A Direct Role for NKG2D/MICA Interaction in Villous Atrophy during Celiac Disease

Hüe, Sophie; Mention, Jean Jacques; Monteiro, Renato C.; Zhang, Shaoling; Cellier, Christophe; Schmitz, J; Verkarre, Virginie; Fodil, Nassima; Bahram, Seiamak; Cerf‐Bensussan, Nadine; Caillat‐Zucman, Sophie

doi:10.1016/j.immuni.2004.06.018

Cited by 653 publications

(342 citation statements)

References 57 publications

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“…On the other hand, MICA and MICB are aberrantly expressed in autoimmune diseases, such as rheumatoid arthritis or celiac disease and they play an important role in their pathogenesis [68,69]. In accordance with this, we have reported the association of atypical forms of celiac disease with MICB*008 [24].…”

Section: Discussionsupporting

confidence: 79%

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

et al. 2007

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MHC class I-related genes A/B (MICA/B) are ligands of the NKG2D receptor expressed on T and NK cells. Their expression is highly restricted in normal tissues, but is upregulated in tumoral and infected cells. We show that the minimal promoter of both genes contains a CCAAT box, which binds to NF-Y, and a GC box, which binds to Sp1, Sp3 and Sp4. We also demonstrate that MICB promoter is polymorphic, showing three single nucleotide polymorphisms (C>G at +16, -341, -408) and a deletion of two base pairs at -66 (AG>-) that is located close to the CCAAT box (-70) and the GC box (-86). Transcriptional activity associated with MICB promoter variants carrying this deletion, present in the 45.3% of Spanish population, showed a remarkable decrease (18-fold, p <0.01). By functional analysis, we show that the deletion plays a critical role in MICB promoter activity by diminishing Sp1 transcriptional activation. These important variations in MICB expression among normal individuals could imply a significant difference in the natural immune response against infections or tumor transformation, and might thereby contribute to an increased aberrant immune response against self cells, providing the molecular basis for the associations of the MICB gene to different autoimmune diseases.

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Section: Discussionsupporting

confidence: 79%

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

et al. 2007

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“…Intestinal intraepithelial lymphocytes are typically increased in florid celiac disease and particularly TCRγδ T cells are overrepresented in the affected small intestinal epithelium. The interaction of the activating receptor NKG2D on a subset of small intestinal TCRγδ T cells with the cognate NKG2D ligand on enterocytes, i.e., the class Ib molecules MICA/B, can induce cytotoxic effector functions in subsets of TCRγδ T cells and CD8 TCRαβ T cells, thus, contributing to the characteristic villous atrophy in patients with florid celiac disease [78,79]. In addition to these lymphocytemediated effects, a disease-exacerbating role has been also ascribed to macrophages in response to the enhanced presence of gliadin in the small intestinal mucosa: Gliadin-derived peptides reportedly directly stimulated peritoneal macrophages for an enhanced secretion of cytokines including TNF and the monocyte recruiting chemokine CCL5 [80].…”

Section: Celiac Diseasementioning

confidence: 99%

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

2009

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Intestinal macrophages, preferentially located in the subepithelial lamina propria, represent the largest pool of tissue macrophages in humans. As an adaptation to the local antigen-and bacteria-rich environment, intestinal macrophages exhibit several distinct phenotypic and functional characteristics. Notably, microbe-associated molecular pattern receptors, including the lipopolysaccharide (LPS) receptors CD14 and TLR4, and also the Fc receptors for IgA and IgG are absent on most intestinal macrophages under homeostatic conditions. Moreover, while macrophages in the intestinal mucosa are refractory to the induction of proinflammatory cytokine secretion, they still display potent phagocytic activity. These adaptations allow intestinal macrophages to comply with their main task, i.e., the efficient removal of microbes while maintaining local tissue homeostasis. In this paper, we review recent findings on the functional differentiation of monocyte subsets into distinct macrophage populations and on the phenotypic and functional adaptations that have evolved in intestinal macrophages in response to their antigen-rich environment. Furthermore, the involvement of intestinal macrophages in the pathogenesis of celiac disease and inflammatory bowel diseases is discussed.

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“…Epithelial IL-15 is an important factor in CD pathogenesis (43,44) and is currently the sole cytokine proposed to contribute to the selective expansion of malignant Lin − IELs in RCDII (6,16). We now show that in the absence of IL-15, CD4 + T-cell cytokines TNF, IL-2, and IL-21 are also able to drive the expansion of nonmalignant and malignant Lin − IEL.…”

Section: Discussionmentioning

confidence: 63%

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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A Direct Role for NKG2D/MICA Interaction in Villous Atrophy during Celiac Disease

Cited by 653 publications

References 57 publications

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

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

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