In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Anderson, Robert P.; Dégano, Pilar; Godkin, Andrew; Jewell, D P; Hill, Adrian V. S.

doi:10.1038/73200

Cited by 515 publications

(476 citation statements)

References 21 publications

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“…In addition, the HCD4/DQ8 mice responded to a number of gliadin-derived peptides, while the HCD4/DQ6 responses were minimal in number and degree. Several of the gliadin peptides to which the HCD4/DQ8 mice respond have been implicated as being pathogenic in celiac disease in humans (11,27).…”

Section: Discussionmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

137

107

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We have investigated the genetic basis of the immune response to dietary gluten in HCD4/DQ8 and HCD4/DQ6 double transgenic mice. Mice were immunized with gluten i.p. or individual peptides s.c. and spleen or draining lymph node T cells were challenged in vitro. Strong proliferative responses to gluten were seen in the HCD4/DQ8 mice, whereas the HCD4/DQ6 mice responded to gluten poorly. A series of overlapping peptides spanning gliadin were synthesized. The HCD4/DQ8 mice reacted to many of the individual peptides of gliadin, while the HCD4/DQ6 mice were relatively unresponsive. T cells isolated from HCD4/DQ8 mice also responded well to modified (deamidated) versions of the gliadin peptides, whereas HCD4DQ6 mice did not. The T cell response to gluten was CD4 dependent and DQ restricted and led to the production of cytokines IL-6, TGF-β, and IL-10. Finally, intestinal lymphocytes isolated from gluten-fed HCD4/DQ8 mice displayed an activated phenotype. These data suggest that this HLA class II transgenic murine model of gluten sensitivity may provide insight into the initiation of the MHC class II-restricted gluten sensitivity in celiac disease.

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Section: Discussionmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

137

107

View full text Add to dashboard Cite

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“…Animals were sacrificed on day 6, 8, and 10 after infection and virus titers were measured in the supernatants of lung homogenates (33). For MHC restriction studies peptides heat shock protein (Hsp)3-13 (KTIAYDEEARR) (34) and ␣-gliadin 57-73 (QLQPFPQPELPYPQPQS) (35) were synthesized using F-moc chemistry by Chiron (Emeryville, CA). Mice were immunized with 50 g of synthetic peptide emulsified 1/1 (v/v) in CFA (Difco, Detroit, MI) administered s.c. into the tail base and hind footpad.…”

Section: Influenza Infection and T Cell Assaysmentioning

confidence: 99%

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

Chen

Dudek

Wijburg

et al. 2002

The Journal of Immunology

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MHC class II haplotypes control the specificity of Th immune responses and susceptibility to many autoimmune diseases. Understanding the role of HLA class II haplotypes in immunity is hampered by the lack of animal models expressing these genes as authentic cis-haplotypes. In this study we describe transgenic expression of the autoimmune prone HLA DR3-DQ2 haplotype from a yeast artificial chromosome (YAC) containing an intact ∼320-kb region from HLA DRA to DQB2. In YAC-transgenic mice HLA DR and DQ gene products were expressed on B cells, macrophages, and dendritic cells, but not on T cells indicating cell-specific regulation. Positive selection of the CD4 compartment by human class II molecules was 67% efficient in YAC-homozygous mice lacking endogenous class II molecules (Aβnull/null) and expressing only murine CD4. A broad range of TCR Vβ families was used in the peripheral T cell repertoire, which was also purged of Vβ5-, Vβ11-, and Vβ12-bearing T cells by endogenous mouse mammary tumor virus-encoded superantigens. Expression of the HLA DR3-DQ2 haplotype on the Aβnull/null background was associated with normal CD8-dependent clearance of virus from influenza-infected mice and development of CD4-dependent protection from otherwise lethal infection with Salmonella typhimurium. HLA DR- and DQ-restricted T cell responses were also elicited following immunization with known T cell determinants presented by these molecules. These findings demonstrate the potential for human MHC class II haplotypes to function efficiently in transgenic mice and should provide valuable tools for developing humanized models of MHC-associated autoimmune diseases.

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“…Therefore, the proportion of positive RA patients may be underestimated. The difficulty of identifying autoimmune T-cell epitopes is highlighted by a study on celiac disease, in which the patients had to be challenged with gliadin to detect the dominant epitope [17].…”

Section: Discussionmentioning

confidence: 99%

“…The four peptides 10-26, 50-70, 120-133, and 152-170 were found to fulfill this criterium, although 10-26 bound weakly to DR Ã 0101, 120-133 weakly to DR Ã 0404, and 152-170 weakly to DR Ã 0401. Therefore, these epitopes, followed by peptides [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193], and 289-306, were considered best candidates to detect hnRNP-A2 specific T cells in patients with RA.…”

Section: Selection Of T-cell Epitope Candidates Possibly Associated Wmentioning

confidence: 99%

Immunodominant T‐cell epitopes of hnRNP‐A2 associated with disease activity in patients with rheumatoid arthritis

et al. 2010

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The heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) has been described as an important autoantigen in rheumatoid arthritis (RA) since it is targeted by autoantibodies, autoreactive T cells, and is aberrantly expressed in synovial cells in patients. To identify hnRNP-A2-specific T-cell epitopes possibly associated with pathogenicity, we used an innovative approach. We first scanned 280 overlapping hnRNP-A2 peptides for binding to the RA-associated class II molecules HLA-DR4 and HLA-DR1, leading to a comprehensive selection of binders. The selected peptides were tested in IFN-c-specific ELISPOT assay: PBMC from 18% of RA patients showed a significant IFN-c response to hnRNP-A2 peptides, 15% to the overlapping sequences 117-133 and/or 120-133, whereas PBMC from healthy individuals tested negative. We measured proliferative responses to these two peptides in another cohort of patients with RA or osteoarthritis: positive responses were found in 28% of RA, but also in 11% of osteoarthritis patients and these responses could be blocked by anti-MHC class II Ab. Remarkably, the presence of 117/120-133-specific T cells was significantly associated with active disease in RA patients, and bone erosion appeared to be more common in T-cell positive patients. These data suggest involvement of hnRNP-A2 specific cellular autoimmune responses in RA pathogenesis.

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In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Cited by 515 publications

References 21 publications

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

Immunodominant T‐cell epitopes of hnRNP‐A2 associated with disease activity in patients with rheumatoid arthritis

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