Amy Major
Last active: 8/19/2015

Profile

Atherosclerosis is the leading cause of death in the United States. Although thought of as mainly a problem of dyslipidemia, atherosclerosis is gaining recognition as an immune mediated, inflammatory disease. Many basic science and clinical studies have made a strong correlation between the presence of antigen-specific humoral and cellular immunity, as well as markers of inflammation in animal models and individuals with atherosclerosis. Therefore, it is increasingly important to conduct research to define the mechanisms of immune-mediated modulation of atherogenesis. Understanding the link between accelerated atherosclerosis and autoimmunity will make it possible to translate basic science findings to exploit innovative therapeutic avenues for CHD. Recent data from my laboratory in B cell-deficient apolipoprotein E (apoE) knockout mice suggests that at least one mechanism of B cell-mediated protection may be clearance of modified, oxidized LDL by production of autoantibodies specific for oxLDL or associated proteins such as b-glycoprotein I (apolipoprotein H). However, B cells can also influence the inflammatory response via antibody-independent mechanisms and mainly through the regulation of T cell mediated immunity. Understanding the importance of B cells in atherosclerosis will be important for determining how the presence of autoantibody influences CHD in the normal population and in antibody-mediated disease such as SLE. A second research interest is aimed at examining the role of natural killer T (NKT) cells in atherogenesis. NKT cells are a component of the innate immune system and have been shown to down-regulate inflammation in such autoimmune diseases as type-1 diabetes and multiple sclerosis. Because of their regulatory nature, NKT cells might play an important role in the pathogenesis of atherosclerosis. Data suggest that activation of NKT cells in apoE-deficient mice exacerbates aortic lesion formation compared to control animals. Therefore, unlike other inflammatory diseases, NKT cells may be responsible for increasing inflammation in the artery wall leading to acceleration of the atherosclerotic process. In addition, I have shown that the hyperlipidemic environment associated with atherosclerosis has dramatic effects on NKT cell numbers and functions. These data demonstrate the important interaction between lipid homeostasis and immunity. The mechanisms for NKT cell-mediated enhanced lesion formation and the effects of lipids on this unique subset of T lymphocytes are the focus of future studies and will increase our knowledge of the role of innate immunity in CHD. Finally, I have initiated studies to develop an animal model of accelerated atherosclerosis in systemic lupus erythematosus (SLE). Atherosclerosis has recently gained interest as a major cause of mortality in lupus patients. In fact, with all other risk factors being equal, including hypertension, hyperlipidemia, diabetes and obesity, the risk of coronary events in SLE patients is approximately 8 times greater compared to non-SLE controls and approximately 30% of deaths in SLE are atherosclerosis related. Future plans for this project are to determine which specific immune factor is most important for the modifications in atherosclerosis observed in the chimeric mice. Understanding how the presence of SLE exacerbates the atherosclerotic condition is essential to optimize risk reduction for coronary heart disease (CHD) while treating the SLE-associated inflammation. In summary, my research goals are designed to better understand the role of immunity in atherosclerosis and how dyslipidemia can modulate immunity. Ultimately, I hope such studies will impact the development of immune-based therapy for the treatment of CHD and will increase the knowledge regarding accelerated atherogenesis in chronic autoimmunity such as SLE .

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells. Covarrubias R, Wilhelm AJ, Major AS (2014) PLoS One 9(7): e102236
    › Primary publication · 25050824 (PubMed) · PMC4106787 (PubMed Central)
  2. A possible secondary immune response in adipose tissue during weight cycling: The ups and downs of yo-yo dieting. Anderson-Baucum EK, Major AS, Hasty AH (2014) Adipocyte 3(2): 141-5
    › Primary publication · 24719788 (PubMed) · PMC3979879 (PubMed Central)
  3. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Wilhelm AJ, Rhoads JP, Wade NS, Major AS (2015) Ann Rheum Dis 74(4): 778-85
    › Primary publication · 24395554 (PubMed) · PMC4083014 (PubMed Central)
  4. Bone marrow deficiency of MCPIP1 results in severe multi-organ inflammation but diminishes atherogenesis in hyperlipidemic mice. Yu F, Du F, Wang Y, Huang S, Miao R, Major AS, Murphy EA, Fu M, Fan D (2013) PLoS One 8(11): e80089
    › Primary publication · 24223214 (PubMed) · PMC3819309 (PubMed Central)
  5. Expanding the therapeutic frontier in atherosclerosis. Major AS (2013) J Cardiovasc Pharmacol 62(3): 237-8
    › Primary publication · 23945275 (PubMed) · PMC3902169 (PubMed Central)
  6. Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J (2013) J Am Heart Assoc 2(2): e000093
    › Primary publication · 23563994 (PubMed) · PMC3647260 (PubMed Central)
  7. Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. Gabriel CL, Smith PB, Mendez-Fernandez YV, Wilhelm AJ, Ye AM, Major AS (2012) Am J Physiol Endocrinol Metab 303(11): E1313-24
    › Primary publication · 23032686 (PubMed) · PMC3774080 (PubMed Central)
  8. Humanizing the problem of transplant vasculopathy. Méndez-Fernández YV, Major AS (2012) Arterioscler Thromb Vasc Biol 32(2): 163-4
    › Primary publication · 22258896 (PubMed) · PMC4578289 (PubMed Central)
  9. What fans the fire: insights into mechanisms of inflammation in atherosclerosis and diabetes mellitus. Major AS, Harrison DG (2011) Circulation 124(25): 2809-11
    › Primary publication · 22184043 (PubMed) · PMC3963008 (PubMed Central)
  10. The problem of accelerated atherosclerosis in systemic lupus erythematosus: insights into a complex co-morbidity. Wade NS, Major AS (2011) Thromb Haemost 106(5): 849-57
    › Primary publication · 21979131 (PubMed) · PMC3306215 (PubMed Central)
  11. Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice. van Leuven SI, Mendez-Fernandez YV, Wilhelm AJ, Wade NS, Gabriel CL, Kastelein JJ, Stroes ES, Tak PP, Major AS (2012) Ann Rheum Dis 71(3): 408-14
    › Primary publication · 21953346 (PubMed) · PMC3306213 (PubMed Central)
  12. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Ma LJ, Corsa BA, Zhou J, Yang H, Li H, Tang YW, Babaev VR, Major AS, Linton MF, Fazio S, Hunley TE, Kon V, Fogo AB (2011) Am J Physiol Renal Physiol 300(5): F1203-13
    › Primary publication · 21367915 (PubMed) · PMC3094053 (PubMed Central)
  13. The inhibitory FcγRIIb modulates the inflammatory response and influences atherosclerosis in male apoE(-/-) mice. Mendez-Fernandez YV, Stevenson BG, Diehl CJ, Braun NA, Wade NS, Covarrubias R, van Leuven S, Witztum JL, Major AS (2011) Atherosclerosis 214(1): 73-80
    › Primary publication · 21084088 (PubMed) · PMC3052995 (PubMed Central)
  14. Statin therapy in lupus-mediated atherogenesis: two birds with one stone? van Leuven SI, Mendez-Fernandez YV, Stroes ES, Tak PP, Major AS (2011) Ann Rheum Dis 70(2): 245-8
    › Primary publication · 21068103 (PubMed) · PMC3306212 (PubMed Central)
  15. Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice. Wilhelm AJ, Zabalawi M, Owen JS, Shah D, Grayson JM, Major AS, Bhat S, Gibbs DP, Thomas MJ, Sorci-Thomas MG (2010) J Biol Chem 285(46): 36158-69
    › Primary publication · 20833724 (PubMed) · PMC2975238 (PubMed Central)
  16. Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia. Braun NA, Mendez-Fernandez YV, Covarrubias R, Porcelli SA, Savage PB, Yagita H, Van Kaer L, Major AS (2010) Arterioscler Thromb Vasc Biol 30(9): 1758-65
    › Primary publication · 20539017 (PubMed) · PMC2963029 (PubMed Central)
  17. Natural killer T cells and atherosclerosis: form and function meet pathogenesis. Braun NA, Covarrubias R, Major AS (2010) J Innate Immun 2(4): 316-24
    › Primary publication · 20375560 (PubMed) · PMC2895753 (PubMed Central)
  18. The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice. Wade NS, Stevenson BG, Dunlap DS, Major AS (2010) Lupus 19(1): 34-42
    › Primary publication · 19850656 (PubMed) · PMC2802678 (PubMed Central)
  19. Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity. Wilhelm AJ, Zabalawi M, Grayson JM, Weant AE, Major AS, Owen J, Bharadwaj M, Walzem R, Chan L, Oka K, Thomas MJ, Sorci-Thomas MG (2009) Arterioscler Thromb Vasc Biol 29(6): 843-9
    › Primary publication · 19286630 (PubMed) · PMC2761013 (PubMed Central)
  20. Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice. Braun Na, Wade NS, Wakeland EK, Major AS (2008) Lupus 17(12): 1070-8
    › Primary publication · 19029274 (PubMed) · PMC2662384 (PubMed Central)
  21. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Overton CD, Yancey PG, Major AS, Linton MF, Fazio S (2007) Circ Res 100(5): 670-7
    › Primary publication · 17303763 (PubMed)
  22. The role of invariant natural killer T cells in lupus and atherogenesis. Major AS, Singh RR, Joyce S, Van Kaer L (2006) Immunol Res 34(1): 49-66
    › Primary publication · 16720898 (PubMed) · PMC2291524 (PubMed Central)
  23. Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. Major AS, Joyce S, Van Kaer L (2006) Trends Mol Med 12(6): 270-8
    › Primary publication · 16651026 (PubMed)
  24. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Stanic AK, Stein CM, Morgan AC, Fazio S, Linton MF, Wakeland EK, Olsen NJ, Major AS (2006) Proc Natl Acad Sci U S A 103(18): 7018-23
    › Primary publication · 16636270 (PubMed) · PMC1459011 (PubMed Central)
  25. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. Burleigh ME, Babaev VR, Yancey PG, Major AS, McCaleb JL, Oates JA, Morrow JD, Fazio S, Linton MF (2005) J Mol Cell Cardiol 39(3): 443-52
    › Primary publication · 16040051 (PubMed)
  26. Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Su YR, Dove DE, Major AS, Hasty AH, Boone B, Linton MF, Fazio S (2005) Circulation 111(18): 2373-81
    › Primary publication · 15851589 (PubMed)
  27. Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice. Major AS, Wilson MT, McCaleb JL, Ru Su Y, Stanic AK, Joyce S, Van Kaer L, Fazio S, Linton MF (2004) Arterioscler Thromb Vasc Biol 24(12): 2351-7
    › Primary publication · 15472130 (PubMed)
  28. Proatherogenic role for NK cells revealed. Linton MF, Major AS, Fazio S (2004) Arterioscler Thromb Vasc Biol 24(6): 992-4
    › Primary publication · 15178571 (PubMed)
  29. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. Su YR, Ishiguro H, Major AS, Dove DE, Zhang W, Hasty AH, Babaev VR, Linton MF, Fazio S (2003) Mol Ther 8(4): 576-83
    › Primary publication · 14529830 (PubMed)
  30. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Major AS, Fazio S, Linton MF (2002) Arterioscler Thromb Vasc Biol 22(11): 1892-8
    › Primary publication · 12426221 (PubMed)
  31. Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice. Fazio S, Babaev VR, Burleigh ME, Major AS, Hasty AH, Linton MF (2002) J Lipid Res 43(10): 1602-9
    › Primary publication · 12364544 (PubMed)
  32. Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice. Yoshida H, Hasty AH, Major AS, Ishiguro H, Su YR, Gleaves LA, Babaev VR, Linton MF, Fazio S (2001) Circulation 104(23): 2820-5
    › Primary publication · 11733401 (PubMed)
  33. Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((-/-)) mice. Major AS, Dove DE, Ishiguro H, Su YR, Brown AM, Liu L, Carter KJ, Linton MF, Fazio S (2001) Arterioscler Thromb Vasc Biol 21(11): 1790-5
    › Primary publication · 11701467 (PubMed)
  34. Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo. Ishiguro H, Yoshida H, Major AS, Zhu T, Babaev VR, Linton MF, Fazio S (2001) J Biol Chem 276(39): 36742-8
    › Primary publication · 11477092 (PubMed)
  35. A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. Swift LL, Farkas MH, Major AS, Valyi-Nagy K, Linton MF, Fazio S (2001) J Biol Chem 276(25): 22965-70
    › Primary publication · 11304532 (PubMed)
  36. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. Fazio S, Major AS, Swift LL, Gleaves LA, Accad M, Linton MF, Farese RV (2001) J Clin Invest 107(2): 163-71
    › Primary publication · 11160132 (PubMed) · PMC198874 (PubMed Central)
  37. Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta2-microglobulin-deficient mice. Major AS, Cuff CF (1997) J Virol 71(8): 5782-9
    › Primary publication · 9223466 (PubMed) · PMC191832 (PubMed Central)
  38. Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response. Major AS, Cuff CF (1996) J Virol 70(9): 5968-74
    › Primary publication · 8709219 (PubMed) · PMC190617 (PubMed Central)