Organ-specific protection mediated by cooperation between vascular and epithelial barriers

Key Points The classical concept of immune privilege as an exclusion of immune cells has been extended to include sites of immune tolerance induction, such as the intestine. Barriers can be grouped into three main categories: first, protective barriers consisting of tightly regulated endothelial layers, such as the blood–brain barrier and the inner blood–retinal barrier; second, more permissive endothelial layers, such as the gut–vascular barrier; and third, immunomodulatory selective epithelial gateways, such as the blood–cerebrospinal fluid barrier, intestinal epithelial barrier and outer blood–retinal barrier. The intestinal microbiota can influence the functionality of not only proximal intestinal barriers but also other vascular barriers that are present at distant sites, such as the brain, eye and testis. Disruption of intestinal barriers and leakage of bacteria and/or bacterial metabolites can lead to the failure of other barriers at distant sites and the development of various neurological, metabolic and intestinal disorders. Here, the authors discuss the role of cellular barriers in establishing immune privilege, both in the intestine and in other organs, such as the brain and the eyes. They compare protective epithelial and vascular barriers in different organs and examine how several pathologies are linked to the disruption of these barriers. Immune privilege is a complex process that protects organs from immune-mediated attack and damage. It is accomplished by a series of cellular barriers that both control immune cell entry and promote the development of tolerogenic immune cells. In this Review, we describe the vascular endothelial and epithelial barriers in organs that are commonly considered to be immune privileged, such as the brain and the eye. We compare these classical barriers with barriers in the intestine, which share features with barriers of immune-privileged organs, such as the capacity to induce tolerance and to protect from external insults. We suggest that when intestinal barriers break down, disruption of other barriers at distant sites can ensue, and this may underlie the development of various neurological, metabolic and intestinal disorders.