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M. Benagiano et al.
and pro-coagulant β2GPI-specific Th17, Th1 and Th17/Th1 infiltrate in human atherosclerotic lesions of patients with SLE-APS and may represent a key pathogen- ic atherothrombotic mechanism.
Many self antigens, such as oxLDL, may theoretically be involved in SLE-APS atherosclerosis; oxLDL-specific peripheral blood-derived T cells displaying a Th1 profile were reported in APS patients.33 However, there is no information on whether these cells are actively involved in atherosclerotic tissue lesions of SLE-APS patients. In addition, β2GPI was found to bind ox-LDL34 raising the issue of whether or not the immune response is against ox-LDL or β2GPI itself.
The relevance of the data presented in this paper con- sists in the demonstration that all ten SLE-APS patients with clinically severe atherothrombosis harbored in their target tissues, such as atherosclerotic lesions, in vivo-acti- vated CD4+ T cells able to react to β2GPI. CD4+ T cells specific for β2GPI were found also in the plaques of SLE aPL-positive patients but not in SLE aPL-negative patients
nor in atherosclerotic patients without SLE. The results suggested that β2GPI drive inflammation in atherosclerot- ic plaques in SLE-APS and SLE aPL-positive patients, while in SLE aPL-negative patients and in non-SLE patients other antigens are involved in sustaining plaque inflammation. With the experimental procedure used in this study, the proportion of β2GPI-specific CD4+ T-cell clones generated from atherosclerotic plaques of atherothrombotic SLE- APS patients is remarkably higher than the frequency of β2GPI-specific T cells found in their peripheral blood.
In order to investigate plaque instability, we investigat- ed fresh T cells coming from the atherosclerotic plaques of SLE-APS patients and we found that plaque-derived CD4+ T cells specifically produce IFN-g and IL-17 in response to both β2GPI and to mitogen stimulation. Studying at clonal level the β2GPI-specific T cells found in the inflammatory atherosclerotic infiltrates of SLE-APS we found that 42% were polarized T helper 1 cells, 38% were Th17/Th1 cells, 15% were polarized Th17 cells, 5% were Th0 cells, and no T cells were polarized Th2 cells. The lack of Th2 cells
A
B
Figure 5. Induction of tissue factor (TF) synthesis and procoagulant activity (PCA) by atherosclerotic plaque β2GPI-specific T cells derived from systemic lupus erythematosus patients with antiphospho- lipid syndrome. Atherosclerotic plaque β2GPI-specif- ic T cells induce TF production and PCA by autolo- gous monocytes. To assess their ability to induce TF production and PCA by autologous monocytes, β2GPI-specific Th clones were co-cultured with autologous monocytes in the presence of medium () or β2GPI () (A). TF production by monocytes was assessed by ELISA. The results shown represent TF levels induced by T-cell clones over the TF produc- tion in cultures of monocytes alone. Atherosclerotic plaque-derived β2GPI-specific T-cell-induced PCA in autologous monocytes (B). β2GPI-specific Th clones were co-cultured with autologous monocytes in the presence of medium () or β2GPI (). At the end of the culture period, cells were disrupted and total PCA was quantitated as reported in the Methods section. The results shown represent PCA induced by T-cell clones in monocytes over the PCA in cul- tures of monocytes alone.
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haematologica | 2019; 104(12)