BAFF Receptor Deficiency Reduces the Development of Atherosclerosis in Mice—Brief Report

Sage, Andrew P.; Tsiantoulas, Dimitrios; Baker, Lauren; Harrison, James; Masters, Leanne; Murphy, Deirdre; Loinard, Céline; Binder, Christoph J.; Mallat, Ziad

doi:10.1161/atvbaha.111.244731

Cited by 144 publications

(134 citation statements)

References 19 publications

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“…However, bone marrow transfer also induces some changes in the B cell compartment, for example, in the balance between B1a and B1b cells in the periphery. Nevertheless, similar and corroborating findings from bone marrow transplant and nonbone marrow transplant studies involving B cells 29,30 suggest this model continues to provide valuable information. Future studies are required to understand the specific contribution of CD4+ T cells and the relative atheroprotective contributions of antibody binding to oxLDL versus secondary necrotic cells.…”

Section: 44supporting

confidence: 54%

“…[25][26][27] We and others have shown follicular B2 cell interactions with CD4 + T cells, antagonized by marginal zone B2 cells, promote pathogenic T cell responses in the atherosclerotic setting. [28][29][30][31][32][33] Few models have, therefore, addressed the specific role of antibodies in isolation without impacting on other B cell functions. Altogether, it is hard to predict the …”

Section: Meet the First Author See P 198mentioning

confidence: 99%

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X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

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Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.Objective: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. Methods and Results:We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/ XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. Conclusions:

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Section: 44supporting

confidence: 54%

Section: Meet the First Author See P 198mentioning

confidence: 99%

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

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“…Deletion of the BAFF receptor (BAFFR), necessary for B2 development, was also recently shown to be protective in at least two studies (968,1528). Like the anti-CD20 antibody infusion studies, BAFFR deficiency resulted in marked selective reduction of B2 cells with little effect on B1a cells.…”

Section: The Atherogenic Effect Of Igg Appears To Depend On the Targetmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

384

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…On the other hand, use of anti-CD20 to deplete B-2 cells in mice, which spared B-1 cells in the peritoneum, reduced atherosclerosis, as well as activation and proliferation of DCs and CD4 + T cells, suggesting that B-2 cells were proatherogenic by several mechanisms (60,94). Furthermore B cell-activating factor receptor (BAFF-R) deficiency, which causes a reduction in B-2 but not B-1 cells, also reduced lesion development and macrophage and T cell infiltration (95,96). However, recent data demonstrated a role for the Id3-CCR6 pathway in mediating aortic B cell homing, and demonstrated that resident adventitial B cells mediated protection from early atherosclerosis in part through inhibiting intimal macrophage accumulation (97).…”

Section: B Cells and Ab Responses In Atherosclerosis B-1 Cells And Igmentioning

confidence: 99%

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Lichtman¹,

Binder²,

Tsimikas³

et al. 2013

J. Clin. Invest.

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Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

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BAFF Receptor Deficiency Reduces the Development of Atherosclerosis in Mice—Brief Report

Cited by 144 publications

References 19 publications

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Molecular Biology of Atherosclerosis

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

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