mTOR Pathway Is Activated in Endothelial Cells from Patients with Takayasu Arteritis and Is Modulated By Serum IgG

Jérôme Hadjadj¹, Guillaume Canaud², Tristan Mirault³, Maxime Samson⁴, Patrick Bruneval⁵, Alexis Regent⁶, Claire Goulvestre⁷, Veronique Witko-Sarsat⁸, Nathalie Costedoat-Chalumeau⁹, Loïc Guillevin for the French Vasculitis Study Group¹⁰, Luc Mouthon¹¹ and Benjamin Terrier¹², ¹Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Hospital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Team Neutrophils and Vasculitis, INSERM U1016, Cochin Institute, Paris, France, Paris, France, ²Department of Nephrology and Transplantation, Necker-Enfants Malade, Université Paris Descartes, Sorbonne Paris Cité, INSERM U1151, Necker-Enfants Malades Hospital, Paris, France AP-HP, Paris, France, PARIS, France, ³Department of Vascular Medicine, Georges Pompidou European Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Paris, France, ⁴Dijon University Hospital, Dijon, France, ⁵HEGP, Paris, France, ⁶National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France, ⁷Department of Immunology, Hospital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France, Paris, France, ⁸Team Neutrophils and Vasculitis, INSERM U1016, Cochin Institute, LABEX Inflamex, Université Sorbonne Paris Cité, 75013, Paris, France, Paris, France, ⁹Service de médecine interne Pôle médecine, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares de l’île de France, Paris, France, ¹⁰Service de Médecine Interne, Centre de Référence Maladies Auto-Immunes et Auto-Inflammatoires Systémiques Rares, Hôpital Cochin, Paris, France, ¹¹Service de Médecine Interne, Hôpital Cochin, Centre de référence national pour les maladies systémiques autoimmunes rares d’Ile de France, DHU Authors, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France ;Université Paris Descartes Sorbonne Paris, Paris, France, ¹²Service de Médecine Interne, Hôpital Cochin, Centre de référence national pour les maladies systémiques autoimmunes rares d’Ile de France, DHU Authors, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France, Paris, France

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: giant cell arteritis, mTor, takayasu arteritis and vasculitis

Session Information

Date: Wednesday, November 8, 2017

Title: Vasculitis III: Pathogenesis

Session Type: ACR Concurrent Abstract Session

Session Time: 9:00AM-10:30AM

Background/Purpose: Takayasu arteritis (TA) and giant cell arteritis (GCA) are large-vessel vasculitis characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells, leading to ischemic events. We hypothesized that mammalian target of rapamycin (mTOR) pathway could drive vascular inflammation and remodelling in large-vessel vasculitis.

Methods: To study activation of mTOR pathway in injured vessels from patients with TA and GCA, we evaluated phosphorylation of S6RP (p-S6RP) and AKT (p-AKT Ser 473) by immunofluorescence analysis on aorta and temporal arteries biopsies, which reflect activation of mTORC1 and mTORC2, respectively. To investigate the potential role of antibodies binding to ECs in the activation of mTOR pathway, sera from patients with TA, GCA and healthy controls (HCs) were screened for the presence of antibodies against ECs (AECA) using indirect immunofluorescence (IIF) and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients with AECA on mTOR pathway activation and cell proliferation. Target antigens of AECA were investigated by Western-blotting.

Results: Immunofluorescence analysis on tissues revealed that adventitial vessels from aorta’s vasa vasorum from TA patients were strongly positive for both p-S6RP and p-AKT (Ser 473) in ECs but not in vascular smooth muscle cells, showing that both mTORC1 and mTORC2 were specifically activated in ECs in TA, but not in ECs from GCA patients and HCs (Figure 1). Using IIF and cellular ELISA, we observed higher levels of AECA in TA patients compared to GCA and healthy controls (HCs) with these two techniques. 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 or HCs. mTORC1 was activated through PI3K-AKT pathway, suggesting that recruitment of AKT to the cell membrane is necessary for activation of the mTOR pathway induced by serum IgG in TA. Finally, purified IgG from TA induced a significant ECs proliferation compared to GCA and HCs IgG, and this effect was decreased after ECs exposure with sirolimus, a specific mTOR inhibitor, and PI3K inhibitor. Sera obtained from TA patients with positive screening of AECA bound predominantly to an endothelial cell antigen with a molecular weight between 60 and 65 kDa.

Conclusion: Our results suggest that antibodies against ECs drive vascular inflammation leading then to vascular remodelling in TA through activation of mTOR pathway in ECs, but not in GCA. Inhibition of mTOR pathway could represent an alternative therapeutic option in TA.

Figure 1 :

Disclosure: J. Hadjadj, None; G. Canaud, None; T. Mirault, None; M. Samson, None; P. Bruneval, None; A. Regent, None; C. Goulvestre, None; V. Witko-Sarsat, None; N. Costedoat-Chalumeau, None; L. Guillevin for the French Vasculitis Study Group, None; L. Mouthon, None; B. Terrier, None.

To cite this abstract in AMA style:

Hadjadj J, Canaud G, Mirault T, Samson M, Bruneval P, Regent A, Goulvestre C, Witko-Sarsat V, Costedoat-Chalumeau N, Guillevin for the French Vasculitis Study Group L, Mouthon L, Terrier B. mTOR Pathway Is Activated in Endothelial Cells from Patients with Takayasu Arteritis and Is Modulated By Serum IgG [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mtor-pathway-is-activated-in-endothelial-cells-from-patients-with-takayasu-arteritis-and-is-modulated-by-serum-igg/. Accessed .

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