Inhibition of the mTORC Pathway in the Antiphospholipid Syndrome
Does the mammalian target of rapamycin complex (mTORC) pathway mediate the vasculopathy associated with antiphospholipid syndrome (APS)?
Immunostaining and in vitro experiments were used to analyze mTORC pathway activation in tissues from patients with primary or secondary APS nephropathy, and from autopsy specimens from persons with catastrophic APS. The effect of sirolimus was also studied in kidney-transplant recipients with APS.
Intrarenal vessels from patients with APS nephropathy and vessels from catastrophic APS patients showed activation of the mTORC pathway in endothelial cells. Immunoglobulin G (IgG) antibodies from patients with APS stimulated mTORC in cultured endothelial cells via the phosphatidylinositol 3-kinase (PI3K)–AKT pathway. Patients with APS nephropathy who underwent transplantation and were receiving sirolimus had no recurrence of vascular lesions and showed decreased vascular proliferation on biopsy, as compared with patients with AP antibodies who were not receiving sirolimus. Seven of 10 patients treated with sirolimus (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%).
The authors concluded that the mTORC pathway is involved in the vascular lesions associated with APS.
APS is associated with thrombosis and a vasculopathy that affects small and medium vessels. Renal dysfunction in APS is associated with a thrombotic microangiopathy that often recurs following renal transplantation. Although AP antibodies are thought to be pathogenic in this disease, the downstream pathways are unclear. This study provides evidence that the mTORC is activated in APS vasculopathy and that targeting this pathway with rapamycin (sirolimus) may prevent the vasculopathy. Further studies will be useful to confirm the benefits of sirolimus in this disease, as well as uncover additional mechanistic details involved in AP antibody mTORC activation.
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