentin Vlassov Alexander Gabibov Alexander Gabibov Alexey Belogurov Alexey Belogurov |
| author_facet | Azad Mamedov Nadezhda Vorobyeva Ioanna Filimonova Maria Zakharova Maria Zakharova Ivan Kiselev Vitalina Bashinskaya Natalia Baulina Alexey Boyko Alexey Boyko Alexander Favorov Alexander Favorov Olga Kulakova Rustam Ziganshin Ivan Smirnov Ivan Smirnov Alina Poroshina Igor Shilovskiy Musa Khaitov Yuri Sykulev Olga Favorova Valentin Vlassov Alexander Gabibov Alexander Gabibov Alexey Belogurov Alexey Belogurov |
| author_sort | Azad Mamedov |
| collection | DOAJ |
| description | 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 HA308−316 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. |
| first_indexed | 2024-12-11T06:22:20Z |
| format | Article |
| id | doaj.art-8c3a43fbbe5040a5b6fcdecb478f2687 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T06:22:20Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-8c3a43fbbe5040a5b6fcdecb478f26872022-12-22T01:17:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-01-011010.3389/fimmu.2019.03088384844Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic PeptidesAzad Mamedov0Nadezhda Vorobyeva1Ioanna Filimonova2Maria Zakharova3Maria Zakharova4Ivan Kiselev5Vitalina Bashinskaya6Natalia Baulina7Alexey Boyko8Alexey Boyko9Alexander Favorov10Alexander Favorov11Olga Kulakova12Rustam Ziganshin13Ivan Smirnov14Ivan Smirnov15Alina Poroshina16Igor Shilovskiy17Musa Khaitov18Yuri Sykulev19Olga Favorova20Valentin Vlassov21Alexander Gabibov22Alexander Gabibov23Alexey Belogurov24Alexey Belogurov25Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaInstitute of Gene Biology, Russian Academy of Sciences, Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaNeuroimmunological Department of the Federal Center of Cerebrovascular Diseases and Stroke, Moscow, RussiaSidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD, United StatesVavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, RussiaPirogov Russian National Research Medical University, Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaInstitute of Fundamental Medicine and Biology, Kazan (Volga) Federal University, Kazan, RussiaNational Research Center Institute of Immunology FMBA of Russia, Moscow, RussiaNational Research Center Institute of Immunology FMBA of Russia, Moscow, RussiaNational Research Center Institute of Immunology FMBA of Russia, Moscow, RussiaDepartment of Microbiology, Thomas Jefferson University, Philadelphia, PA, United StatesPirogov Russian National Research Medical University, Moscow, Russia0Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia1Department of Fundamental Medicine, Lomonosov Moscow State University, Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia1Department of Fundamental Medicine, Lomonosov Moscow State University, Moscow, RussiaRisk 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 HA308−316 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.03088/fullmyelin basic proteinmultiple sclerosishuman leukocyte antigenprotective alleleepitope libraryhemagglutinin |
| spellingShingle | Azad Mamedov Nadezhda Vorobyeva Ioanna Filimonova Maria Zakharova Maria Zakharova Ivan Kiselev Vitalina Bashinskaya Natalia Baulina Alexey Boyko Alexey Boyko Alexander Favorov Alexander Favorov Olga Kulakova Rustam Ziganshin Ivan Smirnov Ivan Smirnov Alina Poroshina Igor Shilovskiy Musa Khaitov Yuri Sykulev Olga Favorova Valentin Vlassov Alexander Gabibov Alexander Gabibov Alexey Belogurov Alexey Belogurov Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides Frontiers in Immunology myelin basic protein multiple sclerosis human leukocyte antigen protective allele epitope library hemagglutinin |
| title | Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides |
| title_full | Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides |
| title_fullStr | Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides |
| title_full_unstemmed | Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides |
| title_short | Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides |
| title_sort | protective allele for multiple sclerosis hla drb1 01 01 provides kinetic discrimination of myelin and exogenous antigenic peptides |
| topic | myelin basic protein multiple sclerosis human leukocyte antigen protective allele epitope library hemagglutinin |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.03088/full |
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