Alimentary TractSerum immunoglobulin a from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation☆,☆☆
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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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2016, Journal of Biological ChemistryCitation Excerpt :Notwithstanding, we would like to discuss some potentially important aspects. The differential effects of antibodies targeting different epitopes may explain why studies using polyclonal anti-TG2 sera from CD patients show conflicting and inconclusive results regarding the effects of antibodies on TG2 catalytic function (37, 39–50). Although our observations indicate that celiac anti-TG2 antibodies may modulate extracellular TG2 activity, our incomplete understanding of TG2 biology and activity in the extracellular matrix makes it difficult to properly assess this.
Immunopathology of Celiac Disease
2015, Mucosal Immunology: Fourth EditionThe role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut
2014, Cytokine and Growth Factor ReviewsThe function of tissue transglutaminase in celiac disease
2012, Autoimmunity ReviewsCitation Excerpt :An in vitro study that used T84 crypt epithelial cell differentiation in a fibroblast coculture model provided indirect evidence of a blocking function for anti-tTG antibodies by showing that the TGF-β-dependent differentiation of T84 crypt epithelial cells can be prevented by the addition of a blocking antibody to TGF-β or of IgA autoantibodies to tTG. On this basis, local overproduction of the autoantibodies has been suggested to contribute to the mucosal transformation observed in the celiac lesion [64]. An inhibitory effect of IgA and IgG anti-tTG antibodies from serum of celiac patients as well as monoclonal anti-tTG antibodies against both in vitro and in situ activities of tTG was shown by Esposito et al. [66].
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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.
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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.