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Niche-specific B-1 cell heterogeneity. B-1 cells from distinct anatomic regions display functional heterogeneity in IgM antibody production, arising from both extrinsic microenvironmental factors and intrinsic differences. Peritoneal cavity (PerC) B-1 cells secrete less IgM constitutively compared with B-1 cells from spleen, bone marrow, perivascular adipose tissue (PVAT), and adventitial tertiary lymphoid organs (ATLOs). In the PerC, PC-1 (plasma cell alloantigen 1) expression distinguishes B-1a cells with high capacity to produce IgM (PC-1 lo ), from those with low capacity to produce IgM (PC-1 hi ). The src family kinase Lck also maintains the hyporesponsiveness of PerC B-1a cells. Additional heterogeneity in the PerC B-1 population is evidenced by distinct IgH repertoires expressed by PerC B-1a vs B-1b cells, with PerC B-1a cells expressing more germline sequences that lack N additions and a preference for V H 11/V H 12 family gene segments. In contrast, splenic B-1a cells produce more IgM constitutively in a manner dependent on the transcription factor IRF4 (interferon regulatory factor 4), and the splenic B-1a IgH repertoire contains more N additions and greater VDJ gene segment diversity. The transcription factor Id3 inhibits B-1b cell number and consequently IgM antibody production. Bone marrow (BM) B-1 cells also produce more IgM constitutively compared with PerC B-1 cells, and IL (interleukin)-5 has been shown to maintain the BM IgM-secreting cell population. The PVAT contains type 2 innate lymphoid cells (ILC-2) that secrete IL-5 in response to IL-33. Whether ILC-2-derived IL-5 is responsible for maintaining the high constitutive IgM production that occurs in PVAT is unknown. ATLOs contain an abundance of IL-10 producing B-1b cells. B-1 cell trafficking between these compartments relies on adhesion molecules. The chemokine receptor CXCR (C-X-C motif chemokine receptor) 5 mediates B-1 cell trafficking between the spleen and the PerC. CXCR4 mediates B-1 cell migration to the bone marrow. CCR6 (C-C chemokine receptor type 6) and L-selectin mediate B-1 localization to the PVAT and aorta. BCR indicates B-cell receptor; and TLR, toll-like receptor.
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Atherosclerosis—the major underlying pathology of cardiovascular disease—is characterized by accumulation and subsequent oxidative modification of lipoproteins within the artery wall, leading to inflammatory cell infiltration and lesion formation that can over time result in arterial stenosis, ischemia, and downstream adverse events. The contributi...
Contexts in source publication
Context 1
... Although the origins and migratory capacities of B-1 cells from different sites are not completely understood, it is clear that functional heterogeneity exists within the B-1 compartments; some B-1 cells contribute to constitutive natural IgM secretion (predominantly B-1 cells within spleen and BM), whereas serosal B-1 cells seem to be primed for rapid response to stimuli via migration and differentiation into antibody-secreting cells. 22 An exciting recent realization is the heterogeneity in the B-1 population at the level of the BCR (Figure 2 ...
Context 2
... Steady-state B-1 localization to the PerC depends on the chemokine/receptor pairs CXCR (C-X-C chemokine receptor type) 5/CXCL13 62 and CXCR4/CXCL12, 115 as well as the integrins α4β1 and CD9. 63 CXCR5/CXCL13 is required for both B-1 cell trafficking to the PerC via the omentum 62,116 and B-1 cell trafficking out of the PerC into the spleen 63 ( Figure 2). ...
Context 3
... Although the origins and migratory capacities of B-1 cells from different sites are not completely understood, it is clear that functional heterogeneity exists within the B-1 compartments; some B-1 cells contribute to constitutive natural IgM secretion (predominantly B-1 cells within spleen and BM), whereas serosal B-1 cells seem to be primed for rapid response to stimuli via migration and differentiation into antibody-secreting cells. 22 An exciting recent realization is the heterogeneity in the B-1 population at the level of the BCR (Figure 2 ...
Context 4
... Steady-state B-1 localization to the PerC depends on the chemokine/receptor pairs CXCR (C-X-C chemokine receptor type) 5/CXCL13 62 and CXCR4/CXCL12, 115 as well as the integrins α4β1 and CD9. 63 CXCR5/CXCL13 is required for both B-1 cell trafficking to the PerC via the omentum 62,116 and B-1 cell trafficking out of the PerC into the spleen 63 ( Figure 2). ...
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... In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and promote macrophage cell death and necrotic core formation, whereas subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit the development of atherosclerosis [36]. Although B lymphocytes are relatively small in number compared to T lymphocytes and are also thought to be an important regulator of pro-and antiinflammatory effects in atherosclerosis, B1 lymphocytes appear to attenuate atherosclerosis, whereas B2 lymphocytes can aggravate this process [37]. ...
Nutritional status is associated with prognosis in acute coronary syndrome (ACS) patients. Although the Global Registry of Acute Coronary Events (GRACE) risk score is regarded as a relevant risk predictor for the prognosis of ACS patients, nutritional variables are not included in the GRACE score. This study aimed to compare the prognostic ability of the Geriatric Nutritional Risk Index (GNRI) and Prognostic Nutritional Index (PNI) in predicting long-term all-cause death in ACS patients undergoing percutaneous coronary intervention (PCI) and to determine whether the GNRI or PNI could improve the predictive value of the GRACE score. A total of 799 patients with ACS who underwent PCI from May 2018 to December 2019 were included and regularly followed up. The performance of the PNI in predicting all-cause death was better than that of the GNRI [C-index, 0.677 vs. 0.638, p = 0.038]. The addition of the PNI significantly improved the predictive value of the GRACE score for all-cause death [increase in C-index from 0.722 to 0.740; IDI 0.006; NRI 0.095; p < 0.05]. The PNI was superior to the GNRI in predicting long-term all-cause death in ACS patients undergoing PCI. The addition of the PNI to the GRACE score could significantly improve the prediction of long-term all-cause death.
... B1-CDP migrates to inflammatory sites and can phagocytose debris while maintaining lymphoid cell-surface markers [53]. Additional references discussing the human B1-cell surface markers: [21,23,25,52,[74][75][76][77][78][79]. ...
... Notably, B2 cells do not produce GM-CSF [73,102]. The proposed main B1-cell subgroups are depicted in Figure 1B [60,65,68,78,[103][104][105][106][107][108]. However, it remains to be established whether these B1-cell subtypes in humans are committed subsets or adaptations of a multifunctional B1-precursor cell to the tissue environment. ...
Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), traditionally considered a chronic autoimmune attack against the insulating myelin sheaths around axons. However, the exact etiology has not been identified and is likely multi-factorial. Recently, evidence has been accumulating that implies that autoimmune processes underlying MS may, in fact, be triggered by pathological processes initiated within the CNS. This review focuses on a relatively unexplored immune cell-the "innate-like" B1 lymphocyte. The B1 cell is a primary-natural-antibody-and anti-inflammatory-cytokine-producing cell present in the healthy brain. It has been recently shown that its frequency and function may differ between MS patients and healthy controls, but its exact involvement in the MS pathogenic process remains obscure. In this review, we propose that this enigmatic cell may play a more prominent role in MS pathology than ever imagined. We aim to shed light on the human B1 cell in health and disease, and how dysregulation in its delicate homeostatic role could impact MS. Furthermore, novel therapeutic avenues to restore B1 cells' beneficial functions will be proposed.
... 3 B1-CDP migrates to inflammatory sites and can phagocytose debris while maintaining lymphoid cell-surface markers [53]. Additional references discussing the human B1-cell surface markers: [21,23,25,52,[74][75][76][77][78][79]]. ...
... Notably, B2 cells do not produce GM-CSF [73,102]. The proposed main B1-cell subgroups are depicted in Figure 1B [60,65,68,78,[103][104][105][106][107][108]. However, it remains to be established whether these B1-cell subtypes in humans are committed subsets or adaptations of a multifunctional B1-precursor cell to the tissue environment. ...
A conceptual paper on the role of B1 cells in the ethiopathogenesis of multiple sclerosis
... IgG is further divided into four subclasses (IgG [1][2][3][4]. Ongoing results showed that IgM antibodies can act as atheroprotectives ( Figure 1A), while IgE and IgG antibodies may have proatherogenic features with contradictory data for IgG [12,13]. Concerning IgG subclasses, no robust data of their putative role in chronic inflammation of cardiovascular disease are available. ...
... Recent findings show that T cells are not the strict conductors of B cells as formerly thought. Rather data have clarified that the B cells conduct important features of the cellular immune activation in AS [13,14]. The basis for this astonishing perspective is given by the fact that B cells can regulate directly T cell activities via antigen presentation, co-stimulation, and cytokine production [13,14]. ...
... Rather data have clarified that the B cells conduct important features of the cellular immune activation in AS [13,14]. The basis for this astonishing perspective is given by the fact that B cells can regulate directly T cell activities via antigen presentation, co-stimulation, and cytokine production [13,14]. In the following, we discuss aspects of these interesting new findings and rank data from animal models as possibly useful in the future as a basis for new diagnostic/therapeutic concepts in the management of human cardiovascular diseases. ...
Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, and immune cells. Undoubtedly, the immune response is a most important piece of the pathological puzzle in AS. Although macrophages and T cells have been the focus of research in recent years, B cells producing antibodies and regulating T and natural killer (NKT) cell activation are more important than formerly thought. New results show that the B cells exert a prominent role with atherogenic and protective facets mediated by distinct B cell subsets and different immunoglobulin effects. These new insights come, amongst others, from observations of the effects of innovative B cell targeted therapies in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases associate with AS, and the beneficial side effects of B cell subset depleting (modifying) therapies on atherosclerotic concomitant disease, have been observed. Moreover, the CANTOS study (NCT01327846) showed impressive results of immune-mediated inflammation as a new promising target of action for the fight against atherosclerotic endpoints. This review will reflect the putative role of B cells in AS in an attempt to connect observations from animal models with the small spectrum of the thus far available human data. We will also discuss the clinical therapeutic potency of B cell modulations on the process of AS.
... For example, the fetal-derived B-1 subtype is atheroprotective due to its IgM responses against ox-LDL, 183 while the bone marrow-derived B-2 subtype is proatherogenic. 184,185 ...
Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the incidence and complications of atherosclerosis, there are relatively limited data in the clinical and preclinical literature to rigorously address mechanisms underlying sex as a biological variable in atherosclerosis. In multiple histological and imaging studies, overall plaque burden and markers of inflammation appear to be greater in men than women and are predictive of cardiovascular events. However, while younger women are relatively protected from cardiovascular disease, by the seventh decade, the incidence of myocardial infarction in women ultimately surpasses that of men, suggesting an interaction between sex and age. Most preclinical studies in animal atherosclerosis models do not examine both sexes, and even in those that do, well-powered direct statistical comparisons for sex as an independent variable remain rare. This article reviews the available data. Overall, male animals appear to have more inflamed yet smaller plaques compared to female animals. Plaque inflammation is often used as a surrogate end point for plaque vulnerability in animals. The available data support the notion that rather than plaque size, plaque inflammation may be more relevant in assessing sex-specific mechanisms since the findings correlate with the sex difference in ischemic events and mortality and thus may be more reflective of the human condition. Overall, the number of preclinical studies directly comparing plaque inflammation between the sexes is extremely limited relative to the vast literature exploring atherosclerosis mechanisms. Failure to include both sexes and to address age in mechanistic atherosclerosis studies are missed opportunities to uncover underlying sex-specific mechanisms. Understanding the mechanisms driving sex as a biological variable in atherosclerotic disease is critical to future precision medicine strategies to mitigate what is still the leading cause of death of men and women worldwide.
Rationale:
Femoral atherosclerotic plaques are less inflammatory than carotid plaques histologically, but limited cell-level data exist regarding comparative immune landscapes and polarization at these sites.
Objectives:
We investigated intraplaque leukocyte phenotypes and transcriptional polarization in 49 total patients undergoing femoral (N=23) or carotid (N=26) endarterectomy using single-cell ribonucleic acid sequencing (scRNA-seq; N=13), flow cytometry (N=24), and immunohistochemistry (N=12).
Findings:
Comparative scRNA-seq of CD45 positive-selected leukocytes from femoral (N=9; 35265 cells) and carotid (N=4; 30655 cells) plaque revealed distinct transcriptional profiles. Inflammatory foam cell-like macrophages and monocytes comprised 2.5- to 4-fold higher proportions of myeloid cells in carotid plaques, whereas non-inflammatory foam cell-like macrophages and LYVE1-overexpressing resident-like macrophages comprised 3.5- to 9-fold higher proportions of myeloid cells in femoral plaque (p<0.001 for all). A significant comparative excess of CCR2+ macrophages in carotid versus femoral plaque was observed by flow cytometry in a separate validation cohort. B cells were more prevalent and exhibited a comparatively anti-inflammatory profile in femoral plaque, whereas cytotoxic CD8+ T cells were more prevalent in carotid plaque.
Conclusion:
Human femoral plaques exhibit distinct macrophage profiles and diminished CD8+ T cell populations compared with carotid plaques. Experimental models elucidating determinants of plaque site-specific cell polarization cues are warranted.
This review discusses the problem of diagnostics of atherosclerosis from the standpoint of the need of developing new approaches and principles for more effective detection of this disease at the early stages of its course in the humans. The insufficiently studied basic stages and mechanisms of lipid metabolism are indicated, which in the future may have diagnostic value. The lipid composition of blood plasma and its fractions, which are associated with a high risk of the occurrence and development of cardiovascular disease (CVD) is assessed. The determining of the role of cholesterol, lipoproteins and apolipoproteins in the pathogenesis of atherosclerosis, a wide variability of the atherogenic lipid profile and its direct relationship with calcium metabolism in atherosclerotic damage of the vascular wall is accentuated. It is shown that the basis of dyslipidemia and civilization diseases (atherosclerosis, obesity, diabetes mellitus) is a disorder of the mechanisms of neurohumoral regulation of lipid metabolism. The immunological mechanisms of the pathogenesis of atherosclerotic process and the marker signs that identify this process are discussed in details. A generalized scheme of peroxidation of blood plasma lipoproteins and the subsequent molecular-cellular stages of the formation of atherosclerotic plaques in the intima of the vascular wall is presented. The current modern methods of diagnosing dyslipidemia are briefly described and the lipid-lowering effects of certain drugs are noted, a forecast is given for the creation of new, more effective statins. In conclusion, the work confirms the importance of studying the qualitative composition of lipids and the expansion of physico-chemical and molecular genetic diagnostic methods for studying metabolism.
The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD.
