Gastroenterology

Gastroenterology

Volume 116, Issue 3, March 1999, Pages 566-572
Gastroenterology

Alimentary Tract
Serum immunoglobulin a from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation,☆☆

https://doi.org/10.1016/S0016-5085(99)70178-2Get rights and content

Abstract

Background & Aims: Celiac disease is characterized by disturbed jejunal crypt-villus axis biology with immunoglobulin (Ig) A deposits underlining the epithelium. The aim of this study was to test whether celiac disease serum IgA (reticulin/endomysial autoantibodies) interferes with the mesenchymal-epithelial cell cross-talk. Methods: Differentiation of T84 epithelial cells was induced with IMR-90 fibroblasts or transforming growth factor β in three-dimensional collagen gel cultures. The effects of purified celiac IgA and monoclonal tissue transglutaminase antibodies (CUB7402) were studied by adding the antibodies to the cocultures. Results: Active celiac disease IgA, reactive for tissue transglutaminase, significantly inhibited T84 epithelial cell differentiation (P < 0.001) and increased epithelial cell proliferation (P = 0.024). Similar effects were obtained with antibodies against tissue transglutaminase. Conclusions: Celiac disease–associated IgA class antibodies disturb transforming growth factor β–mediated fibroblast–epithelial cell cross-talk in this in vitro crypt-villus axis model. This primary finding indicates that celiac disease–specific autoantibodies may also contribute to the formation of the gluten-triggered jejunal mucosal lesion in celiac disease.

GASTROENTEROLOGY 1999;116:566-572

Section snippets

Cell lines and cultures

The human intestinal epithelial cell line T84 (CCL 248) and human embryonic lung fibroblast cell line IMR-90 (CCL 186) were purchased from American Type Culture Collection (Rockville, MD). The passages used for T84 cells were 60–70 and for IMR-90 12–19. T84 epithelial cells were cultured in Dulbecco's modified Eagle medium and Ham's F-12 (DMEM/F12, 1:1; GIBCO BRL, Paisley, Scotland) supplemented with 5% heat-inactivated fetal calf serum (FCS; GIBCO BRL) to 90% confluency. Fibroblasts were

Effects of celiac disease patient sera IgA on T84 epithelial cell differentiation

Table 1 shows that T84 intestinal epithelial cells, when given IMR-90 fibroblast support, organized into luminal formations within type I collagen gel.

Antibodies against TGF-β reduced significantly the number of luminal formations. The luminal formations with columnar epithelial cells express enterocyte-like differentiated epithelial cells12; this type of luminal formation is referred to as differentiated-type colony in this study.

To show that the celiac disease autoantigen, typically

Discussion

Using a three-dimensional fibroblast–epithelial cell coculture as a model for crypt-villus axis biology, in which deep-crypt secretory epithelial T84 cells organize and differentiate,12 we show now for the first time that celiac disease–associated IgA class antibodies inhibit both fibroblast- and hTGF-β1–induced intestinal crypt epithelial cell differentiation in vitro. The ability of purified serum IgA to inhibit epithelial cell differentiation correlates with the presence of endomysial

Acknowledgements

The authors thank Anna-Liisa Siponen and Jorma Kulmala for technical assistance.

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    Address requests for reprints to: Markku Mäki, M.D., Celiac Disease Study Group, Institute of Medical Technology, University of Tampere, P.O. BOX 607, FIN-33101 Tampere, Finland. e-mail: [email protected]; fax: (358) 3-215-7746.

    ☆☆

    Supported by the Medical Research Council, the Academy of Finland, Sigrid Juselius Foundation, Medical Research Fund of Tampere University Hospital, and Päivikki and Sakari Sohlberg Foundation.

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