Atherosclerosis is a chronic disease characterized by lipid infiltration and inflammatory cell recruitment in the vessel wall promoting plaque progression that can lead to serious clinical consequences such as myocardial infarction and stroke. While mechanisms of monocyte and T lymphocyte recruitment and function in the vessel wall have been extensively studied 8-10, the role of B lymphocytes remains incompletely understood. In atherosclerosis-prone mouse models, the loss of B cells results in significantly increased lesion size which was attenuated by replacement of B cells 11.12. B cells and plasma cells have been demonstrated in both the intima of plaques as well as in the adventitia of humans and animals7 """""""" 13-19, yet nothing is known about the factors that regulate B cell homing to the vessel wall or the importance of vessel wall-associated B cells. IgM and IgG antibodies have been detected in atherosclerotic plaques and titers of antibodies against various oxidized LDL (oxLDL) epitopes have been described17 . 19 """""""" 20. These antioxLDL antibodies have been shown to attenuate atherosclerosis2 0- 24 """""""" The helix-loop-helix factor, Id3, has been implicated in the growth and differentiation of B lymphocytes, but nothing is known about the effect of Id3 on B cell homing, specific antibody production, inflammatory cell recruitment in the vessel or atherosclerosis. Exciting preliminary data from our laboratory demonstrates an aortic-specific reduction in B cell number and circulating levels of a specific IgM to oxPL correlating with an increase in atherosclerosis fomnation in ApoE-1 - mice null for the Id3 gene compared with ApoE-I- controls. Adoptive transfer of B cells from Id3+1+ ApoE-I- or Id3-1- ApoE-I- mice to jJMT ApoE-1 - mice lacking mature B cells provides evidence that Id3 regulates aortic-specific B cell homing and that Id3 is important for B cell mediated atheroprotection. Our data further provides evidence that Id3 regulates B cell expression of specific chemokines: CXCR4, CXCR7, and CCR6 but not CXCR5 or CCR7 (chemokine receptors known to regulate B cell homing to lymphoid tissue), providing a potential mechanism whereby Id3 may regulate B cell homing specifically to the aorta. Interestingly, adoptive transfer studies revealed that aortas containing B cells (from Id3+1+ ApoE-1 - donors) demonstrated differences in the overall inflammatory cell profile compared with aortas with significantly fewer B cells (from Id3-1 - ApoE-I- donors). Moreover, through our collaboration with Dr. Sam Tsimikas, we show reduced levels of the atheroprotective anti-oxLDL IgM (E06) produced in response to Western diet feeding in the Id3-1- ApoE-I- compared to the Id3+1+ ApoE-I-. Thus, through close collaboration with Drs. Sam TSimikas, Tim Bender and Yuan Zhuang, not only do we have novel findings and novel reagents in hand, but we have also built a team of leading experts in vascular disease, Id3, B cells and immunoglobulin production that uniquely positions us to make contributions toward understanding the mechanisms whereby B cells mediate atheroprotection
The leading cause of death and disability in Western societies is atherosclerosis (a chronic disease characterized by cholesterol build up in the artery wall stimulating blood borne cells to enter the artery wall as a reaction. This process can result in the formation of blockages in the artery that can lead to serious clinical consequences such as myocardial infarction and stroke. Some of the blood borne cells that enter the artery (such as B lymphocytes) are not bad and may play a protective role. We have identified that Id3 (a protein that regulates the expression of genes) appears to regulate the entry of these protective cells into the artery wall. Our proposal seeks to determine mechanisms whereby Id3 controls the entry of these protective cells to the artery wall and how they might be exerting their protective effects. Further understanding of these mechanisms may lead to the development of early strategies to prevent atherosclerosis before it manifests as a clinical problem.
| Morris-Rosenfeld, Samuel; Lipinski, Michael J; McNamara, Coleen A (2014) Understanding the role of B cells in atherosclerosis: potential clinical implications. Expert Rev Clin Immunol 10:77-89 |
| Manichaikul, Ani; Rich, Stephen S; Perry, Heather et al. (2014) A functionally significant polymorphism in ID3 is associated with human coronary pathology. PLoS One 9:e90222 |
| Perry, Heather M; Oldham, Stephanie N; Fahl, Shawn P et al. (2013) Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation. Arterioscler Thromb Vasc Biol 33:2771-9 |
| Lipinski, Michael J; Campbell, Kirsti A; Duong, Son Q et al. (2012) Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice. Arterioscler Thromb Vasc Biol 32:2855-61 |
| Cutchins, Alexis; Harmon, Daniel B; Kirby, Jennifer L et al. (2012) Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion. Arterioscler Thromb Vasc Biol 32:317-24 |
| Doran, Amanda C; Lipinski, Michael J; Oldham, Stephanie N et al. (2012) B-cell aortic homing and atheroprotection depend on Id3. Circ Res 110:e1-12 |
| Campbell, Kirsti A; Lipinski, Michael J; Doran, Amanda C et al. (2012) Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res 110:889-900 |
