Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin

Wal, Yvonne van de; Kooy, Yvonne; Veelen, Peter A. van; Peña, Salvador; Mearin, Luisa; Molberg, Øyvind; Lundin, Knut E.A.; Sollid, Ludvig M.; Mutis, Tuna; Benckhuijsen, Willemien E.; Drijfhout, Jan W.; Koning, Frits

doi:10.1073/pnas.95.17.10050

Cited by 227 publications

(183 citation statements)

References 23 publications

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“…The ability to generate an HLA-DQ-restricted response to naturally occurring epitopes supports the concept that naturally occurring peptides are responsible for the initiation of disease (or at least gluten sensitivity) (24). This does not exclude the possibility that altered peptides (deamidation by tTG or otherwise) are also antigenic either during initiation of disease or later in the disease.…”

Section: Discussionmentioning

confidence: 50%

“…The exception to this is the 11-mer native peptide of gliadin (206 -217) that can induce proliferation in DQ8 T cell lines in its native form (41). Interestingly, a similar peptide overlapping 206 -217 induced a jejunal inflammation when instilled into the jejunum of a patient with celiac disease (24). Our observations in the DQ8 mouse suggest that both native gliadin peptides and deamidated peptides can evoke T cell responses in a DQ-restricted fashion.…”

Section: Discussionmentioning

confidence: 73%

“…Previous studies using human T cell clones have indicated that a peptide spanning residues 206 -217 of gliadin was particularly antigenic for DQ8 ϩ T cell lines derived from patients with celiac disease, and that deamidation of certain residues of this peptide by tTG increases antigenicity (12,24).…”

Section: T Lymphocytes From Hcd4/dq8 Mice Respond To Synthetic Peptidmentioning

confidence: 99%

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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: 50%

Section: Discussionmentioning

confidence: 73%

Section: T Lymphocytes From Hcd4/dq8 Mice Respond To Synthetic Peptidmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Malignant RCDII Lin − IEL lines and gluten-specific CD4 + T-cell lines and clones were isolated and cultured as described previously (25,27,62). To generate CD4 + supernatants for Lin − IEL stimulation, the clones were activated via their T-cell receptors, by stimulation with either gluten peptide-loaded PBMCs or plate-bound antibodies to CD3 and CD28.…”

Section: Methodsmentioning

confidence: 99%

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

Kooy–Winkelaar

Bouwer

Janssen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin − IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin − IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin − IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4 + T cells. We now show that gluten-specific CD4 + T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin − IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4 + T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-x L . Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4 + T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin − IELs and CD3 − CD56 + IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4 + T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.celiac disease | refractory celiac disease | enteropathy-associated T-cell lymphoma | small-molecule inhibitor | intraepithelial lymphocyte

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“…The K562 cell agglutinating activity of wheat has been known for many years [21] to screen cereal toxicity for celiac patients [22]. The majority of the studies performed in the past to assess gluten toxicity with immunochemical methods, the main immunotoxic peptides were identified, and in some cases, also a complete characterization of the digestion mixture was obtained [23]. In the recent years, the advances in the field of mass spectrometry allowed more accurate peptides identification, especially in the case of recombinant gliadin and synthetic peptides [24][25][26][27].…”

Section: Characterization Of the Peptides Deriving From Gluten Digestionmentioning

confidence: 99%

Celiac Disease: Gluten Peptides Characterization after In Vitro Digestion

Prandi¹

2017

Wheat Improvement, Management and Utilization

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Gluten proteins are characterized by the high glutamine and proline content; thus, during gluten digestion, several resistant peptides are produced. Some of them contain sequences that, in celiac patients, are able to trigger an immunological reaction. The prolamin fraction of different wheat samples was submitted to in vitro digestion, and the peptides generated were analysed using liquid chromatography coupled to mass spectrometry techniques. Several wheat varieties were analysed, showing large differences in the production of immunotoxic peptides on digestion. After simulated gastrointestinal digestion of wheat, emerged that peptides containing sequences known to elicit the adaptive immune response derived mainly from γ-gliadin, whereas peptides containing sequences involved in the innate immune response were distributed among α-gliadin and γ-gliadin and low-molecular-weight glutenins. From the results, no major differences due to the different cultivation places were observed. On the other hand, statistically significant differences are present among the genotypes tested, especially for the immunogenic peptides. The possible development would be the selection of wheat genotypes with reduced amount of immunogenic sequences, to reduce the exposure of people and decrease the risk of new cases of disease.

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Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin

Cited by 227 publications

References 23 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

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

Celiac Disease: Gluten Peptides Characterization after In Vitro Digestion

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