HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes

Thomas P. Finn, Richard E. Jones, Cathleen Rich, Rony Dahan, Jason Link, Chella S. David, Yuan K. Chou, Halina Offner, Arthur A. Vandenbark

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501 -restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.

Original languageEnglish (US)
Pages (from-to)100-114
Number of pages15
JournalJournal of Neuroscience Research
Volume78
Issue number1
DOIs
StatePublished - Oct 1 2004

Fingerprint

Myelin Sheath
HLA Antigens
Multiple Sclerosis
Epitopes
Peptides
Myelin-Oligodendrocyte Glycoprotein
Proteolipids
Alleles
T-Lymphocytes
Antigen Presentation
Valine
Glycine
Proteins
Antigens

Keywords

  • Antigen presentation
  • HLA risk in MS
  • HLA-transgenic mice
  • Myelin peptides

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Finn, T. P., Jones, R. E., Rich, C., Dahan, R., Link, J., David, C. S., ... Vandenbark, A. A. (2004). HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes. Journal of Neuroscience Research, 78(1), 100-114. https://doi.org/10.1002/jnr.20227

HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes. / Finn, Thomas P.; Jones, Richard E.; Rich, Cathleen; Dahan, Rony; Link, Jason; David, Chella S.; Chou, Yuan K.; Offner, Halina; Vandenbark, Arthur A.

In: Journal of Neuroscience Research, Vol. 78, No. 1, 01.10.2004, p. 100-114.

Research output: Contribution to journalArticle

Finn, TP, Jones, RE, Rich, C, Dahan, R, Link, J, David, CS, Chou, YK, Offner, H & Vandenbark, AA 2004, 'HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes', Journal of Neuroscience Research, vol. 78, no. 1, pp. 100-114. https://doi.org/10.1002/jnr.20227
Finn, Thomas P. ; Jones, Richard E. ; Rich, Cathleen ; Dahan, Rony ; Link, Jason ; David, Chella S. ; Chou, Yuan K. ; Offner, Halina ; Vandenbark, Arthur A. / HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes. In: Journal of Neuroscience Research. 2004 ; Vol. 78, No. 1. pp. 100-114.
@article{aa82c973fc5d4a3184fde5bcf35df678,
title = "HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes",
abstract = "Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501 -restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.",
keywords = "Antigen presentation, HLA risk in MS, HLA-transgenic mice, Myelin peptides",
author = "Finn, {Thomas P.} and Jones, {Richard E.} and Cathleen Rich and Rony Dahan and Jason Link and David, {Chella S.} and Chou, {Yuan K.} and Halina Offner and Vandenbark, {Arthur A.}",
year = "2004",
month = "10",
day = "1",
doi = "10.1002/jnr.20227",
language = "English (US)",
volume = "78",
pages = "100--114",
journal = "Journal of Neuroscience Research",
issn = "0360-4012",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes

AU - Finn, Thomas P.

AU - Jones, Richard E.

AU - Rich, Cathleen

AU - Dahan, Rony

AU - Link, Jason

AU - David, Chella S.

AU - Chou, Yuan K.

AU - Offner, Halina

AU - Vandenbark, Arthur A.

PY - 2004/10/1

Y1 - 2004/10/1

N2 - Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501 -restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.

AB - Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501 -restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.

KW - Antigen presentation

KW - HLA risk in MS

KW - HLA-transgenic mice

KW - Myelin peptides

UR - http://www.scopus.com/inward/record.url?scp=4644305285&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4644305285&partnerID=8YFLogxK

U2 - 10.1002/jnr.20227

DO - 10.1002/jnr.20227

M3 - Article

C2 - 15372502

AN - SCOPUS:4644305285

VL - 78

SP - 100

EP - 114

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

IS - 1

ER -