Potential natural immunization against atherosclerosis in hibernating bears

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Abstract

Brown bears ( Ursus arctos) hibernate for 5–6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9–107.9) vs 782.3, IQR (422.8–1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis.

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Immunity, atherosclerosis and cardiovascular disease

Johan Frostegård (2013)

Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune-stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti-inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed.

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Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.

Yury Miller, Soo-Ho Choi, Philipp Wiesner … (2011)

Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating "oxidation-specific" epitopes. In this review, we discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of "pattern recognition receptors" (PRRs). By analogy with microbial "pathogen-associated molecular patterns" (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent "danger (or damage)-associated molecular patterns" (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Furthermore, because many PAMPs on microbes share molecular identity and/or mimicry with oxidation-specific epitopes, such PAMPs provide a strong secondary selecting pressure for the same set of oxidation-specific PRRs as well. Because lipid peroxidation is ubiquitous and a major component of the inflammatory state associated with atherosclerosis, the understanding that oxidation-specific epitopes are DAMPs, and thus the target of multiple arcs of innate immunity, provides novel insights into the pathogenesis of atherosclerosis. As examples, we show that both cellular and soluble PRRs, such as CD36, toll-like receptor-4, natural antibodies, and C-reactive protein recognize common oxidation-specific DAMPs, such as oxidized phospholipids and oxidized cholesteryl esters, and mediate a variety of immune responses, from expression of proinflammatory genes to excessive intracellular lipoprotein accumulation to atheroprotective humoral immunity. These insights may lead to improved understanding of inflammation and atherogenesis and suggest new approaches to diagnosis and therapy.

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Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.

Johan Frostegård, Ann-Kristin Ulfgren, Pernilla Nyberg … (1999)

The atherosclerotic lesion contains large numbers of macrophages and T lymphocytes. This suggests that a cellular immune response may take place in the lesion, and oxidized lipoproteins, heat shock proteins, and micro-organisms have been implied as candidate antigens. However, the effector mechanisms elicited by this response have been largely unclear. We have therefore analyzed endarterectomy specimens by immunohistochemistry and reverse transcription-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleukin-2 and interferon-7, were found in a large proportion of plaques (IL-2 in 50% and interferon-gamma in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleukin-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaques by immunohistochemistry, mRNA for interleukin-4 in 10% and for interleukin-5 in 40% by PCR). This demonstrates the presence of a predominantly pro-inflammatory, Th1-type T cell response in atherosclerosis. This conclusion was further supported by the expression of the pro-inflammatory cytokine, interleukin-1 by plaque macrophages and endothelial cells. In addition, the chemokine interleukin-8 and the macrophage differentiation-stimulating cytokine, granulocyte-monocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitment and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transforming growth factor-beta1-3 and its carrier protein, latent TGF-beta binding protein, were found in large amounts in all plaques. Together, these results show that a pro-inflammatory, Thl type cellular immune response takes place in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the lesion.

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Author and article information

Contributors

Johan Frostegård: Johan.frostegard@ki.se

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 9 June 2021

Publication date PMC-release: 9 June 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 12120

Affiliations

[1 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Division of Immunology and Chronic Disease, Institute of Environmental Medicine, , Karolinska Institutet, ; Stockholm, Sweden

[2 ]GRID grid.15895.30, ISNI 0000 0001 0738 8966, Department of Cardiology, Faculty of Health, , Örebro University, ; Örebro, Sweden

[3 ]GRID grid.420127.2, ISNI 0000 0001 2107 519X, Norwegian Institute for Nature Research, ; 7485 Trondheim, Norway

[4 ]GRID grid.6341.0, ISNI 0000 0000 8578 2742, Department of Wildlife, Fish and Environmental Studies, , Swedish University of Agricultural Sciences, ; 901 83 Umeå, Sweden

[5 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, , Karolinska Institutet, ; Stockholm, Sweden

Article

Publisher ID: 91679

DOI: 10.1038/s41598-021-91679-1

PMC ID: 8190116

PubMed ID: 34108551

SO-VID: 48b11def-594e-49d5-b78c-f11cd115a7b4

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 24 November 2020

Date accepted : 31 May 2021

Funding

Funded by: vetenskapsrådet

Funded by: Karolinska Institute

Open Access :

Open access funding provided by Karolinska Institute.

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ScienceOpen disciplines: Uncategorized

Keywords: adaptive immunity,antimicrobial responses,innate immunity,immunology,cardiology,cardiovascular biology

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ScienceOpen disciplines: Uncategorized

Keywords: adaptive immunity, antimicrobial responses, innate immunity, immunology, cardiology, cardiovascular biology

Potential natural immunization against atherosclerosis in hibernating bears

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Most cited references 53

Immunity, atherosclerosis and cardiovascular disease

Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.

Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.

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