Cardiovascular Research 2002 56(2):178-180; doi:10.1016/S0008-6363(02)00652-1
© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Chlamydia pneumoniae inside the atherosclerotic plaque—does it affect plaque inflammation and plaque progression?
Allard C van der Wal*
Department of Cardiovascular Pathology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
* Tel.: +31-20-566-5633; fax: +31-20-691-4738. a.c.vanderwal{at}amc.uva.nl
Received 27 August 2002; accepted 28 August 2002
See article by Ezzahiri et al. [5] (pages 269–276) in this issue.
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1. Introduction
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Exposure to
Chlamydia pneumoniae (Cp) is very common among the
human population world-wide. Circa 50% of adults bear antibodies
to Cp and re-infections occur frequently: most people have 2–3
infections in a lifetime
[1]. In Cardiovascular Medicine, interest
for such a common opportunistic agent was initiated by insights
in seroepidemiologic associations between Cp infection and the
risk of atherosclerotic vascular disease, myocardial infarction
and stroke
[2]. Atherosclerosis has recently been classified
as a chronic inflammatory disease
[3], so potentially the disease
could indeed be initiated or modulated by infectious agents.
Still, despite numerous clinical and pathological observations
that suggest a link between Cp infection and atherosclerosis
(
Table 1), the underlying pathophysiological mechanisms are
far from elucidated. Is Cp infection capable of initiating atherosclerosis
or has it only a contributory role superimposed on effects of
classical risk factors? Does systemic Cp infection affect plaque
growth/thrombosis through circulating proinflammatory molecules
(cytokines, acute phase proteins) or is Cp itself pathologically
active inside the atherosclerotic plaque? And, is this of clinical
relevance at all? An unsolved issue derived from these questions
is whether or not Cp, invading the plaque in parasitized mononuclear
cells, could influence the inflammatory response inside atherosclerotic
lesions. An item of clinical importance also, since plaque inflammation
increases the risk of plaque disruption, and hence thrombotic
occlusion of the vessel
[4].
In this issue of
Cardiovascular Research, Ezzahiri et al.
[5] provide interesting insights in this matter by describing increased
T-cell infiltration and increased plaque maturation in Cp-infected
hypercholesterolemic mice.
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2. Chlamydia pneumoniae infection and plaque inflammation
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The authors investigated atherosclerotic plaque inflammation
in hypercholesterolemic (fat fed Apo E3 Leiden) mice exposed
to Cp infection, which was visualised by quantifying the numbers
of infiltrated CD4 immunopositive T-lymphocytes in lesions.
Mice were infected twice, plaque composition was evaluated at
different time intervals up to 9 months post infection and compared
with mock-infected Apo E3 Leiden mice at each time point. Infection
resulted in a significant increase in T-cell infiltration (0.29
cells/µm
2 in mock infected mice vs. 2.63 cells/µm
2 in Cp-infected mice) only in the early stages of infection,
whereas at later stages (after 6 months) no substantial effect
on the influx of T cells was noticed. In addition Cp was detected
immunocytochemically in the subendothelial areas of about 30%
of investigated plaques. Do these findings indicate that Cp
infection initiates plaque inflammation? Not likely, since both
in animals and in humans adequate serum levels of atherogenic
lipids are required to produce something like a fatty streak
or an atherosclerotic plaque with a lipid core. Lesions that
are basically inflammatory in nature
[3], also in the absence
of Cp. And moreover, in
normocholesterolemic mice Cp infection
leads to inflammatory changes in blood vessels but no evidence
of atherosclerotic plaque formation can be found
[6]. Still,
an aggravating effect on plaque inflammation, which is concluded
from this study, should be considered of equal importance. The
current belief is that plaque progression is an episodic rather
than a continuous process. Multiple infections (2–3 in
a life time) therefore, could implicate several episodes of
increased T-cell infiltration and associated remodelling of
the plaque composition (see below). A feature of Cp is their
persistence in tissues; the bacterial antigens remain accessible
to immune competent cells and are capable of sustaining inflammation
for at least 4 weeks
[7]. The inflammatory response in some
but not all human plaques bears immune memory for
Chlamydia antigens. T-cell lines raised from symptomatic carotid artery
plaques in our laboratory showed antigenic specificity for Chlamydial
antigens in circa 50% of plaques (all derived from different
patients)
[8]. This indicates that plaques in a subpopulation
of patients are at least suitable for Cp-mediated inflammation.
The point of view that Cp infection (among other inflammatory
triggers) indeed may contribute to plaque inflammation is supported
by several recently published observations. Increased numbers
of activated plaque T cells
[9], circulating Cp-positive T cells
[10] and Cp-containing plaque tissue
[11] have all been detected
in blood and symptomatic plaques of patients with ischemic coronary
syndromes.
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3. Chlamydia pneumoniae infection and plaque progression
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In human atherosclerosis, the progression and maturation of
lesions can be graded histomorphologically according to the
American Heart Classification of lesions. Ezzahiri et al.
[5] extrapolated this classification to the situation in mice and
systematically graded lesion morphology, in order to compare
plaque progression in mock-infected and Cp-infected mice at
different time intervals post infection (p.i.). Cp-infected
mice showed a significant shift towards more lesions with a
lipid core (type IV) at 6 months p.i. and more lesions with
a fibrous cap (type V) at 9 months p.i. when compared with mock-infected
mice. This suggests that infection indeed has accelerated the
process of plaque maturation towards a more complex morphology.
Although still speculative, but supported by lots of experimental
work on plaque cells previously published
[3,12], the secretory
products of activated immune cell could be held responsible
for this effect. Unfortunately, the authors did not further
explore whether T cells expressed activation antigens such as
CD40 ligand or interleukin 2 receptors, of pivotal importance
since only activated T cells modulate the plaque morphology
through a burst of cytokine production.
Finally, the extent of plaque formation was evaluated by means of planimetric quantification of lesional areas in the aortic arch of all mice, but no effects of Cp infection on lesion number and size of plaques could be detected. This seems to be a controversial point, since some investigators also did not notice any significant differences in lesion size between infected and control animals, whereas others reported accelerated plaque growth after infection with Cp (see discussion of Ezzahiri et al. [5] for references). The authors assume that, apart from differences in infection protocols and time intervals of data analysis, also species specific features could provide an explanation for such divergent results. This might indeed be valid, but at the same time raises the question how these data relate to the situation in human atherosclerosis, particularly when plaque growth comes into the discussion. Mice and men share many pathogenetic mechanisms of plaque formation, such as inflammation, lipid accumulation, SMC hyperplasia, and a fibrotic response, but the lesions in both species look morphologically different. And notably, disrupted and thrombosed plaques are extremely rare in aortas of hyperlipidemic mice, and were not found in the present study with CP-infected mice.
Nonetheless, despite these limitations, the present work provides another step forward in the intriguing possibility that a widespread opportunistic pathogen, Cp, will be capable of maintaining or accelerating plaque inflammation, in combination with hypercholesterolemia (Table 2).
View this table:
[in this window]
[in a new window]
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Table 2 Areas of research implicating evidence for a role of chlamydia infection in atherosclerotic plaque inflammation
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References
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- Ngeh J., Gupta S. Chlamydia pneumoniae and atherosclerosis—what we know and what we don’t. Clin Microbiol Infect (2002) 8:2–13.[CrossRef][Web of Science][Medline]
- Saikku P., Leinonen M., Matilla K., et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet (1988) 2:983–986.[Web of Science][Medline]
- Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med (1999) 340:1269–1276.[Free Full Text]
- Van der Wal A.C., Becker A.E. Plaque rupture—pathologic basis of plaque stability and instability. Cardiovasc Res (1999) 41:334–344.[Free Full Text]
- Ezzahiri R., Nelissen-Vrancken H.J.M.G., Kurvers H.A.J.M., Stassen F.R.M., Vliegen I., Grauls G.E.L.M., van Pul M.M.L., Kitselaar P.J.E.H.M., Bruggeman C.A. Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates formation of complex lesions in Apo E3-Leiden mice. Cardiovasc Res (2002) 56:269–276.[Abstract/Free Full Text]
- Blessing E., Lin T.M., Campbell L.A., et al. Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice. Infect Immun (2000) 68:4765–4768.[Abstract/Free Full Text]
- King L.E., Stratton C.W., Mitchell W.M. Chlamydia pneumoniae in chronic skin wounds: a focused review. J Invest Dermatol Proc (2001) 6:233–237.[CrossRef]
- De Boer O.J., van der Wal A.C., Houtkamp M.A., et al. Unstable atherosclerotic plaques contain T-cells that respond to Chlamydia pneumoniae. Cardiovasc Res (2000) 48:402–408.[Abstract/Free Full Text]
- Van der Wal A.C., Piek J.J., de Boer O.J., et al. Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes. Heart (1998) 80:14–18.[Abstract/Free Full Text]
- Kaul R., Uphoff J., Yadlapalli S., Wenman W.M. Detection of Chlamydia pneumoniae DNA in CD3+ lymphocytes from healthy blood donors and patients with coronary artery disease. Circulation (2000) 102:2341–2346.[Abstract/Free Full Text]
- Muhlestein J.B., Hammond E.H., Carlquist J.F., et al. Increased incidence of chlamydia species within the coronary arteries of patient with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol (1996) 27:1555–1561.[Abstract]
- Libby P. Current concepts of the pathogenesis of acute coronary syndromes. Circulation (2001) 104:365–372.[Free Full Text]
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1. Introduction
2. Chlamydia pneumoniae...