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Published online before print May 8, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070776

Accepted for publication March 11, 2008.

Article

Genetically Programmed Biases in Th1 and Th2 Immune Responses Modulate Atherogenesis

Stephanie Schulte, Galina K. Sukhova, and Peter Libby@

From the Department of Medicine, Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

@ To whom correspondence should be addressed. E-mail: plibby{at}rics.bwh.harvard.edu.


  Abstract

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.






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Copyright © 2008 by the American Society for Investigative Pathology.