Glycosphingolipid-associated β-1,4 galactosyltransferase is elevated in patients with systemic lupus erythematosus

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Abstract

Objective

β-1,4 galactosyltransferase-V (β-1,4 GalT-V) is an enzyme that synthesises a glycosphingolipid known as lactosylceramide, which has been implicated in general inflammation and atherosclerosis. We asked if β-1,4 GalT-V was present at elevated levels in patients with SLE, a disease which is associated with increased risk of atherosclerosis.

Methods

In this case–control observational study, serum samples were obtained from patients with SLE who are part of the Johns Hopkins Lupus Cohort. Control serum samples were obtained from healthy adult community members recruited from the Baltimore area. All serum samples (n=50 in the SLE group and n=50 in the healthy control group) were analysed with enzyme-linked immunoassays. These assays used antibodies raised against antigens that enabled us to measure the absorbance of oxidised phosphocholines per apolipoprotein B-100 (ox-PC/apoB) and the concentration of lipoprotein(a) (Lp(a)) and β-1,4 GalT-V.

Results

Absorbance of ox-PC/apoB and concentrations of Lp(a) and β-1,4 GalT-V were significantly higher in the SLE serum samples as compared with the control serum (p<0.0001).

Conclusions

We conclude that patients with SLE have elevated levels of β-1,4 GalT-V and ox-PC, which have previously been recognised as risk factors for atherosclerosis.

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Most cited references 34

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The bimodal mortality pattern of systemic lupus erythematosus.

M A Bookman, Vernita Gordon, Murray B. Urowitz … (1976)

The changing pattern of mortality in systemic lupus erythematosus (SLE) led to an examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit. During the follow-up 11 patients died; six patients died within the first year after diagnosis (group I) and five patients died an average of 8.6 years (from 2.5 to 19.5 years) after diagnosis (group II). In those who died early, the SLE was active clinically and serologically, and nephritis was present in four. Their mean prednisone dose was 53.3 mg/day. In four patients a major septic episode contributed to their death. In those who died late in the course of the disease, only one patient had active lupus and none had active lupus nephritis. Their mean prednisone dose was 10.1 mg/day taken for a mean of 7.2 years. In none was sepsis a contributing factor to their death. All five of these patients had had a recent myocardial infarction at the time of death; in four, ti was the primary cause of death. Mortality in SLE follows a bimodal pattern. Patients who die early in the course of their disease, die with active lupus, receive large doses of steroids and have a remarkable incidence of infection. In those who die late in the course of the disease, death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.

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Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus.

Michelle Petri, Laurence Magder (2012)

Patients with systemic lupus erythematosus (SLE) are at excess risk of cardiovascular events (CVEs). There is uncertainty regarding the relative importance of SLE disease activity, medications, or traditional risk factors in this increased risk. To gain insight into this, the authors analyzed data from a cohort of 1,874 patients with SLE who were seen quarterly at a single clinical center (April 1987-June 2010) using pooled logistic regression analysis. In 9,485 person-years of follow-up, the authors observed 134 CVEs (rate = 14.1/1,000 person-years). This was 2.66 times what would be expected in the general population based on Framingham risk scores (95% confidence interval: 2.16, 3.16). After adjustment for age, CVE rates were not associated with duration of SLE. However, they were associated with average past levels of SLE disease activity and recent levels of circulating anti-double-stranded DNA. Past use of corticosteroids (in the absence of current use) was not associated with CVE rates. However, persons currently using 20 mg/day or more of corticosteroids had a substantial increase in risk even after adjustment for disease activity. Thus, consistent with findings in several recent publications among cohorts with other diseases, current use of corticosteroids was associated with an increased risk of CVEs. These results suggest a short-term impact of corticosteroids on CVE risk.

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Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.

Sohvi Hörkkö, Michael R. Miller, H Itabe … (1998)

We recently cloned monoclonal IgM autoantibodies which bind to epitopes of oxidized low-density lipoprotein (OxLDL) from apoE-deficient mice (EO- autoantibodies). We now demonstrate that those EO- autoantibodies that were originally selected for binding to copper-oxidized low-density lipoproteins (CuOx-LDL), also bound both to the oxidized protein and to the oxidized lipid moieties of CuOx-LDL. The same EO- autoantibodies showed specific binding to products of oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine (OxPAPC) and to the specific oxidized phospholipid, 1-palmitoyl-2-(5-oxovaleroyl)-phosphatidyl-choline (POVPC), whereas oxidation of fatty acids (linoleic or arachidonic acid) or cholesteryl esters (cholesteryl-oleate or cholesteryl-linoleate) did not yield any binding activity. Those EO- autoantibodies that bound to oxidized phospholipids (e.g., EO6) inhibited the binding and degradation of CuOx-LDL by mouse peritoneal macrophages up to 91%, whereas other IgM EO- autoantibodies, selected for binding to malondialdehyde (MDA)-LDL, had no influence on binding of either CuOx-LDL or MDA-LDL by macrophages. F(ab')2 fragments of EO6 were equally effective as the intact EO6 in preventing the binding of CuOx-LDL by macrophages. The molar ratios of IgM to LDL needed to maximally inhibit the binding varied from approximately 8 to 25 with different CuOx-LDL preparations. Finally, a POVPC-bovine serum albumin (BSA) adduct also inhibited CuOx-LDL uptake by macrophages. These data suggest that oxidized phospholipid epitopes, present either as lipids or as lipid-protein adducts, represent one class of ligands involved in the recognition of OxLDL by macrophages, and that apoE-deficient mice have IgM autoantibodies that can bind to these neoepitopes and inhibit OxLDL uptake.

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Author and article information

Journal

Journal ID (nlm-ta): Lupus Sci Med

Journal ID (iso-abbrev): Lupus Sci Med

Journal ID (hwp): lupusscimed

Journal ID (publisher-id): lupus

Title: Lupus Science & Medicine

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2053-8790

Publication date Collection: 2020

Publication date (Electronic): 13 July 2020

Volume: 7

Issue: 1

Electronic Location Identifier: e000368

Affiliations

[1 ]departmentDepartment of Pediatrics , Johns Hopkins University , Baltimore, Maryland, USA

[2 ]departmentDivision of Rheumatology , Johns Hopkins University School of Medicine , Baltimore, Maryland, USA

[3 ]departmentHeart and Vascular Institute , Johns Hopkins University School of Medicine , Baltimore, Maryland, USA

[4 ]departmentLancaster General Health Physicians , Penn Medicine , Lancaster, Pennsylvania, USA

[5 ]departmentDivision of Pediatric Cardiology , Johns Hopkins University School of Medicine , Baltimore, Maryland, USA

Author notes

[Correspondence to ] Dr Subroto Chatterjee; schatte2@ 123456jhmi.edu

Author information

Vignesh Sadras http://orcid.org/0000-0002-3202-4483

Michelle A Petri http://orcid.org/0000-0003-1441-5373

Article

Publisher ID: lupus-2019-000368

DOI: 10.1136/lupus-2019-000368

PMC ID: 7359192

PubMed ID: 32665303

SO-VID: 4fea406e-7afb-4cf6-8b91-c90e48894d21

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 27 October 2019

Date revision received : 30 May 2020

Date accepted : 04 June 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: PO-1 HL-107153

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: RO1-AR43727

Award ID: RO1-AR69572

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Keywords: systemic lupus erythematosus,atherosclerosis,lipids,inflammation

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Keywords: systemic lupus erythematosus, atherosclerosis, lipids, inflammation

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Glycosphingolipid-associated β-1,4 galactosyltransferase is elevated in patients with systemic lupus erythematosus

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Abstract

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Cures Within Reach: Autoimmune Lymphoproliferative Syndrome (ALPS)

Most cited references 34

The bimodal mortality pattern of systemic lupus erythematosus.

Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus.

Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.

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