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Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis
The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoim...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wiley Subscription Services, Inc., A Wiley Company
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128712/ https://www.ncbi.nlm.nih.gov/pubmed/21413052 http://dx.doi.org/10.1002/hep.24299 |
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author | Hov, Johannes R Kosmoliaptsis, Vasilis Traherne, James A Olsson, Marita Boberg, Kirsten M Bergquist, Annika Schrumpf, Erik Bradley, J Andrew Taylor, Craig J Lie, Benedicte A Trowsdale, John Karlsen, Tom H |
author_facet | Hov, Johannes R Kosmoliaptsis, Vasilis Traherne, James A Olsson, Marita Boberg, Kirsten M Bergquist, Annika Schrumpf, Erik Bradley, J Andrew Taylor, Craig J Lie, Benedicte A Trowsdale, John Karlsen, Tom H |
author_sort | Hov, Johannes R |
collection | PubMed |
description | The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10(−32) and P = 1.8 × 10(−22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (Hepatology 2011;53:1967-1976) |
format | Online Article Text |
id | pubmed-3128712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Wiley Subscription Services, Inc., A Wiley Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-31287122011-07-07 Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis Hov, Johannes R Kosmoliaptsis, Vasilis Traherne, James A Olsson, Marita Boberg, Kirsten M Bergquist, Annika Schrumpf, Erik Bradley, J Andrew Taylor, Craig J Lie, Benedicte A Trowsdale, John Karlsen, Tom H Hepatology Autoimmune, Cholestatic and Biliary Disease The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10(−32) and P = 1.8 × 10(−22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (Hepatology 2011;53:1967-1976) Wiley Subscription Services, Inc., A Wiley Company 2011-06 /pmc/articles/PMC3128712/ /pubmed/21413052 http://dx.doi.org/10.1002/hep.24299 Text en Copyright © 2011 American Association for the Study of Liver Diseases http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Autoimmune, Cholestatic and Biliary Disease Hov, Johannes R Kosmoliaptsis, Vasilis Traherne, James A Olsson, Marita Boberg, Kirsten M Bergquist, Annika Schrumpf, Erik Bradley, J Andrew Taylor, Craig J Lie, Benedicte A Trowsdale, John Karlsen, Tom H Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title | Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title_full | Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title_fullStr | Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title_full_unstemmed | Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title_short | Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis |
title_sort | electrostatic modifications of the human leukocyte antigen-dr p9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis |
topic | Autoimmune, Cholestatic and Biliary Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128712/ https://www.ncbi.nlm.nih.gov/pubmed/21413052 http://dx.doi.org/10.1002/hep.24299 |
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