HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes
Thomas P Finn1, Richard E Jones, Cathleen Rich
1Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
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.
Insights
Human leucocyte antigen (HLA) class II alleles like DRB1*1501 are linked to multiple sclerosis (MS) risk. This study found that the DRB1*1502 allele presents myelin peptides similarly to DRB1*1501, suggesting other factors influence MS susceptibility.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Molecular Biology
Background:
- Susceptibility to multiple sclerosis (MS) is genetically associated with human leucocyte antigen (HLA) class II alleles, including DRB1*1501.
- The HLA-DRB1*1502 allele, differing at position 86, is not genetically associated with MS.
- Investigating antigen-presenting differences between these alleles may elucidate MS pathogenesis.
Purpose of the Study:
- To determine if T-cell responses to DRB1*1501-restricted myelin peptides are diminished in transgenic DRB1*1502-expressing mice.
- To compare the antigen-presenting capabilities of HLA-DRB1*1501 and HLA-DRB1*1502 alleles.
Main Methods:
- Generation of transgenic mice expressing HLA-DRB1*1502.
- Assessment of T-cell responses to known DRB1*1501-restricted myelin peptides (MOG, PLP) in transgenic mice.
- Comparison of peptide immunogenicity in transgenic mice and healthy human donors.
Main Results:
- Transgenic DRB1*1502 mice showed moderate to strong T-cell responses to several DRB1*1501-binding motif myelin peptides, including encephalitogenic MOG-35-55.
- These peptides were also immunogenic in humans expressing either DRB1*1501 or DRB1*1502.
- Weak or absent responses were observed only for peptides with unfavorable DRB1*1501 binding motifs in DRB1*1502 mice.
Conclusions:
- The DRB1*1502 allele does not appear to cause a lack of antigen presentation for the tested myelin peptides.
- The differential genetic association of DRB1*1501 and DRB1*1502 with MS susceptibility is unlikely due to impaired antigen presentation by DRB1*1502.
- Other mechanisms involving DRB1*1501 may contribute to increased MS susceptibility.
