Zonulin (pre-HP2)

Author: Gianpiero Pescarmona
Date: 10/04/2012


Figure 1. Proposed role of abnormal intestinal permeability in the pathogenesis of celiac disease.
Gliadin and its immunomodulatory/inflammatory fragments are present in the intestinal lumen (1), which induces MyD88-dependent zonulin release (2). Zonulin release causes opening of tight junctions and gliadin passage across the tight junction barriers in subjects with dysregulation of the zonulin system (3). After tissue transglutaminase deamidation (4), gliadin peptides bind to human leukocyte antigen receptors present on the surface of antigen-presenting cells (5). Alternatively, gliadin can act directly on antigen-presenting cells (6), causing MyD88-dependent release of both zonulin and cytokines (7). Gliadin peptides are then presented to T lymphocytes (8), which process is followed by an aberrant immune response, both humoral (9) and cell-mediated (10), in genetically susceptible individuals. This interplay between innate and adaptive immunity is ultimately responsible for the autoimmune process targeting intestinal epithelial cells, leading to the intestinal damage typical of celiac disease (11). AEA, anti-endomysium antibodies; AGA, anti-gliadin antibodies; APC, antigen-presenting cell; tTG, anti-tissue transglutaminase; B, B lymphocyte; P, plasma cell; T, T lymphocyte; Tk, lymphocyte T killer; TTG, tissue transglutaminase.

Intestinal zonulin: open sesame! 2001

Mechanisms of gliadin-induced zonulin release, increased intestinal permeability, and onset of autoimmunity. The production of specific gliadin-derived peptides by digestive enzymes causes CXCR3-mediated, MyD88-dependent zonulin release (2) and subsequent transactivation of EGFR by PAR2 leading to small intestine TJ disassembly (3). The increased intestinal permeability allows non-self antigens (including gliadin) to enter the lamina propria (4), where they are presented by HLA-DQ, -DR molecules (5). The presentation of one or more gliadin peptides leads to abrogation of oral tolerance (switch to Th1/Th17 response) and a marked increase in peripheral immune responses to gliadin. Furthermore, gliadin-loaded dendritic cells migrate from the small intestine to mesenteric and/or pancreatic lymph nodes (6) where they present gliadin-derived antigens. This presentation leads to migration of CD4−CD8− γδ and CD4−CD8+ αβ T cells to the target organ (gut and/or pancreas) where they cause inflammation (7). Implementation of a gluten-free diet or treatment with the zonulin inhibitor AT1001 (8) prevents the activation of the zonulin pathway and, therefore, of the autoimmune process targeting the gut or pancreatic β-cells.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer 2011

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