B Cell Subsets and Atherosclerosis: Updates and Emerging Concepts

Atherosclerosis is a chronic disease of the arterial wall largely driven by inflammation; hence, therapeutics targeting inflammatory pathways are considered an attractive strategy in atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to describe the randomized, placebo-controlled clinical trials currently investigating the impact of anti-inflammatory strategies in ASCVD patients, to discuss novel insights and targets into the role of innate immunity in atherosclerosis and to address the promise of local drug delivery as opposed to systemic therapies in atherosclerotic disease. The first clinical trials using systemic anti-inflammatory drugs in ASCVD patients might be able to strengthen the case for immunomodulation once showing an improved ASCVD outcome. Several specific targets in innate immunity bear therapeutic potential, of which some have already entered the clinical arena. To prevent immunosuppression by systemic effects, drug delivery systems are increasingly being applied to locally attenuate plaque inflammation. Anti-inflammatory therapies seem promising for future treatment of ASCVD. In view of the risk of immunosuppression in case of long term and systemic use of anti-inflammatory drugs, there is a clinical need for highly selective and targeted therapies in patients with atherosclerosis.

As cell function is influenced by niche-specific factors in the cellular microenvironment, methods to dissect cell localization and migration can provide further insight on cell function. B-1a cells are a unique B cell subset in mice that produce protective natural IgM antibodies against oxidation-specific epitopes that arise during health and disease. B-1a cell IgM production differs depending on B-1a cell location, and therefore it becomes useful from a therapeutic standpoint to target B-1a localization to niches supportive of high antibody production. Here we describe a method to target B-1a cell migration to the bone marrow by retroviral-mediated overexpression of the C-X-C motif chemokine receptor 4 (CXCR4). Gene induction in primary murine B cells can be challenging and typically yields low transfection efficiencies of 10-20% depending on technique. Here we demonstrate that retroviral transduction of primary murine B-1a cells results in 30-40% transduction efficiency. This method utilizes adoptive cell transfer of transduced B-1a cells into B cell-deficient recipient mice so that donor B-1a cell migration and localization can be visualized. This protocol can be modified for other retroviral constructs and can be used in diverse functional assays post-adoptive transfer, including analysis of donor cell or host cell phenotype and function, or analysis of soluble factors secreted post B-1a cell transfer. The use of distinct donor and recipient mice differentiated by CD45.1 and CD45.2 allotype and the presence of a GFP reporter within the retroviral plasmid could also enable detection of donor cells in other, immune-sufficient mouse models containing endogenous B cell populations.

Atherosclerotic cardiovascular disease (ASCVD) is a major global health concern linked to significant morbidity and mortality. Recent research has explored the relationship between ASCVD and periodontitis, a prevalent inflammatory oral condition. Epidemiological studies have suggested a strong association between periodontitis and ASCVD, even proposing that periodontal disease could be a modifiable risk factor for cardiovascular conditions. This review critically analyzes the current evidence for a potential causal role for periodontitis in ASCVD. While randomized controlled trials (RCTs) have demonstrated reductions in surrogate markers of cardiovascular risk following periodontal interventions, these studies remain inconclusive regarding their direct effects on cardiovascular events. Preclinical studies in animal models have suggested a potential causal relationship between periodontitis and ASCVD, proposing several biological mechanisms to explain this connection. These studies, however, are limited in their ability to definitively prove causality. The positive associations observed in epidemiological studies between periodontitis and ASCVD may also be influenced by various biases, such as confounding and collider stratification. Moreover, our systematic review of Mendelian randomization studies on the causal relationship between periodontitis and ASCVD found no evidence of a genetic causality, further challenging the causal hypothesis. This review underscores the need for further high-quality research clarifying the relationship between periodontitis and ASCVD to better guide clinical practice and public health policy.

Immune response to three doses of mRNA SARS-CoV-2 vaccines in CD19-targeted chimeric antigen receptor Tcell immunotherapy recipients.

Objectives: To compare the efficacy of tocotrienol and tocopherol in the management of patients with atherosclerotic cardiovascular diseases. Method: The systematic review was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines 2020, and comprised literature search from 2002 till January 5, 2023, on PubMed, Google Scholar, Cochrane Library, Google, Wiley-Inter Science Library, Medline, SpringerLink and Taylor and Francis databases. The search was conducted using key words, such as: “tocopherol”, “tocotrienol”, “vitamin E”, “dyslipidaemia”, “cardiovascular diseases” “cardioprotective”, “hypercholesterolemia” and “atherosclerosis” along with Boolean operators. Human clinical studies regarding the use of tocotrienol or tocopherol or comparison of its efficacy in patients having atherosclerosis, dyslipidaemia leading to cardiovascular diseases, and studies including details of efficacy of any of the four alpha, beta, gamma, delta isomers of tocopherol or tocotrienol were included. Pertinent data from the eligible studies was retrieved and reviewed. Results: Of the 516 articles identified, 12(2.3%) were subjected to detailed analysis. Tocotrienol showed better anti-oxidant efficacy by decreasing inflammatory biomarkers, normalising serum lipid parameters and modulating micro-ribonucleic acid involved in cardiovascular diseases. Tocopherol shown heterogeneity of results by either decreasing or increasing the risk of mortality in atherosclerotic cardiovascular diseases. Conclusion: Compared to tocopherol, tocotrienol was found to be safe and potential candidate for improving cardiovascular health in the management of atherosclerotic cardiovascular diseases. Key Words: Cardiovascular diseases, Vitamin E, Atherosclerosis, Tocotrienol, Dyslipidaemia, Tocopherol, Hypercholesterolemia, Human studies.

Atherosclerosis and related complications still represent the major cause of morbidity and mortality in the western world. The mechanisms that govern the progression and destabilization of atheromatous lesions are multiple and complex. Despite their widespread use, lipid-lowering agents do not provide sufficient protection from future clinical cardiovascular-associated events. Interest in the role of immunity in atherosclerosis and support for this relationship has grown significantly over recent years. This paradigm, in which inflammation is an instrumental process in plaque development and rupture, is further supported by studies showing that immune subsets are operative in atherosclerosis. Regulatory T-cell subpopulations consist of lymphocytes--with several phenotypic markers--that share the ability to suppress, by various mechanisms, inflammatory responses. These regulatory T cells consist of subsets such as interleukin-10 secreting type I regulatory cells, type 3 effector T-helper cells that produce transforming growth factor-beta, as well as adaptive and natural CD4(+)CD25(+) regulatory T cells. In this Review, I focus on the direct and indirect evidence for the involvement of regulatory T cells in atherogenesis in experimental models and in humans. The growing knowledge of the role of regulatory T cells could result in the future development of novel therapeutic modalities to attenuate atherosclerosis and stabilize vulnerable plaques.

Who am I? (re-)Defining fibroblast identity and immunological function in the age of bioinformatics.

B-1 and B-2 B cell subsets carry out a diverse array of functions that range broadly from responding to innate stimuli, antigen presentation, cytokine secretion and antibody production. In this review, we first cover the functional roles of the major murine B cell subsets. We then highlight emerging evidence, primarily in preclinical rodent studies, to show that select B cell subsets are a therapeutic target in obesity and its associated co-morbidities. High fat diets promote accumulation of select murine B cell phenotypes in visceral adipose tissue. As a consequence, B cells exacerbate inflammation and thereby insulin sensitivity through the production of autoantibodies and via cross-talk with select adipose resident macrophages, CD4(+) and CD8(+) T cells. In contrast, interleukin (IL)-10-secreting regulatory B cells counteract the proinflammatory profile and improve glucose sensitivity. We subsequently review data from rodent studies that show pharmacological supplementation of obesogenic diets with long chain n-3 polyunsaturated fatty acids or specialized pro-resolving lipid mediators synthesized from endogenous n-3 polyunsaturated fatty acids boost B cell activation and antibody production. This may have potential benefits for improving inflammation in addition to combating the increased risk of viral infection that is an associated complication of obesity and type II diabetes. Finally, we propose potential underlying mechanisms throughout the review by which B cell activity could be differentially regulated in response to high fat diets.

Atherosclerosis is a hardening and narrowing of arteries causing a reduction of blood flow. It is a leading cause of death in industrialized countries as it causes heart attacks, strokes, and peripheral vascular disease. Pathogenesis of the atherosclerotic lesion (atheroma) relies on the accumulation of cholesterol-containing low-density lipoproteins (LDL) and on changes of artery endothelium that becomes adhesive for monocytes and lymphocytes. Immunomediated inflammatory response stimulated by lipoprotein oxidation, cytokine secretion and release of pro-inflammatory mediators, worsens the pathological context by amplifying tissue damage to the arterial lining and increasing flow-limiting stenosis. Formation of thrombi upon rupture of the endothelium and the fibrous cup may also occur, triggering thrombosis often threatening the patient’s life. Purinergic signaling, i.e., cell responses induced by stimulation of P2 and P1 membrane receptors for the extracellular nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine), has been implicated in modulating the immunological response in atherosclerotic cardiovascular disease. In this review we will describe advancements in the understanding of purinergic modulation of the two main immune cells involved in atherogenesis, i.e., monocytes/macrophages and T lymphocytes, highlighting modulation of pro- and anti-atherosclerotic mediated responses of purinergic signaling in these cells and providing new insights to point out their potential clinical significance.

The role of dendritic cells in asthma

The oxidation of lipoproteins is a critical factor in the initiation, progression, and destabilization of atherosclerotic lesions. Reactive oxygen species and enzymes in the vessel wall modify lipoproteins to generate a variety of oxidation-specific epitopes (OSE). OSE are pro-inflammatory, immunogenic, and pro-atherogenic by activating macrophages leading to foam cell formation, apoptosis, and necrotic cores. OSE activate the innate and adaptive immune systems that lead to pro-inflammatory responses. The immunological properties of OSE have facilitated the generation and characterization and modification of murine and human monoclonal antibodies as imaging agents. Nuclear and magnetic resonance techniques have been used to visualize OSE in preclinical models. OSE-targeted antibodies have been derivatized with radioisotopes or complexed with gadolinium, manganese, and iron oxide nanoparticles to facilitate in vivo imaging of atherosclerotic lesions. OSE-targeted antibody uptake in the vessel wall is proportional to plaque burden in early and intermediate lesions allowing quantitation of the extent of atherosclerosis. In intervention studies, imaging of OSE allows the detection of atherosclerosis regression and features of plaque stabilization. Translation of these approaches to humans may provide sensitive techniques to image, diagnose, and monitor high-risk atherosclerotic lesions, guide optimal therapeutic interventions, and evaluate efficacy of novel therapeutic agents.

Intratumoral IL-12 Gene Therapy Results in the Crosspriming of Tc1 Cells Reactive Against Tumor-associated Stromal Antigens

Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (−). Electronegative L5 and LDL (−) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (−) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (−) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1β (IL-1β). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (−) and discuss the potential targeting of LOX-1 or IL-1β signaling as new therapeutic modalities for these diseases.

Salvia miltiorrhiza-Derived Sal-miR-58 Induces Autophagy and Attenuates Inflammation in Vascular Smooth Muscle Cells

The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW). A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed. LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1). Figure 1. Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, …