Page 974 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 69 Inflammation and Atherothrombosis 941

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local sites of inflammation. Nevertheless, ACS patients have a 22 (PTPN22). This enzyme plays a key role in controlling the
lower induction of Treg after TCR stimulation with anti-CD3 intensity of the early TCR signal transduction acting on LCK and
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and anti-CD28 antibodies. Notably, the defective TCR-induced on Zap70.
Treg generation is partially recovered 1 year after the index event,
suggesting a transient phenomenon present during the acute PLAQUE FISSURE WITHOUT SYSTEMIC
phase of the disease. Thus defects in the Treg compartment might INFLAMMATION
affect the plaque stability by impairing a balanced immune
response in atherosclerosis. Indeed, Treg have been implicated When plaque fissure occurs without systemic inflammatory activa-
in the inhibition of effector T cells, in the suppression of endo- tion, other mechanisms, including emotional and physical stress or
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thelial and macrophage activation, and in the modulation of changes in plaque composition, may play a pathogenic role. The
cholesterol metabolism. ability of systemic stress to induce plaque fissure might be related
to sympathetic nervous system activation and catecholamine
B Cells release associated with increased heart rate, increased blood
The contribution of B cells in autoimmunity is well recognized. pressure, and coronary vasoconstriction. Besides the fissuring of
The function of B cells has been evaluated in various animal vulnerable plaque, these conditions favor platelet activation, hyper-
models of atherosclerosis; B1a cells and their secretion of IgM coagulability, and intense coronary microvascular constriction.
seem to mediate the protective effects of B cells, whereas B2 cells It has been demonstrated that the highest shear stress is present
are proatherogenic through modulation of T cell–dependent at the level of the shoulder region of the fibrous cap. Changes
mechanisms. in plaque composition may be another possible cause of plaque
Moreover, antibodies against several oxidation-specific epitopes fissure. Indeed local changes in pH, temperature, cholesterol
of low-density lipoprotein and other atherosclerosis-related saturation, and hydration promote cholesterol crystallization in
antigens are found in animals and humans, both in the circulation the lipid core associated with quick volume expansion, potentially
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and in atherosclerotic plaques. The mechanisms by which these causing plaque fissure and thrombosis. These mechanisms may be
antibodies act remain unclear, and it is unresolved whether they amplified by crystallization of free cholesterol from erythrocyte
represent an epiphenomenon of chronic immune stimulation membranes when intraplaque hemorrhage occurs.
or a disease-specific phenomenon.
PLAQUE EROSION
TCR Signaling Alteration in ACS
The first step in lymphocyte activation is TCR binding of specific Plaque Erosion: Pathological Findings
peptides presented by APC. TCR triggering initiates a cascade Plaque erosion is associated with coronary instability in about
of phosphorylation events that culminate in the activation and one-third of patients. Eroded plaques are characterized by
nuclear translocation of transcription factors (Chapter 12). A thrombus formation at the site of a denuded fibrous atheroscle-
complex molecular coordination is required, including positive rotic plaque. Endothelial denudation leads to the exposure of
and negative feedback loops necessary to avoid lymphocyte hyper- the intima that often shows a pathological thickening and consists
reactivity and the breaking of immune tolerance. The proper predominantly of vascular smooth muscle cells and proteoglycans,
tuning of TCR signaling is critical also for T-cell differentiation. heavily glycosylated proteins able to form large complexes by
Indeed, in addition to the cytokine environment, the induction binding other proteoglycans, hyaluronan, and collagen. There
of different T-helper cell lineages is driven by TCR-mediated are no pathognomonic features to identify plaque erosion. An
signal strength. eroded plaque in a histological specimen is recognized when
CD4 T cells from ACS patients show enhanced response to serial sectioning of thrombosed arterial segments fails to reveal
TCR stimulation and have a lower setting of the T-cell activation plaque rupture. Compared with plaque fissure, which typically
threshold, attributable to enhanced amplification of proximal has a large lipid pool, plaque erosion shows intact internal and
TCR-mediated signals. 23,25 Intriguingly, some of these abnormali- external elastic laminas and a well-developed media (unlike
ties are confined to the acute phase of ACS, whereas others persist plaque rupture, where the internal lamina is often disrupted and
also during the stable phase of the disease, suggesting the existence the underlying media is thin and disorganized), rare calcifications,
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of chronic lymphocyte hyperreactivity. and a lower grade of inflammation. There is still no agreement
The molecular TCR signaling alterations observed in ACS on the grade of luminal obstruction related to plaque erosion
include an increase in the positive activation signals, including because some groups have demonstrated that eroded plaques
higher accumulation of CD3 complexes and zeta-chain associated are less obstructive than ruptured plaques with thrombosis, and
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protein kinase of 70 kD (Zap70) in the immunological synapse others report the opposite (Fig. 69.4).
during antigen presentation; higher early tyrosine phosphoryla- The detection of eroded plaques by OCT is based upon
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tion after TCR stimulation; and a defective deactivation of the exclusion criteria. Similar to histological detection, OCT con-
lymphocyte-specific protein tyrosine kinase (LCK). On the other firmation of plaque erosion derives from the absence of fibrous
hand, ACS patients exhibit reduced activity of the inhibitory cap discontinuation after intraluminal thrombi aspiration. It is
molecular patterns such as reduced phosphorylation of Zap70 not always possible to obtain a proper distinction between fissured
at its inhibitory residue Tyr-292, a residue implicated in TCR and eroded plaque by imaging, and it is even more challenging
deactivation; lower expression of PECAM-1, a molecule implicated to distinguish erosion-prone plaques from stable plaques.
in downmodulation of T cell activity; and reduced activation
of CREB, a transcription factor believed to be particularly Mechanisms of Plaque Erosion
important for the generation and maintenance of Treg and for Several studies have highlighted the high frequency of ACS
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IL-2 and IL-10 production. Finally, ACS patients show enhanced associated with plaque erosion in women and in young persons,
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expression of the protein tyrosine phosphatase non–receptor type mostly after stressful events and possibly reflecting acute changes