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Immunopathology of human inflammatory bowel disease

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Conclusions

Mucosal pIgA, and thereby secretory immunity, are disfavored in IBD as revealed by decreased J-chain expression and strikingly increased IgG production by the mucosal immunocytes in both UC and CD. Moreover, a significant shift from IgA2 to the less-resistant IgA1 subclass takes place. Preferential overproduction of IgG1 is seen in UC; and apical deposits of this isotype on the surface epithelium, together with activated complement, is suggestive of a cytotoxic attack related to a brushborder antigen. Comparison of identical twins, discordant with regard to clinical expression of UC, further suggests that this IgG1 response is genetically determined. The IBD lesions furthermore contain many recently recruited and activated T cells as well as monocyte-like macrophages (L1+CD14+) with elevated capacity for production of proinflammatory cytokines (IL-1 and TNF-α) and ROM. Together all these changes reflect less restricted extravasation of precursor cells because of altered expression of adhesion molecules on the microvasculature. Isolated and cultured intestinal endothelial cells subjected to proinflammatory cytokines show enhanced ICAM-1 expression as well as induction of functional E-selectin and MHC class II molecules with antigen-presenting properties.

The immunopathology of IBD thus involves severely altered mucosal homeostasis, apparently reflecting break of tolerance to the indigenous microbial flora, and in addition it appears to include an autoimmune component in UC. The origin of abrogated immunological tolerance at the mucosal level may be alterations both in leukocyte extravasation and in antigen-presenting mechanisms induced by aberrant expression of endothelial and epithelial MHC class II molecules, as well as changed profiles of co-stimulatory molecules on macrophages. A shift from B7.2 on mucosal resident APC to B7.1 on the recently recruited macrophages, may particularly disfavor Th2 immune responses and their associated down-regulatory cytokines. In conclusion, perturbation of a tightly controlled cytokine network with abnormal crosstalk between several mucosal cell types, is probably the first step of a progressive immunopathological development in IBD, but the initiation of this series of events remains undefined.

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    Per Brandtzaeg, Guttorm Haraldsen & Jarle Rugtveit

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Brandtzaeg, P., Haraldsen, G. & Rugtveit, J. Immunopathology of human inflammatory bowel disease. Springer Semin Immunopathol 18, 555–589 (1997). https://doi.org/10.1007/BF00824058

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