Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation

Kébir, Hania; Kreymborg, Katharina; Ifergan, Igal; Dodelet-Devillers, Aurore; Cayrol, Romain; Bernard, Monique; Giuliani, Fabrizio; Arbour, Nathalie; Becher, Burkhard; Prat, Alexandre

doi:10.1038/nm1651

Cited by 1,489 publications

(1,218 citation statements)

References 14 publications

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“…There is scant information on a conceivable linkage between obesity and multiple sclerosis, but one study showed reduced disease deterioration in patients on low fat compared with high fat diet [17]. Although EAE is not an ideal model for MS, data presented here suggest that this association is worth investigating, in particular, since a role for Th17 effectors in the penetration of the blood-brain barrier as well as neuronal pathology has been reported [18].…”

Section: Dio Exacerbates Eaementioning

confidence: 74%

Obesity predisposes to Th17 bias

et al. 2009

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Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity‐associated rises in TNF‐α, IL‐6 and TGF‐β are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T‐cell sublineage, a subset with prominent pro‐inflammatory roles. T‐cells from diet‐induced obese mice expand Th17 cell pools and produce progressively more IL‐17 than lean littermates in an IL‐6‐dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet‐induced obese mice developed more severe early disease and histopathology with increased IL‐17+ T‐cell pools in target tissues. The well‐described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

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Section: Dio Exacerbates Eaementioning

confidence: 74%

Obesity predisposes to Th17 bias

et al. 2009

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“…BBB-EC grown in primary cultures were used to generate an in vitro model of the human BBB, as previously reported [46,50,51]. On day 0, BBB-EC were plated on gelatin-coated 3 mm pore size Boyden chambers (Collaborative Biomedical Products, Bedford, MA, USA) at a density of 2 Â 10 4 cells per well in EC Freshly purified human CD4 + T lymphocytes (10 6 cells) were then added to the upper chamber and allowed to migrate for 24 h across BBB-EC either untreated or pre-activated for 24 h with 500 U/mL IFN-b.…”

Section: Transmigration Assaysmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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IFN-b treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-b in the treatment of MS. We assessed the influence of IFN-b treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4 1 T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5 0 -nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-b increases the expression of ecto-5 0 -nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using a,b-methyleneadenosine-5 0 -diphosphate, a specific inhibitor of ecto-5 0 -nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5 0 -nucleotidase activity and skin microvascular CD73 expression after IFN-b treatment. Upregulation of ecto-5 0 -nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-b on MS via enhancing the endothelial barrier function.Key words: Adenosine . Blood-brain barrier . CD73 . IFN-b . MS Introduction MS is a demyelinating disease characterized by perivascular inflammatory cell infiltrates in the white matter of the CNS. MS is generally thought to be an autoimmune disease in which the immune system attack against self-antigens results in inflammation and neurological symptoms [1]. First line treatment of MS is subcutaneous or intramuscular administration of IFN-b, which leads to a reduced number of relapses and a slower disease progression [2][3][4]. The proposed beneficial effects of IFN-b include a decrease in antigen presentation, MHC class II expression, T-cell proliferation, IFN-b production, ECM degradation, and the expression of adhesion molecules [5]. Moreover, recent reports describe IFN-b as a suppressor of both myeloid [6] and Th17-cells [7]. IFN-b also reduces the number of gadolinium enhancing lesions in brain magnetic resonance imaging of MS patients [2,3,8], which is thought to reflect its ability to regulate the blood-brain barrier (BBB) function [9]. Ecto-5 0 -nucleotidase (CD73; EC 3.1.3.5) is a 70 kDa GPI-anchored glycoprotein. It is abundantly expressed on vascular endothelium and subpopulations of lymphocytes, but not on granulocytes or monocytes [10] and it also circulates in blood in a soluble 2718form [11]. Ecto-5 0 -nucleotidase activity is found on many CNS cell types such as astrocytes, oligodendrocytes, microglial cells and brain EC in many species including human, rat, mouse and bovine [12][13][14][15]. CD73 modulates the extent of immune and inflammatory responses in vitro and in vivo. These effects are mediated via its enzymatic capability ...

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“…The transport of different subsets of cytotoxic T lymphocytes from the blood to the brain and spinal cord is critical for lymphocytic infiltration of the CNS, which in turn results in neuronal death. Th17 lymphocytes, which secrete interleukin-17, are considered to play an important role in neuronal death (Stockinger et al, 2007), and Th17 cells have recently been shown to penetrate the BBB (Kebir et al, 2007). The BBB mechanisms that mediate transport of different subsets of T cells into the CNS represent potentially important therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Aquaporin‐4 Expression and Blood‐Brain and Spinal Cord Barrier Permeability Following Experimental Autoimmune Encephalomyelitis in the Rat

Huang

Wang

et al. 2010

The Anatomical Record

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Aquaporin 4(AQP4) is a water channel protein strongly expressed in the central nervous system in perimicrovessel astrocyte foot processes, the glia limitans, and ependyma. Expression of AQP4 is highest at the bloodbrain barrier and blood-spinal cord barrier, supporting its critical function in material transport across these structures. Recently, presence of the anti-aquaporin-4 antibody in sera has been used as an important diagnostic tool for neuromyelitis optica, suggesting a potential role in central nervous system inflammation. The aim of the present study was to examine AQP4 protein expression in the cerebellum and spinal cord from rats with experimental autoimmune encephalomyelitis. By western blot analysis, AQP4 expression increased during experimental autoimmune encephalomyelitis development, and peaked at onset (lumbar enlargement) or climax (cerebellum) of neurological signs of experimental autoimmune encephalomyelitis. There was also a faster and more pronounced increase in permeability in the cerebellar blood-brain barrier and the lumbar enlargement blood-spinal cord barrier consistent with AQP4 expression, which was manifested by increased Evans Blue leakage and reduced tight junction protein expression. In conclusion, aquaporin upregulation may be involved in the development of inflammation in the acute phase of experimental autoimmune encephalomyelitis, and may correlate with damage to central nervous system barrier function. Anat Rec, 294:46-54, 2011. V V C 2010 Wiley-Liss, Inc.

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Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation

Cited by 1,489 publications

References 14 publications

Obesity predisposes to Th17 bias

Obesity predisposes to Th17 bias

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

The Relationship Between Aquaporin‐4 Expression and Blood‐Brain and Spinal Cord Barrier Permeability Following Experimental Autoimmune Encephalomyelitis in the Rat

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