HYPERCHOLESTEROLEMIA IS ASSOCIATED WITH A T-HELPER (TH)-1 TH2 SWITCH OF THE AUTOIMMUNE-RESPONSE IN ATHEROSCLEROTIC APO-E KNOCKOUT MICE

Atherosclerosis is an inflammatory-fibrotic response to accumulation o f cholesterol in the artery wall. In hypercholesterolemia, low density lipoproteins (LDL) accumulate and are oxidized to proinflammatory com pounds in the arterial intima, leading to activation of endothelial ce lls, macrophages, and T lymphocytes. We have studied immune cell activ ation and the autoimmune response to oxidized LDL in atherosclerotic a po E-knockout mice. Autoantibodies to oxidized LDL exhibited subclass specificities indicative of T cell help, and the increase in antibody titers in peripheral blood was associated with increased numbers of cy tokine-expressing T cells in the spleen. In addition to T cell-depende nt antibodies, IgM antibodies to oxidized LDL were also increased in a po E-knockout mice. This suggests that both T cell-dependent and T cel l-independent epitopes may be present on oxidized LDL, In moderate hyp ercholesterolemia, IgG antibodies were largely of the IgG2a isotype, s uggesting that T cell help was provided by proinflammatory T helper (T h) 1 cells, which are prominent components of atherosclerotic lesions. In severe hypercholesterolemia induced by cholesterol feeding of apo E-knockout mice, a switch to Th2-dependent help was evident. It was as sociated with a loss of IFN-gamma-producing Th1 cells in the spleen, w hereas IL-4-producing Th2 cells were more resistant to hypercholestero lemia. IFN-gamma but not IL-4 mRNA was detected in atherosclerotic les ions of moderately hypercholesterolemic apo E-knockout mice, but IL-4 mRNA appeared in the lesions when mice were made severely hypercholest erolemic by cholesterol feeding. These data show that IFN-gamma-produc ing Th1 cells infiltrate atherosclerotic lesions and provide T cell he lp for autoimmune responses to oxidized LDL in apo E-knockout mice. Ho wever, severe hypercholesterolemia is associated with a switch from Th 1 to Th2, which results not only in the formation of IgG1 autoantibodi es to oxidized LDL, but also in the appearance of Th2-type cytokines i n the atherosclerotic lesions. Since the two subsets of T cells counte ract each other, this switch may have important consequences for the i nflammatory/immune process in atherosclerosis.