Abstract - Autoimmune diseases are characterized by tissue
damage and loss of function due to an immune response that is
directed against specific organs. This review is focused on the
role of impaired intestinal barrier function on autoimmune
pathogenesis. Together with the gut-associated lymphoid
tissue and the neuroendocrine network, the intestinal epithelial
barrier, with its intercellular tight junctions, controls the
equilibrium between tolerance and immunity to non-self
antigens. Zonulin is the only physiologic modulator of
intercellular tight junctions described so far that is involved
in trafficking of macromolecules and, therefore, in tolerance/
immune response balance. When the zonulin pathway is
deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts
traditional theories underlying the development of these
diseases and suggests that these processes can be arrested if
the interplay between genes and environmental triggers is
prevented by re-establishing the zonulin-dependent intestinal
barrier function. Both animal models and recent clinical
evidence support this new paradigm and provide the rationale
for innovative approaches to prevent and treat autoimmune
diseases.