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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.


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.

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Figure 1: Cellular components of brain barriers.
Figure 2: The blood–retinal barrier.
Figure 3: The intestinal barriers.
Figure 4: Impact of the microbiota on physiological barrier functions.
Figure 5: Effect of dysbiosis and barrier failure on disease onset.


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This work is supported by the European Council of Research (Consolidator grant HomeoGUT, 615735), the Italian Association for Cancer Research (AIRC) and the Italian Ministry of Health (Ricerca finalizzata). G.F. is supported by the Italian Ministry of Health (grant GR-2013-02359806) and by Fondazione Cariplo (grant 2016–0472).

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I.S. and M.R. wrote the article and reviewed and edited the manuscript before submission. G.F. contributed to researching data for the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Maria Rescigno.

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The authors declare no competing financial interests.

PowerPoint slides


Inflammatory bowel diseases

(IBDs). Chronic disorders of the intestine characterized by severe inflammation and mucosal tissue destruction. There are two main forms: Crohn's disease, which is a granulomatous segmental inflammation affecting any part of the intestine, and ulcerative colitis, which is a mucosal inflammation involving the rectum and extending for a variable distance along the colon.


Vascularized tissue membranes that envelop superficial central nervous system areas and enclose the parenchyma. The meninges are composed of three layers: the dura mater (outermost, beneath the skull), the arachnoid mater and the pia mater (the innermost layer, which is proximal to the parenchyma).


A type of glial cell that is found in the vertebrate brain and is named for its characteristic star-like shape. Astrocytes provide both mechanical and metabolic support for neurons, thereby regulating the environment in which neurons function.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.


Cells that are embedded in the vascular basement membrane of microvessels. They make close contact with endothelial cells, and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Fenestrated capillaries

A non-continuous vascular bed characterized by the presence of pore-like subcellular structures, or fenestrae, that are responsible for transcellular exchange of molecules. Fenestrated endothelia are located in the intestine, pancreas, endocrine glands, glomeruli of the kidney and liver sinusoids.

Müller cells

The major type of glial cell that is found in the retina. These cells contribute to retinal homeostasis and function and regulate the tightness of the blood–retinal barrier.

Diabetic retinopathy

A condition affecting people with diabetes that causes progressive damage to the retina, the light-sensitive tissue at the back of the eye.

Aqueous humour

The clear immunosuppressive and anti-inflammatory fluid that fills the anterior chamber of the eye.

Anterior chamber-associated immune deviation

(ACAID). A form of eye-derived tolerance in which T helper 1 (TH1)- and TH2-mediated immunity is suppressed but non-inflammatory adaptive immune effectors are present.

Lamina propria

The layer of mucosal tissue directly under the mucosal epithelial cell surface in which effector cells for mucosal immunity reside.

Goblet cells

Mucus-producing cells found in the epithelial-cell lining of the intestine and lungs.

Paneth cells

Specialized enterocytes that are present at the base of the crypts in the intestinal epithelium and that produce antimicrobial proteins and peptides, including phospholipase A2 and defensins.

Pyramidal neurons

Type of nerve cells with a pyramidal-shaped cell body (soma) and two distinct dendrite trees (the longer apical and the shorter basal trees). They are present in most mammalian forebrain structures (cerebral cortex, hippocampus and amygdala), and they are associated with advanced cognitive functions.


A condition in which the balance of the bacterial communities that constitute the intestinal microbiota is altered. Dysbiosis may be a predisposition factor for several diseases.

Lewy pathology

A pathology characterized by the presence of abnormal α-synuclein aggregates (bodies) in the residual neurons of the substantia nigra and in the enteric nervous system. Lewy bodies are the histological hallmark of Parkinson disease.


Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are thought to be the major brain-resident macrophages.


A specialized process involving the degradative delivery of a portion of the cytoplasm or of damaged organelles to the lysosome. Internalized pathogens can also be eliminated by this pathway.

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Spadoni, I., Fornasa, G. & Rescigno, M. Organ-specific protection mediated by cooperation between vascular and epithelial barriers. Nat Rev Immunol 17, 761–773 (2017).

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