Rheumatology 2008 47(Supplement 5):v14-v15; doi:10.1093/rheumatology/ken279
© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The microvascular endothelium in scleroderma
B. Kahaleh1
1Division of Rheumatology and Immunology, University of Toledo College of Medicine, Toledo, OH, USA.
Correspondence to: B. Kahaleh, Division of Rheumatology and Immunology, University of Toledo College of Medicine, 3120 Glendale Ave., Toledo, OH 43617, USA. E-mail: bashar.kahaleh{at}utoledo.edu
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Abstract
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Vascular endothelial injury in SSc leads to a host of pathological
changes in the blood vessels that adversely impact the physiology
of many organ systems and eventually results in a state of chronic
tissue ischaemia. Current hypotheses in SSc vascular disease
pathogenesis suggest a possible infectious or chemical trigger(s)
that activates both cellular and humoral immunity. Products
of immune activation may lead to vascular injury possibly through
the production of autoantibodies and the release of products
of activated T cells that can directly damage the endothelium.
Knowledge of the initial trigger of immune activation in SSc
may offer an opportunity to develop a multiple step strategy
for therapeutic intervention.
KEY WORDS: Scleroderma, Scleroderma vascular disease, Endothelial cells, Raynaud's phenomenon, Endothelial apoptosis, Cytomegalovirus, Anti-endothelial antibodies
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Introduction
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The endothelium normally exists as a continuous monolayer connected
with its closely apposed basal lamina. It is functionally remarkable
in regulating coagulation and fibrinolysis, permeability, vasoreactivity
and cellular metabolism and nutrition.
The microvascular endothelium in SSc is severely damaged, basal laminae are usually thickened and reduplicated, and a vast number of capillaries are missing and obliterated with remarkable absence of new vessel formation. Microvascular endothelial cell (MVEC) injury and apoptosis is a central event in the pathogenesis of SSc vasculopathy that leads to microcirculatory dysfunction and eventual organ failure. Microvascular dysfunction is prominent in the early stages of the disease and progressively worsens as the disease progresses. The dysfunction is manifested by increased permeability and dysregulated control of vascular tone that is clinically best illustrated by the puffy hand stage and by RP. An imbalance in endothelial vascular signals with increased endothelin production and impaired nitric oxide and prostacyclin release mediates the vasospasm and contribute to intimal proliferation and vascular fibrosis and stiffness of the vessel wall. Platelet activation and enhanced coagulation with reduced fibrinolysis lead to fibrin deposits and contribute to the intimal proliferation and luminal narrowing.
MVEC apoptosis may also activate the immune-inflammatory system by dendritic cells and macrophage presentation of self-antigen present in the apoptotic debris to CD8+ T cells [1], and by the direct activation of the alternate complement and coagulation cascades leading to microvascular thrombosis and further vessel compromise [2]. MVEC apoptosis may also confer a state of resistance to apoptosis by the surrounding fibroblasts that may lead to myofibroblast differentiation and tissue fibrotic changes that follow [3]. The mechanism of MVEC apoptosis is not known; however, experimental studies identified multiple pathways that may lead to apoptosis including viral agents, cytotoxic T cells, antibody-dependent cellular cytotoxicity, anti-endothelial antibodies and ischaemia–reperfusion injury (Table 1).
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Viral triggers
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A human Cytomegalovirus (hCMV) instigated process that may lead
to MVEC apoptosis is suspected in SSc because of increased levels
of antibodies to this virus and because of its known association
with vascular intimal proliferation and vasculopathy in graft
rejection and coronary artery bypass restenosis. The evidence
suggests that in SSc, some anti-topoisomerase I antibodies recognize
the epitope—VTLGGAGIWLPP—contained within the hCMV-derived
UL94 protein, which is homologous to the highly expressed MVEC
surface protein NAG-2 (tetraspan novel antigen-2). Moreover,
affinity-purified anti-UL94 peptide antibodies are shown to
induce MVEC apoptosis
in vitro, suggesting a molecular mimicry
mechanism involvement in MVEC apoptosis [
4,
5].
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Cytotoxic T cell
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Cytotoxic T-cell Involvement in MVEC apoptosis is suggested
by histological and experimental findings in the disease. Thus,
it is known that MVEC apoptosis can result from their interaction
with cytotoxic T cells either by Fas or granzymes/perforin-related
mechanisms. For example, CD4
+ T cells can mediate MVEC apoptosis
by a Fas-related mechanism as seen in cytolytic T cells killing
of vascular endothelium in the rejection reaction, whereas the
granzyme/perforin system mediates apoptosis by the major cytotoxic
cells, the CD8+ T cells, NK and LAK cells. Granzymes gain access
to the cells following cellular membrane damage by perforin.
Involvement of cytotoxic T cells in SSc is suggested by the
presence of a 60 kDa protein in SSc sera that was described
as an
endothelial cytotoxic factor. This factor was characterized
as the granular enzyme, and was detected in the perivascular
spaces in SSc skin biopsies.
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Antibody-dependent cellular cytotoxicity
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Antibody-dependent cellular cytotoxicity of vascular endothelium
is reported in up to 40% of the SSc patients. The effector cells
express Fc receptors and are both non-T cells and non-adherent
T lymphocytes, while the antibody is an IgG with MVEC specificity
that mediate MVEC cytotoxicity via the Fas pathway.
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Anti-endothelial antibodies
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Anti-endothelial cells antibodies (AECAs) are present in 40–50%
of the SSc sera and are mostly of the IgG1 isotype. The antibody
titres correlate negatively with pulmonary diffusion capacity
and positively with pulmonary hypertension and with digital
ischaemic ulcers, suggesting a pathological role in the development
of the vascular disease. Some AECA are reported to induce MVEC
apoptosis independent of the fas–fas ligand pathway. This
is clearly shown in the chicken model of SSc [UCD-200], where
serum transfer into normal chicken embryos results in binding
of antibodies to the microvasculature in the chorioallantoic
membrane in association with endothelial apoptosis [
6]. The
exact identity of the endothelial antigen is not known; however,
a topoisomerase 1 specificity for some AECA has been suggested.
Moreover, SSc sera containing ACAs or anti-topoisomerase I antibodies
can induce MVEC apoptosis in association with increased gene
expression of caspase 3 and the SSc autoantigen fibrillin 1
[
7].
The only published proteomic analysis of endothelial antigen(s) recognized by AECA identified 53 proteins consisting of cytoskeleton proteins, proteins involved in cellular mobility, regulation of apoptosis and senescence as well as proteins implicated in clotting and antigen presentation [8].
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Ischaemia–reperfusion injury
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Ischaemia–reperfusion injury is an inflammatory process
that results from interaction between humoral and cellular components
including the complement, cytokine and the contact-activated
cascades. In general, soon after the start of reperfusion, endothelial
dysfunction of ischaemic vascular bed develops. The initial
endothelial dysfunction appears to be related to adhesion molecule
expression and the recruitment of neutrophils and platelets.
MVEC injury is believed to be mediated by superoxide radicals
formed by endothelial cells and by neutrophils, perhaps via
the hypoxanthine–xanthine oxidase pathway. Superoxide
inhibits the release of nitric oxide, prostacyclin, tissue plasminogen
activator, protein S and heparin sulphate from MVEC leading
to impairment of the vascular tone control and the thrombo-resistance
within the microvasculature. Localized ischaemia–reperfusion
vascular insult as RP may lead to remote vascular dysfunction
as noted in the pulmonary vascular beds after mesenteric ischaemia–reperfusion
[
9]. TGF-β appears to be an important and remarkably effective
protective agent in this setting. TGF-β acts by preserving
endothelial function, particularly in the maintenance of endothelium
derived relaxing factor (EDRF) formation. This observation may
explain the reported enhanced expression of TGF-β in the
vessels of primary and secondary RP [
10].
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Conclusions
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The aetiology and pathogenesis of SSc remain unknown. Nonetheless,
signs of vascular injury and devascularization of involved organs
in association with evidence of profound endothelial dysfunction
are well documented. The fact that the vascular tree, particularly
the microcirculation, is the target tissue in this disease is
now well established. It is likely that the immune process is
aimed at the destruction of microvessels leading to the clinically
recognized state of chronic organ ischaemia. Identification
of the initial vascular trigger of immune stimulation is fundamental
to our understanding of the disease. The impact of vasculopathy
on disease complications is clearly demonstrated by the fact
that most of the successful therapeutic interventions in SSc
are directed at the vascular disease (
Table 2). Still, countless
central issues in the pathogenic process of SSc remain poorly
understood. Issues related to the initial trigger in the disease,
the nature of immune activation, mechanisms of intimal proliferation
and the relationship of vascular injury to tissue fibrosis are
some of the unresolved essential questions.
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Acknowledgements
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Supplement: This paper forms part of the supplement entitled
‘Update in systemic sclerosis’. This supplement
was supported by an unrestricted grant from Encysive.
Disclosure statement: The author has declared no conflicts of interest.
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References
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Submitted 30 April 2008;
Accepted 19 June 2008
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Abstract
Introduction