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Th17/Th1 inflammation in lupus atherosclerosis
is an important risk factor in the genesis of atherosclerosis. Indeed, T cells play an important role in the genesis of atherosclerosis that has been defined a Th1-driven immunopathology,35,36 and we have demonstrated that Th1 cells, producing high levels of IFN-g, are crucial for the development of the disease.16,20,22 Given that atherosclero- sis can occur and progress even in IFN-g- or IFN-gR–defi- cient mice, although with a lower lesion burden,37 other Th cells and factors are presumably involved in the genesis of the atheroma. A third subset of effector Th cells, name- ly Th17, has been discovered.38 Th17 cells are potent inducers of tissue inflammation and have been associated with the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions.39,40 In the lymphocytic infiltrates of SLE-APS atherosclerotic plaques, we have found the presence of in vivo-activated plaque-infiltrating T cells able to produce IL-17 and IL-21 in response to β2GPI. Among the clonal progeny of T cells infiltrating the lesions, we demonstrated the presence of β2GPI -specific T cells able to secrete IL-17. A significant number (27%) of IL-17–producing T cells are also IFN-g producers. This finding is in agreement with a previous report that demonstrated the concomitant production of IL-17 and IFN-g by human coronary artery-infiltrating T cells in non SLE patients.41-43 Plaque rupture and throm- bosis are notable complications of atherosclerosis.16,43 The methodology used to obtain the plaque derived T cells encompasses a clonal expansion step, followed by limiting dilution to obtain single clones. The β2GPI-reactive CD4+ T-cell clone found in atherosclerotic plaques were unique, based on the T-cell receptor - Vβ results obtained in the study. The β2GPI -specific T-cell clones revealed their abil- ity, not only to induce macrophage production of TF upon antigen stimulation, but that they were also able to pro- mote PCA.
Th17 cells were shown to play a key role in experimen- tal mouse models of atherosclerosis; IL-17 is proathero- genic in an experimental model of accelerated atheroscle-
44
rosis in the presence of a high fat diet (HFD). In fact, in
−/−
IL-17 mice fed with HFD, the aortic lesion size and lipid
composition as well as macrophage accumulation in the plaques were significantly diminished, and the progres- sion of the process was remarkably reduced compared with WT mice. Furthermore IL-21 was produced by almost all Th1 and Th17/Th1 cells specific for β2GPI. IL- 21 is actually up-regulated in patients with peripheral
Figure 6. Helper function of atherosclerotic plaque β2GPI-specific T cells derived from systemic lupus erythematosus patients with antiphospholipid syndrome. Autologous peripheral blood B cells (5x104) were co-cultured with β2GPI-specific T-cell blasts at a T:B ratio of 0.2, 1, and 5 to 1 in the absence () or presence of β2GPI (). After ten days, culture supernatants were harvested and tested for the presence of IgM, IgG, and IgA by ELISA. Results represent mean value (+/–SE) of Ig levels induced by T-cell clones compared to the Ig spontaneous production in B-cell cultures alone.
AB
Figure 7. Cytotoxic and pro-apoptotic activity of β2GPI-specific atherosclerotic plaque-derived CD4+ T cells derived from systemic lupus erythematosus patients with antiphospholipid syndrome. (A) To assess their cytotoxicity, β2GPI-specific CD4+ T-cell clones were co-cultured at different E:T ratios with 51Cr-labeled autologous Epstein-Barr virus cells pulsed with β2GPI () or medium alone (). 51Cr release was measured as index of specific target cell lysis. (B) To assess their ability to induce apoptosis in target cells, β2GPI-specific CD4+ T-cell clones stimulated with mitogen () or medium alone () were co-cultured with 51Cr-labeled Fas+Jurkat cells, and 51Cr release was measured as the index of apoptotic target cell death.
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