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Novel immunological mechanisms and factors in systemic lupus erythematosus-related cardiovascular disease

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posted on 2024-09-03, 00:36 authored by Anna Cederholm

Systemic Lupus Erythematosus (SLE) is a clinical syndrome of autoimmune origin. It manifests in diverse clinical and serological patterns and is considered to represent a prototype multisystemic autoimmune disease. The etiopathigenesis of SLE remains incompletely understood. Typical of SLE is a production of an array of multiple autoantibodies, some of which are believed to be causative to the pathogenesis. Antiphospholipid antibodies (aPL), which are associated with arterial and venous thrombosis, are an example.

Cardiovascular disease (CVD), due to an underlying atherosclerosis and atherothrombosis, is the leading cause of death worldwide. Nowadays atherosclerosis is considered to be a chronic inflammatory disease, and evidence is accumulating for important role of immune mechanisms in atherothrombosis. During the last decade it has become evident that the incidence of premature cardiovascular disease is dramatically (up to 50 fold) increased in patients with SLE, emerging as the major cause of morbidity and mortality in this population. The link between manifestations of atherosclerosis/atherothrombosis such as coronary heart disease, ischemic cerebrovascular disease or peripheral arterial disease on the background of a systemic chronic inflammatory autoimmune disorder, such as SLE, is a subject of intensive research interest.

Our group has recently demonstrated that a combination of traditional and non-traditional risk factors including dyslipidemia, renal disease, lipid peroxidation, inflammation, and high levels of aPL characterize SLE-patients with CVD and that CVD in SLE is associated with atherosclerosis. This thesis work is aimed at studying potentially contributing autoimmune/immune mechanisms of atherothrombosis and atherosclerosis, as well as non-traditional risk and protective factors in SLE-related cardiovascular disease.

In the first paper, we study effects of plasma from twenty-six women with SLE and CVD (SLE cases), age-matched women with SLE and no history of CVD (SLE controls) and population controls (PC), on cultured human umbilical vein endothelial cells (HUVEC). We demonstrate that binding of Annexin A5, a plasma protein with putative antithrombotic effects, to HUVEC is significantly lower among SLE cases than SLE controls which in its turn is lower among PC. There were no differences in effects of plasma from the study groups on cell viability or apoptosis. Extraction of IgG from plasma restored Annexin A5 binding. Furthermore, absorption of aPL from plasma restored binding, suggesting that aPL play an important role. We hypothesize that decreased Annexin A5 binding to endothelium caused by aPL may be an important mechanisms causing CVD in SLE. We also demonstrate abundant presence of Annexin A5 within atherosclerotic lesions, especially at plaque sites prone to rupture.

In the second paper, we demonstrate that sera with high aPL titers and also a monoclonal antibody against an important phospholipid, a cardiolipin (aCL-mAb), both caused decreased Annexin A5 binding. Preincubation of intravenous immunoglobulin (IVIG) with high aPL titers plasma or with aCL-mAb restored Annexin A5 binding comparable to that of controls. This suggests that IVIG could play a therapeutic role in atherothrombosis, by neutralizing aPL. Still, when IVIG was added to normal healthy serum or to cell culture per se, a small decrease in Annexin A5 was observed. Recently, several reports have indicated that IVIG has CVD as a side effect in some patients, and our findings suggest a causative mechanism.

In the third paper, we compare emerging CVD risk factors including platelet activating factor (PAF) acetylhydrolase (PAF-AH) and soluble phospholipase A2 (sPLA2); heat shock protein (HSP)-related measurements and antibodies against endothelial cells (aEC-abs). Of all these measurements, only PAF-AH was associated with CVD in SLE. We hypothesize that PAF-AH promotes inflammation and atherosclerosis in SLE.

In the fourth paper endothelial factors in relation to CVD in SLE were studied. Endothelial function, as determined by flow-mediated dilatation (FMD) of the brachial artery, did not differ between SLE controls and population controls, suggesting that endothelial dysfunction and possibly CVD may not be a general feature of SLE but instead affect only a subgroup. This possibility should be further clarified in larger controlled prospective studies. SLE cases were not included since they were on nitro-related medications, precluding the FMD determination. Soluble levels of VCAM-1, and thrombomodulin (TM), both markers of endothelial cell activation/damage, where raised among SLE cases, suggesting that endothelial activation is one contributing factor to SLE-related CVD.

Taken together, in these studies a novel mechanism was demonstrated, namely an aPL-induced decreased binding of antithrombotic protein Annexin A5 to endothelium, that may play an important role in SLE-related CVD. We hypothesize that increasing Annexin A5 binding could represent a novel therapy against atherothrombosis, either by administration of Annexin A5, or by neutralizing aPL when present, with neutralizing antibodies from IVIG. Of note, IVIG may also per se have prothrombotic effects through this mechanism. PAF-acetylhydrolase activity and endothelial cell activation may also play a role in promoting CVD and atherosclerosis in SLE.

List of scientific papers

I. Cederholm A, Svenungsson E, Jensen-Urstad K, Trollmo C, Ulfgren AK, Swedenborg J, Fei GZ, Frostegard J (2005). Decreased binding of annexin v to endothelial cells: a potential mechanism in atherothrombosis of patients with systemic lupus erythematosus. Arterioscler Thromb Vasc Biol. 25(1): 198-203.
https://doi.org/10.1161/01.ATV.0000150415.18759.36

II. Cederholm A, Su J, von Landenberg P, Frostegard J (2006). Effects of IVIG and anticardiolipin antibody on annexin A5 binding to endothelial cells. [Manuscript]

III. Cederholm A, Svenungsson E, Stengel D, Fei GZ, Pockley AG, Ninio E, Frostegard J (2004). Platelet-activating factor-acetylhydrolase and other novel risk and protective factors for cardiovascular disease in systemic lupus erythematosus. Arthritis Rheum. 50(9): 2869-76.
https://doi.org/10.1002/art.20432

IV. Svenungsson E, Cederholm A, Jensen-Urstad K, Fei GZ, de Faire U, Frostegard J (2006). Endothelial function and markers of endothelial activation in relation to cardiovascular disease in sytemic lupus erythematosus. [Submitted]

History

Defence date

2006-04-21

Department

  • Department of Medicine, Huddinge

Publication year

2006

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-679-4

Number of supporting papers

4

Language

  • eng

Original publication date

2006-03-31

Author name in thesis

Cederholm, Anna

Original department name

Department of Medicine at Huddinge University Hospital

Place of publication

Stockholm

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