The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice

Abstract

Cardiovascular disease risk is increased in individuals suffering from systemic lupus erythematosus. Understanding the mechanism(s) of systemic lupus erythematosus-accelerated atherosclerosis is critical for the development of effective therapies. Our laboratory previously demonstrated that radiation chimeras of systemic lupus erythematosus-susceptible B6.Sle1.2.3 and low density lipoprotein receptor (LDLr)^—/— mice have augmented atherosclerosis, which is associated with increased T-cell burden and activation in the lesion. The goals of this study were to further define specific immune mechanisms that mediate accelerated atherosclerosis and to determine whether the gene interval Sle3, which is linked to lupus-associated T-cell dysregulation, was sufficient to modulate atherogenesis. We transferred B6.Sle3 or C57Bl/6-derived bone marrow cells into lethally irradiated LDLr^—/— mice (hereafter referred to as LDLr.Sle3 and LDLr.B6, respectively). Sixteen weeks after transplantation, the mice were placed on a western-type diet for 8 weeks. Our analyses revealed that LDLr.Sle3 mice had increased auto-antibody production against double-stranded DNA and cardiolipin compared with LDLr.B6 controls. We also found an increase in atherosclerosis-associated oxLDL antibodies. Antibody isotypes and serum cytokine analysis suggested that the humoral immune response in LDLr.Sle3 mice was skewed toward a Th2 phenotype. This finding is consistent with lupus-associated immune dysregulation. Additionally, LDLr.Sle3 mice had decreased serum cholesterol and triglyceride levels. However, there was no difference in lesion area or cellular composition of lesions between the two groups. These data demonstrate that, despite no change in lesion area, transfer of Sle3-associated T-cell dysregulation alone to LDLr-deficient mice is sufficient to decrease serum cholesterol and to exacerbate humoral immune responses that are frequently associated with atherosclerosis. Lupus (2010) 19, 34—42.

Keywords

atherosclerosis autoimmunity oxidized low density lipoprotein systemic lupus erythematosus T cell

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References

George J. , Harats D. , Gilburd B. , Levy Y. , Langevitz P. , Shoenfeld Y. Atherosclerosis-related markers in systemic lupus erythematosus patients: the role of humoral immunity in enhanced atherogenesis. Lupus 1999; 8: 220-226.

Bacon PA , Stevens RJ , Carruthers DM , Young SP , Kitas GD Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev 2002; 1: 338-347.

Urowitz MB , Bookman AA , Koehler BE , Gordon DA , Smythe HA , Ogryzlo MA The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976; 60: 221-225.

Manzi S. , Selzer F. , Sutton-Tyrrell K. , et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 51-60.

Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809.

Sherer Y. , Tenenbaum A. , Praprotnik S. , et al. Autoantibodies to cardiolipin and beta-2-glycoprotein-I in coronary artery disease patients with and without hypertension. Cardiology 2002; 97: 2-5.

George J. , Harats D. , Shoenfeld Y. Autoimmunity in atherosclerosis. The role of autoantigens. Clin Rev Allergy Immunol 2000; 18: 73-86.

Petri M. , Perez-Gutthann S. , Spence D. , Hochberg MC Risk factors for coronary artery disease in patients with systemic lupus erythematosus . Am J Med 1992; 93: 513-519.

Asanuma Y. , Oeser A. , Shintani AK , et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349: 2407-2415.

10.

Frostegard J. SLE, atherosclerosis and cardiovascular disease . J Intern Med 2005; 257: 485-495.

11.

Svenungsson E. , Jensen-Urstad K. , Heimburger M. , et al. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 2001; 104: 1887-1893.

12.

Morel L. , Rudofsky UH , Longmate JA , Schiffenbauer J. , Wakeland EK Polygenic control of susceptibility to murine systemic lupus erythematosus . Immunity 1994; 1: 219-229.

13.

Morel L. , Yu Y. , Blenman KR , Caldwell RA , Wakeland EK Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain. Mamm Genome 1996; 7: 335-339.

14.

Morel L. , Mohan C. , Yu Y. , et al. Functional dissection of systemic lupus erythematosus using congenic mouse strains. J Immunol 1997; 158: 6019-6028.

15.

Mohan C. , Alas E. , Morel L. , Yang P. , Wakeland EK Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 1998; 101: 1362-1372.

16.

Sobel ES , Satoh M. , Chen Y. , Wakeland EK , Morel L. The major murine systemic lupus erythematosus susceptibility locus Sle1 results in abnormal functions of both B and T cells. J Immunol 2002; 169: 2694-2700.

17.

Mohan C. , Morel L. , Yang P. , Wakeland EK Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity. J Immunol 1997; 159: 454-465.

18.

Mohan C. , Yu Y. , Morel L. , Yang P. , Wakeland EK Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J Immunol 1999; 162: 6492-502.

19.

Zhu J. , Liu X. , Xie C. , et al. T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. J Clin Invest 2005 ; 115: 1869-1878.

20.

Sobel ES , Morel L. , Baert R. , Mohan C. , Schiffenbauer J. , Wakeland EK Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells. J Immunol 2002; 169: 4025-4032.

21.

Stanic AK , Stein CM , Morgan AC , et al. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Proc Natl Acad Sci USA 2006; 103: 7018-7023.

22.

Braun N. , Wade N. , Wakeland E. , Major A. Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr-/- mice. Lupus 2008; 17: 1070-1078.

23.

Liuzzo G. , Kopecky SL , Frye RL , et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999; 100: 2135-2139.

24.

Jonasson L. , Holm J. , Skalli O. , Bondjers G. , Hansson GK Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6: 131-138.

25.

Fazio S. , Major AS , Swift LL , et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest 2001; 107: 163-171.

26.

Shivakumar S. , Tsokos GC , Datta SK T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol 1989; 143: 103-112.

27.

Major AS , Fazio S. , Linton MF B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice . Arterioscler Thromb Vasc Biol 2002; 22: 1892-1898.

28.

Gautier EL , Huby T. , Ouzilleau B. , et al. Enhanced immune system activation and arterial inflammation accelerates atherosclerosis in lupus-prone mice. Arterioscler Thromb Vasc Biol 2007; 27: 1625-1631.

29.

Zampieri S. , Iaccarino L. , Ghirardello A. , et al. Systemic lupus erythematosus, atherosclerosis, and autoantibodies. Ann NY Acad Sci 2005; 1051: 351-361.

30.

Westerweel PE , Luyten RK , Koomans HA , Derksen RH , Verhaar MC Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus. Arthritis Rheum 2007; 56: 1384-1396.

31.

Paiker JE , Raal FJ , von Arb M. Auto-antibodies against oxidized LDL as a marker of coronary artery disease in patients with familial hypercholesterolaemia. Ann Clin Biochem 2000; 37: 174-178.

32.

Wu JT , Wu LL Autoantibodies against oxidized LDL. A potential marker for atherosclerosis . Clin Lab Med 1997; 17: 595-604.

33.

Kobayashi K. , Tada K. , Itabe H. , et al. Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages . Lupus 2007; 16: 929-938.

34.

Binder CJ, Hartvigsen K. , Chang MK , et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004; 114: 427-437.

35.

Shaw PX , Horkko S. , Chang MK , et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 2000; 105: 1731-1740.

36.

Lambert SL , Okada CY , Levy R. TCR vaccines against a murine T cell lymphoma: a primary role for antibodies of the IgG2c class in tumor protection. J Immunol 2004; 172: 929-936.

37.

Finkelman FD , Katona IM , Mosmann TR , Coffman RL IFNgamma regulates the isotypes of Ig secreted during in vivo humoral immune responses. J Immunol 1988; 140: 1022-1027.

38.

Hansson GK Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-90.

39.

Zhou X. , Nicoletti A. , Elhage R. , Hansson GK Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 2000; 102: 2919-2922.

40.

Zhou X. , Robertson AK , Hjerpe C. , Hansson GK Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 864-870.