A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease

Kate Henderson, Jason A Tye-Din, Hugh Harrington Reid, Zhenjun Chen, Natalie Borg, Tim Beissbarth, Arthur Tatham, Stuart I Mannering, Anthony W Purcell, Nadine L Dudek, David A van Heel, James McCluskey, Jamie Rossjohn, Robert P Anderson

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Abstract

The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.
Original languageEnglish
Pages (from-to)23 - 34
Number of pages12
JournalImmunity
Volume27
Issue number1
Publication statusPublished - 2007

Cite this

Henderson, K., Tye-Din, J. A., Reid, H. H., Chen, Z., Borg, N., Beissbarth, T., ... Anderson, R. P. (2007). A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity, 27(1), 23 - 34.
Henderson, Kate ; Tye-Din, Jason A ; Reid, Hugh Harrington ; Chen, Zhenjun ; Borg, Natalie ; Beissbarth, Tim ; Tatham, Arthur ; Mannering, Stuart I ; Purcell, Anthony W ; Dudek, Nadine L ; van Heel, David A ; McCluskey, James ; Rossjohn, Jamie ; Anderson, Robert P. / A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. In: Immunity. 2007 ; Vol. 27, No. 1. pp. 23 - 34.
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title = "A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease",
abstract = "The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.",
author = "Kate Henderson and Tye-Din, {Jason A} and Reid, {Hugh Harrington} and Zhenjun Chen and Natalie Borg and Tim Beissbarth and Arthur Tatham and Mannering, {Stuart I} and Purcell, {Anthony W} and Dudek, {Nadine L} and {van Heel}, {David A} and James McCluskey and Jamie Rossjohn and Anderson, {Robert P}",
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Henderson, K, Tye-Din, JA, Reid, HH, Chen, Z, Borg, N, Beissbarth, T, Tatham, A, Mannering, SI, Purcell, AW, Dudek, NL, van Heel, DA, McCluskey, J, Rossjohn, J & Anderson, RP 2007, 'A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease', Immunity, vol. 27, no. 1, pp. 23 - 34.

A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. / Henderson, Kate; Tye-Din, Jason A; Reid, Hugh Harrington; Chen, Zhenjun; Borg, Natalie; Beissbarth, Tim; Tatham, Arthur; Mannering, Stuart I; Purcell, Anthony W; Dudek, Nadine L; van Heel, David A; McCluskey, James; Rossjohn, Jamie; Anderson, Robert P.

In: Immunity, Vol. 27, No. 1, 2007, p. 23 - 34.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease

AU - Henderson, Kate

AU - Tye-Din, Jason A

AU - Reid, Hugh Harrington

AU - Chen, Zhenjun

AU - Borg, Natalie

AU - Beissbarth, Tim

AU - Tatham, Arthur

AU - Mannering, Stuart I

AU - Purcell, Anthony W

AU - Dudek, Nadine L

AU - van Heel, David A

AU - McCluskey, James

AU - Rossjohn, Jamie

AU - Anderson, Robert P

PY - 2007

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N2 - The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.

AB - The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.

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M3 - Article

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