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  1. 1. Editorial Slides VP Watch, April 17, 2002, Volume 2, Issue 15 Is B Cell Really Protective Against Atherosclerosis?
  2. 2. • Atherosclerosis is associated with activation of immune system. • Atherosclerotic plaques are infiltrated by macrophages and T lymphocytes, some of which recognize oxidized LDL. 1,2 • Auto-antibodies to oxidized LDL and activated components of complement cascade have been shown in atherosclerotic plaques. 1,2
  3. 3.  In 1997, Dansky and colleagues crossed apoE-KO mouse with RAG-1-/- (recombinase-activating gene-1) mouse, which lacks functional T and B cells. They showed 40% reduction of atherosclerosis in offspring chow-fed immunodeficient mice . 9  They also found no difference between apoE/RAG-1 KO mice on high-fat Western-type diet and those on chow-fed in either aortic root lesion size or percent of total aorta occupied by lesions. Fibrous plaques with well-defined caps and necrotic cores were detected in both Western diet-fed E- /R- and E-/R+ animals. 9
  4. 4.  Zhou and colleagues crossed apoE-KO mice with immunodeficient scid/scid mice. They found 73% reduction in aortic fatty streak lesions in offspring compared with immunocompetent apoE-KO mice. 5  By transferring CD4+ T cells from immunocompetent apoE-KO mice to immunodeficient apoE-/- x scid/scid mice they found that atherosclerosis increases from 27% to 79% in recipients. 5
  5. 5. Hansson et al. showed that treatment of apoE-KO mice with intravenous immunoglobulin prevents fatty streak development and also inhibits fibro-fatty plaques formation in these mice through anergization of T cells and reduction of IgM anti-oxLDL antibodies. 2  Shah et al. found that immunization with specific human apoB100 reduces aortic atherosclerosis, inflammation, and alter plaque composition in apoE KO mic. 6
  6. 6.  Unlike others, Palinski and colleagues found that immunization of LDL receptor deficient mice with MDA-LDL generates high titers of antibodies with similar specificity as naturally occurring autoantibodies. Immunized animals showed a significant reduction in the extent of atherosclerotic lesions. 8
  7. 7.  Caligiuri, Hansson, and colleagues discussed that splenectomy increases extent and severity of atherosclerosis in apoE-KO mice. 7  Transfer of spleen cells or B cells from atherosclerotic apoE-KO mice not only rescued the recipients but protected them from development of advanced atherosclerosis. They also showed that B cells from atherosclerotic apoE-KO mice reduces extent of atherosclerosis in splenectomized apoE-KO mice. 7  All of the above reports provide evidence for the role of humoral immune system in atherosclerosis.
  8. 8.  As reported in this week of VP Watch, Dimayuga, Nilsson, and colleagues showed that periadventitial cuff injury to carotid of RAG-1 KO mice (B and T cells deficient) compared with wild type (with and without high fat diet) resulted in a 4- to 5-fold increase in neointimal formation.  They found that B cells transfered from wild type mice (fed normal chow or western diet) to RAG-1 KO mice reduced carotid neointimal formation after injury, compared with that in RAG-1 KO mice without B-cell transfer.
  9. 9. The neointima mostly contained SMCs, with minimal staining for monocytes/macrophages. 10 Serum cholesterol levels were not significantly different between those groups. 10 Reconstitution of Rag-1 KO mice with B cells from normal mice (both fed a western diet) reduced neointimal formation up to 75% compared the effect in Rag-1 KO mice (P<0.05).
  10. 10. Serum Immunoglobulin 0 0.5 1 1.5 2 2.5 WT D0 RAG D0 RAG Brec D0 RAG Brec D21 IgM IgG Serum immunoglobulins of the IgM and IgG2a isotypes were detectable in the wild type (WT) mice before injury (WT D0). RAG-1 KO mice had no detectable immunoglobulins at the same time point (RAG D0), but they had low IgM 48 hours after B-cell transfer (RAG Brec D0). 21 days after B-cell reconstitution, RAG-1 KO mice had detectable serum immunoglobulins of IgM and IgG2a isotypes (RAG Brec D21, n=4). Unreconstituted RAG-1 KO mice had no immunoglobulins at the 21-day time point (n=2, not shown). Sera were from western diet–fed mice. Dimayuga P, Cercek B, Oguchi S, Nordin Fredriksson G, Yano J, Shah PK, Jovinge S, Nilsson J. Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice. Arterioscler Thromb Vasc Biol. 2002; 22: 644–649 48 hr 21 days
  11. 11. Conclusion I. RAG-1 deficiency (lack of functional T and B cell) causes increased neointimal formation. II. Diet affect the response of arterial wall to injury only when the immune system is compromise. III. Transplanted B cells from immune competent to immune deficient injured mice decreases atherosclerosis.
  12. 12. Questions: • If RAG-1 deficient (immune deficient) mice develop significant atherosclerosis, is atherosclerosis still an inflammatory disease?! • If high cholesterol level in apoE/RAG-1 deficient mice is the cause of atherosclerosis how would you explain plaque formation without immune activation?
  13. 13. Questions: • If transplanted B cells were protective against atherosclerosis, what was the mechanism of action, through antibodies or what? If antibodies are the mediator what are the antigen(s)? • Can B cell transplant reverse atherosclerosis or only prevents its progression?
  14. 14. References 1) Stemme, S., B. Faber, J. Holm, O. Wiklund, J.L. Witzum, and G.K. Hansson (1995) T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA. 92: 3893-3897 2) Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest. 1998; 102: 910–918 3) Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol. 2001; 21: 1876–90. 4) Seifert, P.S., and G.K. Hansson (1989) Complement receptors and regulatory proteins in human atherosclerotic lesions. Arteriosclerosis. 9: 802-811 5) Zhou X, Nicoletti A, Elhage R, Hansson GK. Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apoE knockout mice. Circulation. 2000; 102: 2919–2922 6) Odette S. Reyes, Kuang-Yuh Chyu, Juliana Yano, Xioaning Zhao, Bojan Cercek, Sanjay Kaul, Jan Nilsson, Prediman K. Shah; Immunization With a Novel Human Apo B100 Related Peptide Reduces Atherosclerosis and Inflammation in Apo E Null Mice. ACC 2002-Atlanta. 7) Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity carried by B cells of hypercholesterolemic mice. J Clin Invest. 2002; 109: 745–753 8) Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995; 92: 821– 825 9) Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1997; 94: 4642–4646. 10) Dimayuga P, Cercek B, Oguchi S, Nordin Fredriksson G, Yano J, Shah PK, Jovinge S, Nilsson J. Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice. Arterioscler Thromb Vasc Biol. 2002; 22: 644–649