Understanding the role of B cells in atherosclerosis: potential clinical implications

Morris-Rosenfeld, Samuel; Lipinski, Michael J.; McNamara, Coleen A.

doi:10.1586/1744666x.2014.857602

Cited by 22 publications

(12 citation statements)

References 117 publications

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“…B-1a cells produce IgM NAbs in an antigen-independent manner, whereas B-1b cells respond to T cell-independent antigens providing them the capacity to form memory 12, 38 . The work of Haas et al 33 and Alugupalli et al 39 established B-1b cells as the source of T cell-independent memory and support B-1b cells as targets of T cell-independent antigen directed vaccination, which has been discussed as a novel therapeutic against atherosclerosis 18, 19, 30, 40 . As such, understanding the impact of B-1b cells on atherosclerosis and elucidating factors that regulate their activity is of clear importance.…”

Section: Discussionmentioning

confidence: 99%

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

Rosenfeld

Perry

Gonen

et al. 2015

Circulation Research

126

121

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Rationale B cells contribute to atherosclerosis through subset specific mechanisms. Whereas some controversy exists about the role of B-2 cells, B-1a cells are atheroprotective due to secretion of atheroprotective IgM antibodies independent of antigen. B-1b cells, a unique subset of B-1 cells that respond specifically to T cell-independent antigens, have not been studied within the context of atherosclerosis. Objective To determine whether B-1b cells produce atheroprotective IgM antibodies and function to protect against diet induced atherosclerosis. Methods and Results We demonstrate that B-1b cells are sufficient to produce IgM antibodies against oxidation specific epitopes (OSE) on LDL both in vitro and in vivo. Additionally, we demonstrate that B-1b cells provide atheroprotection after adoptive transfer into B and T cell deficient (Rag1−/−Apoe−/−) hosts. We implicate Id3 in the regulation of B-1b cells as B cell-specific Id3 knockout mice (Id3BKOApoe−/−) have increased numbers of B-1b cells systemically, increased titers of OSE-reactive IgM antibodies, and significantly reduced diet-induced atherosclerosis compared to Id3WTApoe−/− controls. Finally, we report that the presence of a homozygous SNP in ID3 in humans that attenuates Id3 function is associated with an increased percentage of circulating B-1 cells and anti-MDA-LDL IgM suggesting clinical relevance. Conclusions These results provide novel evidence that B-1b cells produce atheroprotective OSE-reactive IgM antibodies and protect against atherosclerosis in mice, and suggest that similar mechanisms may occur in humans.

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Section: Discussionmentioning

confidence: 99%

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

Rosenfeld

Perry

Gonen

et al. 2015

Circulation Research

126

121

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“…Natural antibodies directed against antigens associated with these three classes of disease appear to be functional. (1) In mice, a number of adoptive transfer experiments with Apoe −/− recipients have led to the generally accepted paradigm that B-1 cells and the IgM antibodies they produce are atheroprotective, whereas B-2 cells and the IgG antibodies they produce are atherogenic ( 50 , 51 ). Less invasive studies have been carried out with people, and it has been shown that human IgM anti-oxLDL is inversely correlated with cardiovascular and carotid disease ( 12 , 38 , 39 , 52 – 54 ), whereas IgG has been found to be positively correlated with atherosclerosis ( 12 , 52 , 55 – 60 ) or not correlated at all with vessel pathology ( 40 , 61 – 64 ).…”

Section: Disease-associated Natural Antibodies Are Functionalmentioning

confidence: 99%

Natural Antibodies as Rheostats for Susceptibility to Chronic Diseases in the Aged

Rothstein

2016

Front. Immunol.

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Natural antibodies are spontaneously produced in the absence of infection or immunization, and are both anti-microbial and autoreactive. Autoreactive natural antibodies can bind noxious molecules, such as those involved in clinical situations of atherosclerosis (oxLDL), malignancy (NGcGM3), and neurodegeneration (amyloid, tau) and can affect the fate of their targets or the cells bearing them to maintain homeostasis. Clinically relevant natural antibodies have been shown to decline with advancing age in those few situations where measurements have been made. Consistent with this, human B-1 cells that are thought to be responsible for generating natural antibodies also decline with advancing age. These findings together suggest that an age-related decline in amount or efficacy of homeostatic natural antibodies is associated with relative loss of protection against molecules involved in several diseases whose incidence rises in the older age population, and that those individuals experiencing greatest loss are at greatest risk. In this view, natural antibodies act as rheostats for susceptibility to several age-related diseases. These considerations suggest that administration of natural antibodies, or of factors that maintain B-1 cells and/or enhance production of natural antibodies by B-1 cells, may serve to counteract the onset or progression of age-related chronic illness.

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“…Lymphocytes comprise a range of different cell types with different roles in the immune system 14. Low total lymphocyte count is associated with malnutrition and immune suppression,15 and observational studies have shown that it is associated with poor prognosis in patients with ST elevation MI 16.…”

Section: Introductionmentioning

confidence: 99%

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study

et al. 2016

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BackgroundEosinophil and lymphocyte counts are commonly performed in clinical practice. Previous studies provide conflicting evidence of association with cardiovascular diseases.MethodsWe used linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records) programme). We included people aged 30 or older without cardiovascular disease at baseline, and used Cox models to estimate cause-specific HRs for the association of eosinophil or lymphocyte counts with the first occurrence of cardiovascular disease.ResultsThe cohort comprised 775 231 individuals, of whom 55 004 presented with cardiovascular disease over median follow-up 3.8 years. Over the first 6 months, there was a strong association of low eosinophil counts (<0.05 compared with 0.15–0.25×109/L) with heart failure (adjusted HR 2.05; 95% CI 1.72 to 2.43), unheralded coronary death (HR 1.94, 95% CI 1.40 to 2.69), ventricular arrhythmia/sudden cardiac death and subarachnoid haemorrhage, but not angina, non-fatal myocardial infarction, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, subarachnoid haemorrhage or abdominal aortic aneurysm. Low eosinophil count was inversely associated with peripheral arterial disease (HR 0.63, 95% CI 0.44 to 0.89). There were similar associations with low lymphocyte counts (<1.45 vs 1.85–2.15×109/L); adjusted HR over the first 6 months for heart failure was 2.25 (95% CI 1.90 to 2.67). Associations beyond the first 6 months were weaker.ConclusionsLow eosinophil counts and low lymphocyte counts in the general population are associated with increased short-term incidence of heart failure and coronary death.Trial registration numberNCT02014610; results.

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Understanding the role of B cells in atherosclerosis: potential clinical implications

Cited by 22 publications

References 117 publications

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis

Natural Antibodies as Rheostats for Susceptibility to Chronic Diseases in the Aged

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study

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