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Rheumatology (Oxford). 2018 Jun 1;57(6):1011-1020. doi: 10.1093/rheumatology/key017.

mTOR pathway is activated in endothelial cells from patients with Takayasu arteritis and is modulated by serum immunoglobulin G.

Author information

1
INSERM U1016, Cochin Institute, Team Neutrophils and Vasculitis, Paris, France.
2
Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Hospital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
3
LABEX Inflamex, Université Sorbonne Paris Cité, 75013, Paris, France.
4
INSERM U1151, Necker-Enfants Malades Hospital, Paris, France.
5
Department of Nephrology and Transplantation, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
6
Paris Transplant Group, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
7
Department of Vascular Medicine, Georges Pompidou European Hospital, AP-HP, Paris, France.
8
Department of Internal Medicine and Clinical Immunology, François Mitterrand Hospital, Dijon University Hospital; INSERM, UMR1098, University of Bourgogne Franche-Comté, FHU INCREASE, Dijon, France.
9
Department of Pathology, Georges Pompidou European Hospital, AP-HP, Paris, France.
10
Department of Immunology, Hospital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
11
INSERM U1153, Center for Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, France.

Abstract

Objectives:

Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis.

Methods:

We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation.

Results:

IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor.

Conclusion:

Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA.

PMID:
29506143
DOI:
10.1093/rheumatology/key017
[Indexed for MEDLINE]

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