Publications (6) View all
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Article: High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions.
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ABSTRACT: Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.Nature medicine 01/2012; 18(3):441-5. · 27.14 Impact Factor -
Article: Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells.
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ABSTRACT: Patients with celiac disease have permanent intolerance to gluten. Because of the high frequency of this disorder (approximately 1 in 100 individuals), we investigated whether oral tolerance to gluten differs from that to other food proteins. Using transgenic mice that express human HLA-DQ2 and a gliadin-specific, humanized T-cell receptor, we compared gluten-specific T-cell responses with tolerogenic mucosal T-cell responses to the model food protein ovalbumin. Consistent with previous findings, the ovalbumin-specific response occurred in the mesenteric lymph nodes and induced Foxp3(+) regulatory T cells. In contrast, ingestion of deamidated gliadin induced T-cell proliferation predominantly in the spleen but little in mesenteric lymph nodes. The gliadin-reactive T cells had an effector-like phenotype and secreted large amounts of interferon gamma but also secreted interleukin-10. Despite their effector-like phenotype, gliadin-reactive T cells had regulatory functions, because transfer of the cells suppressed a gliadin-induced, delayed-type hypersensitivity response. Ingestion of deamidated gliadin induces differentiation of tolerogenic, type 1 regulatory T cells in spleens of HLA-DQ2 transgenic mice. These data indicate that under homeostatic conditions, the T-cell response to deamidated gliadin is tolerance, which is not conditioned by the mucosal immune system but instead requires interleukin-10 induction by antigen presentation in the spleen.Gastroenterology 04/2011; 141(2):610-20, 620.e1-2. · 11.68 Impact Factor -
Article: CD62L(neg)CD38⁺ expression on circulating CD4⁺ T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls.
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ABSTRACT: The aim of this study was to identify new markers of mucosal T cells to monitor ongoing intestinal immune responses in peripheral blood. Expression of cell-surface markers was studied in mice on ovalbumin (OVA)-specific T cells in the gut-draining mesenteric lymph nodes (MLN) after OVA feed. The effect of the local mucosal mediators retinoic acid (RA) and transforming growth factor-β (TGF-β) on the induction of a mucosal phenotype was determined in in vitro T-cell differentiation assays with murine and human T cells. Tetramer stainings were performed to study gluten-specific T cells in the circulation of patients with celiac disease, a chronic small-intestinal inflammation. In mice, proliferating T cells in MLN were CD62L(neg)CD38(+) during both tolerance induction and abrogation of intestinal homeostasis. This mucosal CD62L(neg)CD38(+) T-cell phenotype was efficiently induced by RA and TGF-β in mice, whereas for human CD4(+) T cells RA alone was sufficient. The CD4(+)CD62L(neg)CD38(+) T-cell phenotype could be used to identify T cells with mucosal origin in human peripheral blood, as expression of the gut-homing chemokine receptor CCR9 and β(7) integrin were highly enriched in this subset whereas expression of cutaneous leukocyte-associated antigen was almost absent. Tetramer staining revealed that gluten-specific T cells appearing in blood of treated celiac disease patients after oral gluten challenge were predominantly CD4(+)CD62L(neg)CD38(+). The total percentage of circulating CD62L(neg)CD38(+) of CD4 T cells was not an indicator of intestinal inflammation as percentages did not differ between pediatric celiac disease patients, inflammatory bowel disease patients and respective controls. However, the phenotypic selection of mucosal T cells allowed cytokine profiling as upon restimulation of CD62L(neg)CD38(+) cells interleukin-10 (IL-10) and interferon-γ (IFN-γ) transcripts were readily detected in circulating mucosal T cells. By selecting for CD62L(neg)CD38(+) expression that comprises 5-10% of the cells within the total CD4(+) T-cell pool we are able to highly enrich for effector T cells with specificity for mucosal antigens. This is of pivotal importance for functional studies as this purification enhances the sensitivity of cytokine detection and cellular activation.The American Journal of Gastroenterology 03/2011; 106(6):1147-59. · 7.28 Impact Factor -
Article: Adaptive T-cell responses regulating oral tolerance to protein antigen.
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ABSTRACT: The term oral (or mucosal) tolerance has been classically defined as the suppression of T- and B-cell responses to an antigen by prior administration of the antigen by the oral route. In recent years, it has become clear that both innate and acquired regulatory immune responses are essential for the development of oral tolerance. As such, mucosal microenvironmental factors such as transforming growth factor- β, prostaglandins but also dietary vitamin A create conditioning of an adaptive regulatory T-cell response that suppresses subsequent antigen-specific responses. Particular resident subsets of antigen presenting dendritic cells are pivotal to convey conditioning signals next to the presentation of antigen. This review discusses the primary mechanisms of adaptive regulatory T-cell induction to ingested soluble protein antigen. However, we also discuss the limitations of our knowledge with respect to understanding the very common food hypersensitivity Celiac disease caused by an aberrant adaptive immune response to the food protein gluten.Allergy 12/2010; 66(4):478-90. · 6.27 Impact Factor -
Article: Seasonal changes in suppressive capacity of CD4+ CD25+ T cells from patients with hayfever are allergen-specific and may result in part from expansion of effector T cells among the CD25+ population.
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ABSTRACT: Suppression of allergen-stimulated peripheral blood CD4(+) CD25(-) effector T cells by CD4(+) CD25(+) regulatory T cells obtained from subjects with allergic rhinoconjunctivitis is reduced during the pollen season when compared with out of season. We examined possible explanations for this effect of seasonal pollen exposure on suppression of allergen responses. CD4(+) CD25(-) and CD4(+) CD25(+) T cells were isolated from blood obtained from 44 volunteers with allergic rhinoconjunctivitis during and out of the UK grass pollen season. Co-cultures were performed with grass pollen extract and house dust mite (HDM) to examine allergen specificity. The frequency of IL-5 and IL-10 producing cells was determined by ELISPOT and the expression of T cell activation markers and the CD25(+) regulatory T cell-associated transcription factor Foxp3 were examined. Lactic acid stripping of IgE was used to determine IgE dependence of T cell responses. The seasonal reduction in suppression by CD4(+) CD25(+) T cells was confirmed and was shown to be allergen specific because suppression of HDM-stimulated cultures was not affected significantly. The CD4(+) CD25(+) population contained IL-5 and IL-10 producing cells but increases in their frequencies with seasonal pollen exposure were not significant. Both activation marker and Foxp3 expression increased during the pollen season. IgE stripping reduced CD4(+) and CD4(+) CD25(-) T cell responses to allergen, but had no effect on suppression by CD4(+) CD25(+) T cells. The seasonal reduction in suppression of grass pollen-stimulated effector T cells by CD4(+) CD25(+) T cells is allergen specific and cannot be explained by increased IgE-facilitated allergen presentation. We suggest that changes in the proportion of effector to regulatory T cells among the CD25(+) population isolated may partially explain these findings, and that trafficking to the site of allergic disease may reduce allergen-specific regulatory T cell numbers in peripheral blood.Clinical & Experimental Allergy 08/2009; 39(11):1693-9. · 5.03 Impact Factor
