Endothelial progenitor cells are differentially impaired in ANCA-associated vasculitis compared to healthy controls

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Abstract

Background

Endothelial progenitor cells (EPC) are of major importance in vascular repair under healthy circumstances. Vascular injury in need of repair occurs frequently in ANCA-associated vasculitis (AAV). A specialized T cell subset enhancing EPC function and differentiation has recently been described. These angiogenic T cells (T _ang) may have an important impact on the vascular repair process. Therefore, the aim of our study was to investigate EPC and T _ang in AAV.

Methods

Fifty-three patients suffering from AAV and 29 healthy controls (HC) were enrolled in our study. Forty-four patients were in remission, nine patients were in active state of disease. Patients were either untreated or were under monotherapy with low-dose steroids (max. 5 mg/day) at the time of sampling. Circulating EPC and T _ang were determined by flow cytometry (FACS). The functional capacity of EPC was assessed by established cell culture methods.

Results

Circulating EPC were significantly decreased in AAV as compared to HC. The capacity of EPC to differentiate and proliferate was differentially impaired in patients as compared to HC. The outgrowth of endothelial colony-forming cells (ECFC) was severely decreased in patients whereas colony-forming units-endothelial cell (CFU-EC) outgrowth was unaffected. ECFC and CFU-EC differentiation was strictly T cell-dependent. Patients with a relapsing disease course had an impaired ECFC outgrowth and expansion of T _ang as compared to patients with a stable, nonrelapsing disease.

Conclusions

The differentiation process of EPC is impaired in AAV. This may favor insufficient vascular repair promoting a relapsing disease course. Finally, these factors may explain a higher cardiovascular morbidity as has been previously documented in AAV.

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Most cited references 24

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The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.

Ronald L Calabrese, Blair Leavitt, A Fauci … (1990)

Criteria for the classification of Wegener's granulomatosis (WG) were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis. For the traditional format classification, 4 criteria were selected: abnormal urinary sediment (red cell casts or greater than 5 red blood cells per high power field), abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these 4 criteria was associated with a sensitivity of 88.2% and a specificity of 92.0%. A classification tree was also constructed with 5 criteria being selected. These criteria were the same as for the traditional format, but included hemoptysis. The classification tree was associated with a sensitivity of 87.1% and a specificity of 93.6%. We describe criteria which distinguish patients with WG from patients with other forms of vasculitis with a high level of sensitivity and specificity. This distinction is important because WG requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone.

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Cardiovascular disease in autoimmune rheumatic diseases.

Ivana Hollan, Pier Meroni, Joseph Ahearn … (2013)

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA). Ischemic events in APA are more likely to be caused by pro-thrombotic state than by enhanced atherosclerosis. Cardiovascular disease (CVD) in ARDs is caused by traditional and non-traditional risk factors. Besides other factors, inflammation and immunologic abnormalities, the quantity and quality of lipoproteins, hypertension, insulin resistance/hyperglycemia, obesity and underweight, presence of platelets bearing complement protein C4d, reduced number and function of endothelial progenitor cells, apoptosis of endothelial cells, epigenetic mechanisms, renal disease, periodontal disease, depression, hyperuricemia, hypothyroidism, sleep apnea and vitamin D deficiency may contribute to the premature CVD. Although most research has focused on systemic inflammation, vascular inflammation may play a crucial role in the premature CVD in ARDs. It may be involved in the development and destabilization of both atherosclerotic lesions and of aortic aneurysms (a known complication of ARDs). Inflammation in subintimal vascular and perivascular layers appears to frequently occur in CVD, with a higher frequency in ARD than in non-ARD patients. It is possible that this inflammation is caused by infections and/or autoimmunity, which might have consequences for treatment. Importantly, drugs targeting immunologic factors participating in the subintimal inflammation (e.g., T- and B-cells) might have a protective effect on CVD. Interestingly, vasa vasorum and cardiovascular adipose tissue may play an important role in atherogenesis. Inflammation and complement depositions in the vessel wall are likely to contribute to vascular stiffness. Based on biopsy findings, also inflammation in the myocardium and small vessels may contribute to premature CVD in ARDs (cardiac ischemia and heart failure). There is an enormous need for an improved CVD prevention in ARDs. Studies examining the effect of DMARDs/biologics on vascular inflammation and CV risk are warranted.

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Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies.

Dae-Hyun Kim, Han Park, Sun Jin Hur … (2007)

The colony number of early endothelial progenitor cells (EPCs) has been used as a quantitative indicator of the number of EPCs in the blood or as a biological marker of cardiovascular diseases. In the present study, we found a subset of T cells that were localized at the center of the EPC colony and played a pivotal role in colony formation and differentiation of early EPCs. We found that CD3+ CD31+ CXCR4+ T cells (referred to as angiogenic T cells in the present study) constituted the center of EPC colonies during cultures of human peripheral blood mononuclear cells. These angiogenic T cells were required for colony formation and differentiation of early EPCs. They secreted high levels of angiogenic cytokines such as vascular endothelial growth factor, interleukin-8, and matrix metalloproteinases. Angiogenic T cells showed superior angiogenic potential to the other subset of T cells in the experiments with regard to Matrigel tube formation, adhesion, transendothelial migration, and collagen invasion assay, mainly through the stromal cell-derived factor 1/CXCR-4 axis. Furthermore, angiogenic T cells enhanced endothelial cell proliferation and function. In vivo study showed that angiogenic T cells play an important role in the process of vessel formation. Clinical study showed that the level of angiogenic T cells in the peripheral blood was well correlated with EPC colony numbers and had inverse relationships with age and the number of risk factors for coronary artery disease. These findings suggest that angiogenic T cells could be a potential therapeutic target for ischemic cardiovascular diseases.

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Author and article information

Contributors

J. W. Cohen Tervaert: +31-(0)43-3881435 , jw.cohentervaert@maastrichtuniversity.nl

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 23 June 2016

Publication date PMC-release: 23 June 2016

Publication date (Print): 2016

Volume: 18

Electronic Location Identifier: 147

Affiliations

[ ]Immunology, Maastricht University, PO Box 5800, 6202 AZ Maastricht, The Netherlands

[ ]Department of Nephrology, University Duisburg-Essen, University Hospital Essen, Essen, Germany

[ ]Department of Neurology, University Hospital Maastricht, Maastricht, The Netherlands

[ ]Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands

[ ]Department of Infectious Diseases, University Duisburg-Essen, University Hospital Essen, Essen, Germany

Article

Publisher ID: 1044

DOI: 10.1186/s13075-016-1044-8

PMC ID: 4918016

PubMed ID: 27338585

SO-VID: 084538c7-6d63-41a3-8f0b-7f0f0b38dc2d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 February 2016

Date accepted : 6 June 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002997, Nierstichting;

Award ID: KBAO.08.0003

Award Recipient : J. W. Cohen Tervaert

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: WI 3723/1-1

Award Recipient : B. Wilde

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ScienceOpen disciplines: Orthopedics

Keywords: endothelial progenitor cells,autoantibodies,vasculitis

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ScienceOpen disciplines: Orthopedics

Keywords: endothelial progenitor cells, autoantibodies, vasculitis

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Endothelial progenitor cells are differentially impaired in ANCA-associated vasculitis compared to healthy controls

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Abstract

Background

Methods

Results

Conclusions

Related collections

Orthopedics

Most cited references 24

The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.

Cardiovascular disease in autoimmune rheumatic diseases.

Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies.

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Cited by 6

Most referenced authors 749