Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Patricia T Illing, Julian P Vivian, Nadine Lee Dudek, Lyudmila Kostenko, Zhenjun Chen, Mandvi Bharadwaj, John J Miles, Lars Kjer-Nielsen, Stephanie Gras, Nicholas A Williamson, Scott R Burrows, Anthony Wayne Purcell, Jamie Rossjohn, James McCluskey

Research output: Contribution to journalArticleResearchpeer-review

401 Citations (Scopus)

Abstract

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in immunological self . The resultant peptide-centric altered self activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.
Original languageEnglish
Pages (from-to)554 - 558
Number of pages5
JournalNature
Volume486
Issue number7404
DOIs
Publication statusPublished - 2012

Cite this

Illing, P. T., Vivian, J. P., Dudek, N. L., Kostenko, L., Chen, Z., Bharadwaj, M., ... McCluskey, J. (2012). Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature, 486(7404), 554 - 558. https://doi.org/10.1038/nature11147
Illing, Patricia T ; Vivian, Julian P ; Dudek, Nadine Lee ; Kostenko, Lyudmila ; Chen, Zhenjun ; Bharadwaj, Mandvi ; Miles, John J ; Kjer-Nielsen, Lars ; Gras, Stephanie ; Williamson, Nicholas A ; Burrows, Scott R ; Purcell, Anthony Wayne ; Rossjohn, Jamie ; McCluskey, James. / Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. In: Nature. 2012 ; Vol. 486, No. 7404. pp. 554 - 558.
@article{6c29e5a7e835421cb1e2e56594e30d4c,
title = "Immune self-reactivity triggered by drug-modified HLA-peptide repertoire",
abstract = "Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in immunological self . The resultant peptide-centric altered self activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.",
author = "Illing, {Patricia T} and Vivian, {Julian P} and Dudek, {Nadine Lee} and Lyudmila Kostenko and Zhenjun Chen and Mandvi Bharadwaj and Miles, {John J} and Lars Kjer-Nielsen and Stephanie Gras and Williamson, {Nicholas A} and Burrows, {Scott R} and Purcell, {Anthony Wayne} and Jamie Rossjohn and James McCluskey",
year = "2012",
doi = "10.1038/nature11147",
language = "English",
volume = "486",
pages = "554 -- 558",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7404",

}

Illing, PT, Vivian, JP, Dudek, NL, Kostenko, L, Chen, Z, Bharadwaj, M, Miles, JJ, Kjer-Nielsen, L, Gras, S, Williamson, NA, Burrows, SR, Purcell, AW, Rossjohn, J & McCluskey, J 2012, 'Immune self-reactivity triggered by drug-modified HLA-peptide repertoire', Nature, vol. 486, no. 7404, pp. 554 - 558. https://doi.org/10.1038/nature11147

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. / Illing, Patricia T; Vivian, Julian P; Dudek, Nadine Lee; Kostenko, Lyudmila; Chen, Zhenjun; Bharadwaj, Mandvi; Miles, John J; Kjer-Nielsen, Lars; Gras, Stephanie; Williamson, Nicholas A; Burrows, Scott R; Purcell, Anthony Wayne; Rossjohn, Jamie; McCluskey, James.

In: Nature, Vol. 486, No. 7404, 2012, p. 554 - 558.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

AU - Illing, Patricia T

AU - Vivian, Julian P

AU - Dudek, Nadine Lee

AU - Kostenko, Lyudmila

AU - Chen, Zhenjun

AU - Bharadwaj, Mandvi

AU - Miles, John J

AU - Kjer-Nielsen, Lars

AU - Gras, Stephanie

AU - Williamson, Nicholas A

AU - Burrows, Scott R

AU - Purcell, Anthony Wayne

AU - Rossjohn, Jamie

AU - McCluskey, James

PY - 2012

Y1 - 2012

N2 - Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in immunological self . The resultant peptide-centric altered self activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

AB - Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in immunological self . The resultant peptide-centric altered self activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22722860

U2 - 10.1038/nature11147

DO - 10.1038/nature11147

M3 - Article

VL - 486

SP - 554

EP - 558

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7404

ER -