Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis.
Atherosclerotic lesions contain T lymphocytes, which orchestrate adaptive immunity and regulate many innate immune pathways. This study examined the influence of Th1 and Th2 helper cell subsets on atherogenesis in two ApoE(-/-) mouse strains, C57BL/6 and BALB/c, which display opposite T-cell subset polarizations. ApoE(-/-) BL/6 mice showed predominant Th1-like immune responses on polyclonal stimulation of splenic CD4(+) T cells and had IgG2a antibodies to oxidized low-density lipoprotein (a disease-related antigen) whereas ApoE(-/-) BALB/c mice displayed predominant Th2 responses by CD4(+) T cells and an IgG1 isotype response toward oxidized low-density lipoprotein. ApoE(-/-) BL/6 and BALB/c mice consumed a high-cholesterol diet for 10, 16, and 24 weeks with equivalent cholesterolemic responses. The Th1-slanted BL/6 mice developed significantly more atherosclerosis in the aortic root and abdominal aorta at all time points compared with BALB/c mice, supporting a proatherogenic role for Th1 response. Progression of atherosclerosis was associated with increased levels of interleukin (IL)-6 in mouse serum and CD4(+) T-cell culture supernatants and increased levels of the acute-phase protein, serum amyloid A (SAA). Both IL-6 and SAA levels rose significantly in ApoE(-/-) BL/6 mice compared with BALB/c mice. The circulating cytokine milieu (IL-6) and acute phase reactants such as SAA may reflect alterations in the Th1/Th2 balance. The results presented here illustrate how genetically determined modifiers of both immune and inflammatory responses can modulate atherogenesis independently of lipid levels.
Schulte
Stephanie
S
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sukhova
Galina K
GK
Libby
Peter
P
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D024042:Collagen Type I; D016207:Cytokines; D007074:Immunoglobulin G; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; D002784:Cholesterol