scholarly journals Sars-CoV2- infection as a trigger of humoral response against apolipoprotein A-1

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Pagano ◽  
S Yerly ◽  
N Suh ◽  
C Le Terrier ◽  
L Farrera-Soler ◽  
...  
Keyword(s):  
Public Health ◽  
General Population ◽  
Molecular Mimicry ◽  
Humoral Response ◽  
Public Institution ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Apolipoprotein A ◽  
Overall Mortality

Abstract Background Unravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights in the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. SARS-CoV-2 autoimmune-mediated inflammation have been reported, but the existence of autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) in COVID-19 remains unexplored. Anti-apoA-1 IgGs have emerged as an independent biomarker for cardiovascular disease and mortality in humans with proinflammatory and proatherogenic functions in vivo and in vitro. Purpose We want to determine i) the degree of homology between SARS-CoV-2, apoA-1, and Toll-like receptor-2 (TLR2) epitopes, ii) the association between anti-SARSCoV2 and anti-apoA-1 IgGs, and iii) their relationship to prognosis. Methods We performed bioinformatics modelling coupled with mimetic peptides engineering, as well as functional and competition assays with antibodies to identify molecular mimicry between SARS-CoV-2, apoA-1 and TLR2 epitopes. Anti-Spike domain 1 (SD1) IgGs, anti-apoA-1 IgGs and against mimic peptides, as well as cytokines were assessed by immunoassays on a case-control (n=101), an intensive care unit (ICU; n=126) with a 28-days follow-up for overall mortality, and a general population cohort (n=663) with available samples in the pre and post-pandemic period. Results Linear sequence homologies and antibodies cross-reactivity between apoA-1, TLR2, and Spike epitopes were identified. Overall, anti-apoA-1 IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (p<0.0001). Significant and similar associations were noted between anti-apoA-1, anti-SARS-CoV-2 IgG, cytokines, and lipid profile. In ICU patients, anti-SARS-CoV-2 and anti-apoA-1 seroconversion rates displayed similar 7-days kinetics, reaching 82% for anti-apoA-1 seropositivity. C-statistics (CS) indicated that baseline anti-Spike/TLR2 mimic-peptide IgGs displayed a significant prognostic accuracy for overall mortality at 28 days (CS: 0.64; p=0.02). In the general population, SARS-CoV-2 exposure increased baseline anti-apoA-1 IgG levels. Conclusions COVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This study was funded by the Swiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), the Fondation de Bienfaisance du Groupe Pictet, the Fondation Ancrage, the Fondation Privée des HUG, and the Center for Emerging Viral Diseases. The De Reuter (grant Nr 657) and the Schmidheiny Foundation.

scholarly journals SARS-CoV2- infection as a trigger of humoral response against apolipoprotein A-1

2021 ◽  
Author(s):  
Sabrina Pagano ◽  
Sabine Yerly ◽  
Benjamin Meyer ◽  
Catherine Juillard ◽  
Noémie Suh ◽  
...  
Keyword(s):  
General Population ◽  
Molecular Mimicry ◽  
Humoral Response ◽  
Cross Reactivity ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Prognostic Accuracy ◽  
Apolipoprotein A ◽  
General Population Cohort ◽  
Mimic Peptide

ABSTRACTAimsUnravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights in the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We want to determine whether SARS-CoV-2 exposure could trigger a humoral response against apolipoprotein A-1 (anti-apoA-1 IgG) through molecular mimicry and assess its relationship to patient prognosis.Methods and ResultsAnti-Spike domain 1 (SD1) IgGs, anti-apoA-1 IgGs and against mimic peptides, as well as cytokines were assessed by immunoassays on a case-control (n=101), an intensive care unit (ICU; n=126) with a 28-days follow-up, and a general population cohort (n=663) with available samples in the pre and post-pandemic period. Linear sequence homologies and antibodies cross-reactivity between apoA-1, TLR2, and Spike epitopes were identified. Overall, anti-apoA-1 IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (p<0.0001). Significant and similar associations were noted between anti-apoA-1, anti-SARS-CoV-2 IgG, cytokines, and lipid profile. In ICU patients, anti-SARS-CoV-2 and anti-apoA-1 seroconversion rates displayed similar 7-days kinetics, reaching 82% for anti-apoA-1 seropositivity. C-statistics (CS) indicated that anti-Spike/TLR2 mimic-peptide IgGs displayed a significant prognostic accuracy for overall mortality at 28 days (CS: 0.64; p=0.02). In the general population, SARS-CoV-2 exposure increased baseline anti-apoA-1 IgG levels.ConclusionsCOVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic.

scholarly journals Apolipoprotein A-I (ApoA-I), Immunity, Inflammation and Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1097 ◽  
Author(s):  
Georgila ◽  
Vyrla ◽  
Drakos
Keyword(s):  
Cancer Biology ◽  
Animal Studies ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Multifunctional Protein ◽  
Cancer Pathogenesis ◽  
Early Cancer Diagnosis ◽  
Apolipoprotein A

Apolipoprotein A-I (ApoA-I), the major protein component of high-density lipoproteins (HDL) is a multifunctional protein, involved in cholesterol traffic and inflammatory and immune response regulation. Many studies revealing alterations of ApoA-I during the development and progression of various types of cancer suggest that serum ApoA-I levels may represent a useful biomarker contributing to better estimation of cancer risk, early cancer diagnosis, follow up, and prognosis stratification of cancer patients. In addition, recent in vitro and animal studies disclose a more direct, tumor suppressive role of ApoA-I in cancer pathogenesis, which involves anti-inflammatory and immune-modulatory mechanisms. Herein, we review recent epidemiologic, clinicopathologic, and mechanistic studies investigating the role of ApoA-I in cancer biology, which suggest that enhancing the tumor suppressive activity of ApoA-I may contribute to better cancer prevention and treatment.

scholarly journals Apolipoprotein A-I stimulates secretion of insulin and matrix metalloproteinases by islets of Langerhans

2018 ◽  
Vol 64 (2) ◽  
pp. 195-200 ◽  
Author(s):  
I.F. Usynin ◽  
O.N. Poteryaeva ◽  
G.S. Russkikh ◽  
A.V. Zubova ◽  
K.Yu. Boiko ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Matrix Metalloproteinases ◽  
Islets Of Langerhans ◽  
Fold Increase ◽  
Serum Levels ◽  
High Density Lipoproteins ◽  
Low Density ◽  
Apo B ◽  
Apolipoprotein A

The development of type 2 diabetes mellitus (DM2) is accompanied by disturbances in lipid metabolism. These include the increase in serum levels of atherogenic fractions of very low-density (VLDL) and low-density lipoproteins (LDL), total cholesterol, triglycerides and apo B. In contrast, the level of antiatherogenic high density lipoproteins (HDL) and the content of apolipoprotein A-I (apoA-I) decreased. To study the effect of the observed metabolic changes on insulin secretion in vitro, we used the islets of Langerhans isolated from the rat pancreas. It has been found that incubation of the islets in the presence of serum of the obese patients and patients with decompensated DM2 leads to a decrease in insulin secretion by 2.4 and 5.0 times, respectively. On the contrary, the addition of HDL to the incubation medium increased the insulin secretion by 3.4 times. A similar effect was observed in the presence of apoA-I, the main protein component of HDL. In the presence of apoA-I, the extracellular activity of matrix metalloproteinases (MMPs) demonstrated a 10-fold increase. The addition of LDL and VLDL to the islets did not change the secretion of insulin and activity of MMP. Our results testify to the important role of HDL and apoA-I in regulation of the insulin secretion by b-cells and the activity of MMPs in the islets of Langerhans.

Abstract 20: Apolipoprotein A-I Influences Regulatory T Cell Development and Proliferation in Homeostasis and Atherogenesis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Dalia E Gaddis ◽  
Amy Wu ◽  
Debbi Yoakum ◽  
Mary Sorci-Thomas ◽  
Catherine C Hedrick
Keyword(s):  
T Cell ◽  
Atherogenic Diet ◽  
Cholesterol Homeostasis ◽  
Major Protein ◽  
Apolipoprotein A ◽  
Brdu Labeling ◽  
And Function ◽  
Treg Development

Apolipoprotein A-I (ApoAI) is the major protein component of HDL. HDL ApoAI is involved in the efflux of cholesterol from cells to maintain cellular cholesterol homeostasis. ApoAI also has anti-inflammatory properties. We previously showed that injecting mice fed an atherogenic diet with ApoAI decreased the number of activated CD4 lymphocytes. Since T regulatory lymphocytes (Treg) play a major role in inhibiting the immune response during atherosclerosis development, we wanted to determine if ApoAI influences Treg development, hypothesizing that ApoAI enhances Treg development. To test this hypothesis, we compared the numbers of Treg in ApoAI-/- mice to B6 mice, and found a 50% decrease in the numbers of Treg in the periaortic LNs (PaLN) of ApoAI-/- mice. BrdU labeling studies showed that ApoAI-/- Treg had a significant 30% reduction in proliferation, suggesting that in the absence of ApoAI and normal cholesterol homeostasis, Tregs have defective proliferation. Functionally, we discovered that ApoAI-/- Treg were significantly less suppressive than B6 Treg in reducing CD4 effector T cell proliferation, suggesting that ApoAI plays a role in both the development and function of Tregs. To determine if the addition of exogenous lipid-free ApoAI could rescue and promote Treg differentiation in ApoAI-/- mice, ApoAI-/- naïve T cells were incubated in vitro with TGFβ and exogenous ApoAI. Addition of ApoAI significantly increased development of naïve ApoA1-/- lymphocytes into Treg. To verify these results in vivo, we fed a novel Treg lineage tracker mouse (LT), Foxp3-YFP-Cre-Rosa26-RFP-ApoE-/- mice a western diet for 15 weeks and administered subcutaneous injections of ApoAI for the last 9 weeks of diet. These mice allow us to identify current functional Tregs and any exTregs that have lost active Treg function in vivo. We found that LT mice treated with ApoAI had a 37% decrease in exTregs and a concomitant 33% increase in current functional Tregs in the aorta. This was accompanied by decreased IFNγ and IL-17 production in PaLN, further confirming our in vitro findings that ApoAI promotes Treg development and function. In conclusion, we have identified a novel role for ApoAI by enhancing Treg development, emphasizing the immune properties of ApoAI for atheroprotection.

scholarly journals Reference intervals for plasma apolipoprotein A-1 determined with a standardized commercial immunoturbidimetric assay: results from the Framingham Offspring Study

1996 ◽  
Vol 42 (4) ◽  
pp. 507-514 ◽  
Author(s):  
J Contois ◽  
J R McNamara ◽  
C Lammi-Keefe ◽  
P W Wilson ◽  
T Massov ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
White Men ◽  
Reference Intervals ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Reference Ranges ◽  
Men And Women ◽  
Apolipoprotein A ◽  
The Mean ◽  
Plasma Apolipoprotein

Abstract We have evaluated a commercially available, standardized immunoturbidimetric assay of apolipoprotein (apo) A-I, the major protein constituent of high-density lipoproteins (HDL). We determined the reference ranges of plasma apo A-I concentration for white men and women and related these values to the risk of coronary heart disease (CHD). The mean between-run CV for this assay was 2.9%. As determined with individuals participating cycle 4 of the Framingham Offspring Study, the mean (+/- SD) apo A-I concentration was 13% lower in 1879 men (1.34 +/- 0.23 g/L) than in 1939 women (1.54 +/- 0.28 g/L) (P&lt;0.001). An apo A-I concentration of 1.20 g/L roughly corresponded to the 25th percentile value in men and the 5th percentile in women, and subjects with a concentration below this value were significantly more likely to have CHD than subjects wit a higher concentration (P&lt;0.001).

Human apolipoprotein A-I: structure determination and analysis of unusual diffraction characteristics

1999 ◽  
Vol 55 (12) ◽  
pp. 2013-2021 ◽  
Author(s):  
David W. Borhani ◽  
Jeffrey A. Engler ◽  
Christie G. Brouillette
Keyword(s):  
Structure Determination ◽  
Density Lipoprotein ◽  
High Density ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Data Set ◽  
Cholesterol Acyl Transferase ◽  
Cell Parameters ◽  
Human Apolipoprotein ◽  
Apolipoprotein A

The crystallization and structure determination of recombinant human apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, is described. The fragment crystallized, residues 44–243 of native apo A-I [apo Δ(1–43)A-I], is very similar to intact native apo A-I in its ability to bind lipid, to be incorporated into high-density lipoproteins and to activate lecithin–cholesterol acyl transferase. Apo Δ(1–43)A-I crystallizes from 1.0–1.4 M sodium citrate pH 6.5–7.5 in space group P212121, with unit-cell parameters a = 97.47, b = 113.87, c = 196.19 Å (crystal form I). The crystals exhibit unusual diffraction intensity spikes and axial extinctions that are discussed in the context of the 4 Å crystal structure. When flash-cooled to 100 K, the crystals diffract synchrotron radiation to 3 Å resolution. Radiation sensitivity and crystal-to-crystal variation have hindered the assembly of a complete 3 Å data set.

Abstract 156: Development of a New Bioactivatable Fluorescent Probe for the Study of the Proteolytic Activities Degrading Apolipoprotein A-I in vitro and in vivo

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Foued Maafi ◽  
Baoqiang Li ◽  
Catherine Gebhard ◽  
Mathieu Brodeur ◽  
Louis Villeneuve ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
Protease Inhibitors ◽  
Near Infrared ◽  
Ex Vivo ◽  
Fold Increase ◽  
High Density Lipoproteins ◽  
Apolipoprotein A ◽  
Proteolytic Activities

Introduction and Objective: The possible benefits of high-density lipoproteins (HDL) against atherosclerosis have been largely attributed to its major protein component, apolipoprotein A-I (apoA-I). However, apoA-I can be degraded by diverse processes, including proteases localized in atherosclerotic plaques, which could reduce the effectiveness of HDL-based therapies. Here we describe the development of a new bioactivatable near-infrared apoA-I-Cy5.5 fluorescent probe and its initial use in the assessment of proteolytic activities that degrade apoA-I in vitro, in vivo and ex vivo. Methods and Results: Fluorescence emission of our probe is quenched by saturation of Cy5.5 fluorophore molecules on the full-length apoA-I protein. In vitro proteolysis of the apoA-I probe showed up to 11-fold increase of near-infrared fluorescence (n=5, P ≤ 0.05). Using this apoA-I-Cy5.5 probe, we were able to quantify proteolytic activities from a wide range of proteases targeting serine (chymase), cysteine (cathepsin S) and metalloproteases (MMP-12). Also, we detected activation of the apoA-I-Cy5.5 probe on aortic cryosections from Ldlr-/--Tg for human apoB atherosclerotic (ATX) mice using an in situ zymography assay and observed that broad-spectrum protease inhibitors protect the probe from protease activities, as shown by decreased fluorescence compared to conditions without protease inhibitors (-54%, n= 6 per group, P ≤ 0.001). In vivo, using a combined Fluorescence Molecular Tomography-Magnetic Resonance imaging system, the injected probe exhibited a trend for increased fluorescence in the aorta when infused in ATX mice compared to C57BL/6J wild-type mice. Ex vivo imaging of these aortas showed a 10-fold increase of fluorescence in ATX (n=5) mice compared to CTL (n=3) mice (P ≤ 0.05). Conclusion: Given the potential importance of HDL functionality in the assessment of cardiovascular risk, this novel protease-activatable apoA-I probe may help to improve HDL-based therapies through better characterization of the alterations of functionality of apoA-I or lipid-poor HDL particles in different pathophysiological settings.

scholarly journals The Mechanism of Bisphenol A Atherogenicity Involves Apolipoprotein A-I Downregulation through NF-κB Activation

2019 ◽  
Vol 20 (24) ◽  
pp. 6281
Author(s):  
Violeta G. Trusca ◽  
Madalina Dumitrescu ◽  
Ioana M. Fenyo ◽  
Irina F. Tudorache ◽  
Maya Simionescu ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Hdl Cholesterol ◽  
Dna Interaction ◽  
Inhibitory Effect ◽  
Environmental Chemicals ◽  
High Density Lipoproteins ◽  
Major Protein ◽  
Dependent Manner ◽  
Atherosclerotic Lesions ◽  
Apolipoprotein A

Apolipoprotein A-I (apoA-I) is the major protein component of high-density lipoproteins (HDL), mediating many of its atheroprotective properties. Increasing data reveal the pro-atherogenic effects of bisphenol A (BPA), one of the most prevalent environmental chemicals. In this study, we investigated the mechanisms by which BPA exerts pro-atherogenic effects. For this, LDLR−/− mice were fed with a high-fat diet and treated with 50 µg BPA/kg body weight by gavage. After two months of treatment, the area of atherosclerotic lesions in the aorta, triglycerides and total cholesterol levels were significantly increased, while HDL-cholesterol was decreased in BPA-treated LDLR−/− mice as compared to control mice. Real-Time PCR data showed that BPA treatment decreased hepatic apoA-I expression. BPA downregulated the activity of the apoA-I promoter in a dose-dependent manner. This inhibitory effect was mediated by MEKK1/NF-κB signaling pathways. Transfection experiments using apoA-I promoter deletion mutants, chromatin immunoprecipitation, and protein-DNA interaction assays demonstrated that treatment of hepatocytes with BPA induced NF-κB signaling and thus the recruitment of p65/50 proteins to the multiple NF-κB binding sites located in the apoA-I promoter. In conclusion, BPA exerts pro-atherogenic effects downregulating apoA-I by MEKK1 signaling and NF-κB activation in hepatocytes.

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