Abstract 1483: The Role of Genetically Programmed Biases in Th1 and Th2 Immune Responses in Atherogenesis
Background: Inflammation occupies a central position in all phases of atherosclerosis. Atherosclerotic lesions contain predominantly CD4+ T lymphocytes. In response to the local cytokine milieu, CD4+ T cells differentiate into a Th1 or Th2 lineage. The influence of Th1 and Th2 helper cell subsets on atherogenesis was studied in two ApoE−/− mouse strains, C57Bl/6 and Balb/c, displaying opposite T cell subset polarization.n
Methods and Results: ApoE−/− Bl/6 mice showed Th1-like immune responses. Splenic CD4+ T cells isolated from these mice produced substantial IFNγ upon polyclonal stimulation (2207.0 +/− 512.0 pg/ml), but low levels of IL-4 (48.8 +/− 16.4 pg/ml). ApoE−/− Bl/6 mice had IgG2a antibodies to oxidized LDL, a disease-specific antigen. In contrast, ApoE−/− Balb/c mice displayed predominant Th2 responses with lower IFNγ (622.1 +/− 76.6 pg/ml) and higher IL-4 production (185.9 +/− 40.8 pg/ml) by CD4+ T cells compared to ApoE−/− Bl/6 mice and an IgG1 isotype response towards oxidized LDL. ApoE−/− Bl/6 and ApoE−/− Balb/c mice consumed a high-cholesterol diet (1.25% cholesterol, 0% cholate) for 10 (n=12) and 16 weeks (n=16). The Th1-slanted ApoE−/− Bl/6 mice had increased plaque size at both timepoints compared to ApoE−/− Balb/c mice (0.362 +/− 0.037 mm2 vs. 0.284 +/− 0.016 mm2, p=0.035 at 10 weeks; 0.619 +/− 0.035 mm2 vs. 0.436 +/− 0.044 mm2, p=0.003 at 16 weeks), supporting the proatherogenic role of Th1. The amount of IFNγ secreted by splenic CD4+ T cells correlated with the extent of lesion formation (r=0.86, p<0.01). Atherosclerosis progression was associated with an increase in the proinflammatory cytokine IL-6 in CD4+ T cell culture supernatants and an increase in the acute phase protein serum amyloid A (SAA). IL-6 and SAA were significantly elevated in ApoE−/− Bl/6 mice compared to ApoE−/− Balb/c mice (IL-6: 189.5 +/− 38.80 pg/ml vs. 51.85 +/− 9.06 pg/ml, p=0.002; SAA: 42.95 +/− 12.21 μg/ml vs. 16.30 +/− 1.42 μg/ml, p=0.034).
Conclusions: These findings support an important role for Th1/Th2 balance in atherosclerotic lesion formation, possibly mediated through increased production of IFNγ and IgG2a-predominant autoimmune responses to oxidized LDL.