Amy S. Major, Ph.D.

Associate Professor

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Faculty Appointments
Associate Professor of Medicine Associate Professor of Pathology, Microbiology and Immunology
Ph.D., Microbiology/Immunology, West Virginia University, Morgantown, West VirginiaB.S., Biology, Wheeling Jesuit University, Wheeling, West Virginia
Office Address
A3335B, MCN
(inside lab at A3314, MCN)
Nashville, TN 37032
Research Description
The broad research focus of Dr. Major's laboratory is to understand immunological mechanisms of cardiovascular disease, specifically atherosclerosis. Atherosclerosis is the number one cause of mortality in developed countries and it is known that both lipids and immunity play significant roles. Work performed in her laboratory has significantly impacted our understanding of how the immune system modulates atherosclerosis as well as how dyslipidema and the atherosclerotic environment influence normal immune function.

It is widely accepted that increased circulating cholesterol (especially LDL) and modifications of lipids are the main culprits in the development of atherosclerosis in the general population. However, over the past three decades, increased focus has been on the role of immune cells, such as B cells and particular subsets of T cells, in the atherogenic process. Dr. Major's laboratory is interested in understanding the relationship between normal and abnormal T and B cell biology and atherosclerosis. Specifically, her lab is trying to understand:

- the relative roles of T and B cells in the atherogenic process;
- how autoimmunity (specifically systemic lupus erythematosus, or lupus) exacerbates the atherosclerotic process;
- how the hyperlipidemic environment associated with atherosclerosis affects immune function (specifically T cells, B cells and immune complexes);
- what molecules, typically associated with lipid homeostasis in health, play roles in lymphocyte activation.

The preclinical models that Dr. Major uses in her studies are the mouse model of atherosclerosis (LDL-receptor deficient or apolipoprotein E deficient) and the mouse model of spontaneous lupus (B6.Sle). Both of these animal models of human disease have been greatly characterized and have pathogenic characteristics relevant to their human disease counterparts. Dr. Major has developed and characterized a novel animal model of lupus-accelerated atherosclerosis by reconstituting lethally-irradiated LDL-receptor deficient mice with the hematopoietic cells from lupus-susceptible mice. The result is an animal that develops lupus and lupus-accelerated atherosclerosis very similar to human lupus patients. The proceeding is a brief narrative of Dr. Major's ongoing projects in the laboratory focused on understanding the relationship between normal and abnormal immune function and atherosclerosis.

Research Keywords
atherosclerosis, Inflammation, B lymphocytes, T lymphocytes, autoimmunity, immune complexes
Haycook CP, Balsamo JA, Glass EB, Williams CH, Hong CC, Major AS, Giorgio TD. PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity. Int J Nanomedicine. 2020; 15: 1215-28. PMID: 32110018, PMCID: PMC7036983, PII: 234850, DOI: 10.2147/IJN.S234850, ISSN: 1178-2013.

Marvin J, Rhoads JP, Major AS. Fc¿RIIb on CD11c+ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr-/- mice. Atherosclerosis [print-electronic]. 2019 Jun; 285: 108-19. PMID: 31051414, PII: S0021-9150(19)30387-9, DOI: 10.1016/j.atherosclerosis.2019.04.221, ISSN: 1879-1484.

Rhoads JP, Major AS. How Oxidized Low-Density Lipoprotein Activates Inflammatory Responses. Crit Rev Immunol. 2018; 38(4): 333-42. PMID: 30806246, PMCID: PMC6527110, PII: 33ef53647edb3659,0c90370c00fe608a, DOI: 10.1615/CritRevImmunol.2018026483, ISSN: 1040-8401.

Rhoads JP, Major AS, Rathmell JC. Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nat Rev Rheumatol [print-electronic]. 2017 May; 13(5): 313-20. PMID: 28381829, PMCID: PMC5502208, PII: nrrheum.2017.54, DOI: 10.1038/nrrheum.2017.54, ISSN: 1759-4804.

Rhoads JP, Lukens JR, Wilhelm AJ, Moore JL, Mendez-Fernandez Y, Kanneganti TD, Major AS. Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and Fc¿R Cooperation and Is Dependent on CARD9. J Immunol [print-electronic]. 2017 Mar 3/1/2017; 198(5): 2105-14. PMID: 28130494, PMCID: PMC5318843, PII: jimmunol.1601563, DOI: 10.4049/jimmunol.1601563, ISSN: 1550-6606.

Zhu L, Giunzioni I, Tavori H, Covarrubias R, Ding L, Zhang Y, Ormseth M, Major AS, Stafford JM, Linton MF, Fazio S. Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-a Inhibition. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2016 Aug; 36(8): 1483-95. PMID: 27365402, PII: ATVBAHA.116.307736, DOI: 10.1161/ATVBAHA.116.307736, ISSN: 1524-4636.

Stocks BT, Wilhelm AJ, Wilson CS, Marshall AF, Putnam NE, Major AS, Moore DJ. Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction. Am. J. Transplant [print-electronic]. 2015 Sep 9/15/2015; PMID: 26372909, DOI: 10.1111/ajt.13449, ISSN: 1600-6143.

Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, DeVay RM, Hong L, Fan D, Predazzi IM, Rashid S, Linton MF, Fazio S. Local Effects of Human PCSK9 on the Atherosclerotic Lesion. J. Pathol [print-electronic]. 2015 Sep 9/3/2015; PMID: 26333678, DOI: 10.1002/path.4630, ISSN: 1096-9896.

Wilhelm AJ, Rhoads JP, Wade NS, Major AS. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann. Rheum. Dis [print-electronic]. 2015 Apr; 74(4): 778-85. PMID: 24395554, PMCID: PMC4083014, PII: annrheumdis-2013-203759, DOI: 10.1136/annrheumdis-2013-203759, ISSN: 1468-2060.

Anderson-Baucum EK, Major AS, Hasty AH. A possible secondary immune response in adipose tissue during weight cycling: The ups and downs of yo-yo dieting. Adipocyte [print-electronic]. 2014 Apr 4/1/2014; 3(2): 141-5. PMID: 24719788, PMCID: PMC3979879, PII: 2013APIDOCYTE137R, DOI: 10.4161/adip.27556, ISSN: 2162-3945.

Covarrubias R, Wilhelm AJ, Major AS. Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells. PLoS ONE. 2014; 9(7): e102236. PMID: 25050824, PMCID: PMC4106787, PII: PONE-D-13-40341, DOI: 10.1371/journal.pone.0102236, ISSN: 1932-6203.

Major AS. Expanding the therapeutic frontier in atherosclerosis [editorial]. J. Cardiovasc. Pharmacol. 2013 Sep; 62(3): 237-8. PMID: 23945275, PMCID: PMC3902169, DOI: 10.1097/FJC.0b013e3182a18bea, ISSN: 1533-4023.

Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J. Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc. 2013 Apr; 2(2): e000093. PMID: 23563994, PMCID: PMC3647260, PII: 2/2/e000093, DOI: 10.1161/JAHA.113.000093, ISSN: 2047-9980.

Gabriel CL, Smith PB, Mendez-Fernandez YV, Wilhelm AJ, Ye AM, Major AS. Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. Am. J. Physiol. Endocrinol. Metab [print-electronic]. 2012 Dec 12/1/2012; 303(11): E1313-24. PMID: 23032686, PMCID: PMC3774080, PII: ajpendo.00665.2011, DOI: 10.1152/ajpendo.00665.2011, ISSN: 1522-1555.

Wilhelm AJ, Major AS. Accelerated atherosclerosis in SLE: mechanisms and prevention approaches. Int J Clin Rheumtol. 2012 Oct 10/1/2012; 7(5): 527-39. PMID: 24672580, PMCID: PMC3963493, DOI: 10.2217/ijr.12.46, ISSN: 1758-4272.

van Leuven SI, Mendez-Fernandez YV, Wilhelm AJ, Wade NS, Gabriel CL, Kastelein JJ, Stroes ES, Tak PP, Major AS. Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice. Ann. Rheum. Dis [print-electronic]. 2012 Mar; 71(3): 408-14. PMID: 21953346, PMCID: PMC3306213, PII: annrheumdis-2011-200071, DOI: 10.1136/annrheumdis-2011-200071, ISSN: 1468-2060.

Wade NS, Major AS. The problem of accelerated atherosclerosis in systemic lupus erythematosus: insights into a complex co-morbidity. Thromb. Haemost [print-electronic]. 2011 Nov; 106(5): 849-57. PMID: 21979131, PMCID: PMC3306215, PII: 11-05-0330, DOI: 10.1160/TH11-05-0330, ISSN: 0340-6245.

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. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am. J. Physiol. Renal Physiol [print-electronic]. 2011 May; 300(5): F1203-13. PMID: 21367915, PMCID: PMC3094053, PII: ajprenal.00468.2010, DOI: 10.1152/ajprenal.00468.2010, ISSN: 1522-1466.

van Leuven SI, Mendez-Fernandez YV, Stroes ES, Tak PP, Major AS. Statin therapy in lupus-mediated atherogenesis: two birds with one stone?. Ann. Rheum. Dis [print-electronic]. 2011 Feb; 70(2): 245-8. PMID: 21068103, PMCID: PMC3306212, PII: ard.2010.133827, DOI: 10.1136/ard.2010.133827, ISSN: 1468-2060.

Mendez-Fernandez YV, Stevenson BG, Diehl CJ, Braun NA, Wade NS, Covarrubias R, van Leuven S, Witztum JL, Major AS. The inhibitory Fc¿RIIb modulates the inflammatory response and influences atherosclerosis in male apoE(-/-) mice. Atherosclerosis [print-electronic]. 2011 Jan; 214(1): 73-80. PMID: 21084088, PMCID: PMC3052995, PII: S0021-9150(10)00872-5, DOI: 10.1016/j.atherosclerosis.2010.10.018, ISSN: 1879-1484.

Braun NA, Mendez-Fernandez YV, Covarrubias R, Porcelli SA, Savage PB, Yagita H, Van Kaer L, Major AS. Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2010 Sep; 30(9): 1758-65. PMID: 20539017, PMCID: PMC2963029, PII: ATVBAHA.110.206045, DOI: 10.1161/ATVBAHA.110.206045, ISSN: 1524-4636.

Braun NA, Covarrubias R, Major AS. Natural killer T cells and atherosclerosis: form and function meet pathogenesis. J Innate Immun [print-electronic]. 2010; 2(4): 316-24. PMID: 20375560, PMCID: PMC2895753, PII: 000296915, DOI: 10.1159/000296915, ISSN: 1662-8128.

Wade NS, Stevenson BG, Dunlap DS, Major AS. The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice. Lupus [print-electronic]. 2010 Jan; 19(1): 34-42. PMID: 19850656, PMCID: PMC2802678, PII: 0961203309345785, DOI: 10.1177/0961203309345785, ISSN: 1477-0962.

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. Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2009 Jun; 29(6): 843-9. PMID: 19286630, PMCID: PMC2761013, PII: ATVBAHA.108.183442, DOI: 10.1161/ATVBAHA.108.183442, ISSN: 1524-4636.

Braun Na, Wade NS, Wakeland EK, Major AS. Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice. Lupus. 2008 Dec; 17(12): 1070-8. PMID: 19029274, PMCID: PMC2662384, PII: 17/12/1070, DOI: 10.1177/0961203308093551, ISSN: 0961-2033.

Overton CD, Yancey PG, Major AS, Linton MF, Fazio S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ. Res [print-electronic]. 2007 Mar 3/16/2007; 100(5): 670-7. PMID: 17303763, PII: 01.RES.0000260204.40510.aa, DOI: 10.1161/01.RES.0000260204.40510.aa, ISSN: 1524-4571.

Major AS, Joyce S, Van Kaer L. Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. Trends Mol Med [print-electronic]. 2006 Jun; 12(6): 270-8. PMID: 16651026, PII: S1471-4914(06)00071-2, DOI: 10.1016/j.molmed.2006.04.004, ISSN: 1471-4914.

Stanic AK, Stein CM, Morgan AC, Fazio S, Linton MF, Wakeland EK, Olsen NJ, Major AS. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2006 May 5/2/2006; 103(18): 7018-23. PMID: 16636270, PMCID: PMC1459011, PII: 0602311103, DOI: 10.1073/pnas.0602311103, ISSN: 0027-8424.

Major AS, Singh RR, Joyce S, Van Kaer L. The role of invariant natural killer T cells in lupus and atherogenesis. Immunol. Res. 2006; 34(1): 49-66. PMID: 16720898, PMCID: PMC2291524, PII: IR:34:1:49, ISSN: 0257-277X.

Burleigh ME, Babaev VR, Yancey PG, Major AS, McCaleb JL, Oates JA, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. J. Mol. Cell. Cardiol. 2005 Sep; 39(3): 443-52. PMID: 16040051, PII: S0022-2828(05)00195-1, DOI: 10.1016/j.yjmcc.2005.06.011, ISSN: 0022-2828.

Su YR, Dove DE, Major AS, Hasty AH, Boone B, Linton MF, Fazio S. Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Circulation [print-electronic]. 2005 May 5/10/2005; 111(18): 2373-81. PMID: 15851589, PII: 01.CIR.0000164236.19860.13, DOI: 10.1161/01.CIR.0000164236.19860.13, ISSN: 1524-4539.

Major AS, Wilson MT, McCaleb JL, Ru Su Y, Stanic AK, Joyce S, Van Kaer L, Fazio S, Linton MF. Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2004 Dec; 24(12): 2351-7. PMID: 15472130, PII: 01.ATV.0000147112.84168.87, DOI: 10.1161/01.ATV.0000147112.84168.87, ISSN: 1524-4636.

Linton MF, Major AS, Fazio S. Proatherogenic role for NK cells revealed [editorial]. Arterioscler. Thromb. Vasc. Biol. 2004 Jun; 24(6): 992-4. PMID: 15178571, PII: 24/6/992, DOI: 10.1161/01.ATV.0000128896.45976.f0, ISSN: 1524-4636.

Su YR, Ishiguro H, Major AS, Dove DE, Zhang W, Hasty AH, Babaev VR, Linton MF, Fazio S. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. Mol. Ther. 2003 Oct; 8(4): 576-83. PMID: 14529830, PII: S1525001603002144, ISSN: 1525-0016.

Major AS, Fazio S, Linton MF. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 2002 Nov 11/1/2002; 22(11): 1892-8. PMID: 12426221, ISSN: 1524-4636.

Fazio S, Babaev VR, Burleigh ME, Major AS, Hasty AH, Linton MF. Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice. J. Lipid Res. 2002 Oct; 43(10): 1602-9. PMID: 12364544, ISSN: 0022-2275.

Yoshida H, Hasty AH, Major AS, Ishiguro H, Su YR, Gleaves LA, Babaev VR, Linton MF, Fazio S. Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice. Circulation. 2001 Dec 12/4/2001; 104(23): 2820-5. PMID: 11733401, ISSN: 1524-4539.

Major AS, Dove DE, Ishiguro H, Su YR, Brown AM, Liu L, Carter KJ, Linton MF, Fazio S. Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((-/-)) mice. Arterioscler. Thromb. Vasc. Biol. 2001 Nov; 21(11): 1790-5. PMID: 11701467, ISSN: 1524-4636.

Ishiguro H, Yoshida H, Major AS, Zhu T, Babaev VR, Linton MF, Fazio S. Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo. J. Biol. Chem [print-electronic]. 2001 Sep 9/28/2001; 276(39): 36742-8. PMID: 11477092, PII: M106027200, DOI: 10.1074/jbc.M106027200, ISSN: 0021-9258.

Swift LL, Farkas MH, Major AS, Valyi-Nagy K, Linton MF, Fazio S. A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. J. Biol. Chem [print-electronic]. 2001 Jun 6/22/2001; 276(25): 22965-70. PMID: 11304532, PII: M100172200, DOI: 10.1074/jbc.M100172200, ISSN: 0021-9258.

Fazio S, Major AS, Swift LL, Gleaves LA, Accad M, Linton MF, Farese RV. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J. Clin. Invest. 2001 Jan; 107(2): 163-71. PMID: 11160132, PMCID: PMC198874, DOI: 10.1172/JCI10310, ISSN: 0021-9738.

Major AS, Rubin DH, Cuff CF. Mucosal immunity to reovirus infection. Curr. Top. Microbiol. Immunol. 1998; 233(Pt 2): 163-77. PMID: 9599937, ISSN: 0070-217X.

Major AS, Cuff CF. Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta2-microglobulin-deficient mice. J. Virol. 1997 Aug; 71(8): 5782-9. PMID: 9223466, PMCID: PMC191832, ISSN: 0022-538X.

Major AS, Cuff CF. Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response. J. Virol. 1996 Sep; 70(9): 5968-74. PMID: 8709219, PMCID: PMC190617, ISSN: 0022-538X.

Available Postdoctoral Position Details
Posted: 9/16/2015
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