Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease

Forsberg, Göte; Hernell, Olle; Melgar, Silvia; Israelsson, Anne; Hammarström, Sten; Hammarström, Marie‐Louise

doi:10.1053/gast.2002.35355

Cited by 156 publications

(183 citation statements)

References 40 publications

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“…The same was true for IL-15, which is not produced by T cells. In short, these findings are consistent with previous reports on the cytokine profiles of CD4 + T cells in CD (19,30,31,(33)(34)(35)(36)(37)(38)(39)(40), and identify additional cytokines produced by a gluten-specific CD4 + T-cell clone.…”

Section: Resultssupporting

confidence: 92%

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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Section: Resultssupporting

confidence: 92%

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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“…Subpopulations of IEL and LPL were retrieved by sequential positive selection using paramagnetic beads charged with anti-CD3 mAb followed by beads charged with a mixture of anti-CD2 and anti-CD7 mAbs (14). IEL and LPL were isolated from intestinal biopsies of children as described (15) and cells of the T cell lineage were retrieved by positive selection using paramagnetic beads charged with a mixture of anti-CD2 and anti-CD7 mAbs. The isolation procedure was performed at 4°C and positively selected cells were frozen within 1 h after exposure to mAb.…”

Section: Isolation Of Leukocytesmentioning

confidence: 99%

Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

Bas

Hammarström

2003

The Journal of Immunology

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Two new 5′-untranslated region (5′UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5′UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5′UTR exon was not expressed in these cells. Conversely, one of the new 5′UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2+CD7+CD3−). This cell population also expressed high levels of mRNA for the pre-T α-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T α-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.

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“…En la EC activa los linfocitos T CD4 þ de la lámina propia y los LIE CD8 þ contribuyen a desencadenar una respuesta Th1 dominada por el IFN-g, el factor de transcripción T-bet y otras citocinas proinflamatorias (TNF-a, IL18, IL21), junto a un descenso de IL10 e TGFb [37][38][39] , y la producción de IL15 por los enterocitos 5 . Este perfil de tipo proinflamatorio, que desaparece en los pacientes en remisión, activa mecanismos efectores del daño tisular, en los que interviene el factor de crecimiento de queratinocitos 40 , y metaloproteinasas de matriz 41,42 , implicados en la degradación de la matriz extracelular y la transformación mucosa.…”

Section: Alteración De La Red De Citocinas Y Mediadores De Inflamaciónunclassified

Inmunología de la enfermedad celíaca

Arranz

Garrote

2010

Gastroenterología y Hepatología

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PALABRAS CLAVEEnfermedad celíaca; Linfocitos T; Péptidos de gluten; HLA-DQ2/DQ8; Transglutaminasa; Citocinas; Anticuerpos Resumen La enfermedad celíaca es un trastorno inflamatorio del intestino delgado inducido por la ingestión de gluten de trigo y otras prolaminas en individuos genéticamente susceptibles, que se manifiesta por linfocitosis intraepitelial y de lámina propia, pérdida de vellosidades, remodelación tisular y presencia de anticuerpos antitransglutaminasa. El modelo patogénico más aceptado depende de la inmunidad adaptativa tras la estimulación de linfocitos T CD4 þ por péptidos de gluten modificados por la transglutaminasa tisular y restricción por moléculas HLA-DQ2/DQ8, que producen citocinas proinflamatorias. El gluten activa también la inmunidad innata y la citotoxicidad epitelial mediada por linfocitos intraepiteliales. Aunque no está claro aún cuál es el efecto de los anticuerpos específicos, la disponibilidad de marcadores serológicos e inmunogenéticos como herramientas diagnósticas ha propiciado el avance en el conocimiento de la enfermedad celíaca y la revisión de los criterios diagnósticos, especialmente en los individuos adultos con expresión mínima o atípica de la enfermedad. & 2009 Elsevier España, S.L. Todos los derechos reservados. KEYWORDSCeliac disease; T lymphocytes; Gluten peptides; HLA-DQ2/DQ8; Transglutaminase; Cytokines; Antibodies Immunology of celiac disease AbstractCeliac disease is an inflammatory disorder of the small intestine induced by intake of wheat gluten and other prolamines in genetically susceptible individuals. This disease is manifested by an increased number of intraepithelial and lamina propria lymphocytes, villous atrophy, tissue remodeling and the presence of anti-transglutaminase antibodies. The most widely accepted pathogenic model is based on adaptive immunity after T CD4 þ lymphocyte stimulation by tissue transglutamine-modified gluten peptides and HLA-DQ2/DQ8 restriction, which produce proinflammatory cytokines. Gluten also activates innate immunity and epithelial cytotoxicity mediated by intraepithelial lymphocytes. Although the effect of specific antibodies remains unclear, the 0210-5705/$ -see front matter & 2009 Elsevier España, S.L. Todos los derechos reservados.

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Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease

Cited by 156 publications

References 40 publications

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

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

Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

Inmunología de la enfermedad celíaca

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