{"doi":"10.3389/fimmu.2019.03088","title":"Protective Allele for Multiple Sclerosis HLA-DRB1*01:01 Provides Kinetic Discrimination of Myelin and Exogenous Antigenic Peptides","abstract":"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.","journal":"Frontiers in Immunology","year":2020,"id":64237,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":339682,"name":"Nadezhda E. Vorobyeva","orcid":"0000-0003-4293-834X","position":1,"is_corresponding":false},{"id":339683,"name":"Ioanna N. Filimonova","orcid":"0000-0001-7271-6823","position":2,"is_corresponding":false},{"id":339684,"name":"М. В. Захарова","orcid":"0000-0002-4946-811X","position":3,"is_corresponding":false},{"id":339685,"name":"И. С. Киселев","orcid":"0000-0003-3366-4113","position":4,"is_corresponding":false},{"id":340898,"name":"Vitalina Bashinskaya","orcid":null,"position":5,"is_corresponding":false},{"id":339686,"name":"Natalia Baulina","orcid":"0000-0001-8767-2958","position":6,"is_corresponding":false},{"id":339687,"name":"Alexey Boyко","orcid":"0000-0003-3306-9541","position":7,"is_corresponding":false},{"id":49990,"name":"Alexander V. Favorov","orcid":"0000-0003-2595-1091","position":8,"is_corresponding":false},{"id":339688,"name":"О. Г. Кулакова","orcid":"0000-0002-5321-3101","position":9,"is_corresponding":false},{"id":159079,"name":"Rustam Ziganshin","orcid":"0000-0002-7931-519X","position":10,"is_corresponding":false},{"id":339689,"name":"I. V. Smirnov","orcid":"0000-0002-0384-6568","position":11,"is_corresponding":false},{"id":339690,"name":"Alina Poroshina","orcid":"0000-0002-0400-2201","position":12,"is_corresponding":false},{"id":339691,"name":"I.P. Shilovskiy","orcid":"0000-0001-5343-4230","position":13,"is_corresponding":false},{"id":339692,"name":"Musa Khaitov","orcid":"0000-0003-4961-9640","position":14,"is_corresponding":false},{"id":339693,"name":"Yuri Sykulev","orcid":"0000-0002-9685-0223","position":15,"is_corresponding":false},{"id":339694,"name":"О. О. Фаворова","orcid":"0000-0002-5271-6698","position":16,"is_corresponding":false},{"id":339695,"name":"Valentin V. Vlassov","orcid":"0000-0003-2845-2992","position":17,"is_corresponding":false},{"id":339696,"name":"Alexander G. Gabibov","orcid":"0000-0001-8665-3288","position":18,"is_corresponding":false},{"id":339697,"name":"Alexey A. Belogurov","orcid":"0000-0002-2033-9621","position":19,"is_corresponding":false},{"id":339681,"name":"A. E. Mamedov","orcid":"0000-0001-9343-4550","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T21:12:32.635050Z","pmid":"32010139","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}