Page 973 - Clinical Immunology_ Principles and Practice ( PDFDrive )

940 Part seven Organ-Specific Inflammatory Disease

increase in the interactions of platelets and leukocytes and in showing a marked increase in Th1 frequency and increased
the amplification of platelet-derived inflammatory signals. These expression of Th1-related effector molecules such as IFN-γ,
findings highlight the role of platelets as immunological cells, signal transducer and activator of transcription 4 (STAT4), and
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critically participating in both inflammatory and thrombotic T-bet . Th1 cells are suspected of regulating the fragility of the
processes. Indeed, platelet TLR2 and related innate immune fibrous cap as well as the thrombogenic potential of the plaque.
transcripts have been associated with cardiovascular disease and IFN-γ can contribute to plaque destabilization in several ways:
its risk factors. Expression of TLR2 in megakaryocytes suggests by the recruitment and activation of macrophages in the ath-
that inflammatory processes, through TLR2 stimulation, can erosclerotic lesions; by reducing collagen synthesis; by increasing
increase megakaryocyte maturation and can modulate mega- the production of extracellular matrix–degrading proteins; and
karyocyte phenotypes, potentially influencing platelet function by activating APC. Furthermore, increased IFN-γ expression
and thrombosis. induces a positive feed-forward loop of Th1 induction sustaining
a proinflammatory state. When activated in the intima, Th1 cells
Activation of Adaptive Immunity produce proinflammatory cytokines and enhance the expression
In patients with ACS and systemic evidence of inflammation, the of CD40 ligand. Ligation of CD40 on APC by CD40 ligand
higher frequency of activated T cells in comparison to patients induces release of extracellular matrix–degrading metallopro-
with SA suggests that the sudden changes leading to coronary teinases and the expression of tissue factor, a key initiator of the
instability might be related to mechanisms involving T-cell immu- coagulation cascade.
nity. In particular, in ACS patients CD4 T-cell subpopulations
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are dysregulated, and their abnormalities are associated with CD4 CD28 T Cells
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worse outcomes, especially in patients with diabetes mellitus. 16-18 CD4 CD28 T cells are distinct from classic helper T cells in
ACS patients have a skewed T-cell differentiation oriented several aspects. This terminally differentiated subpopulation
toward aggressive effector phenotypes and defective regulatory shows an increased resistance to apoptosis and a wide range of
T cells, suggesting that the lymphocyte compartment fails to proinflammatory properties.
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suppress excessive immune responses. Overall, such T-cell CD4 CD28 T cells are present preferentially in unstable
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abnormalities characterize about half of ACS patients. In this ruptured atherosclerotic plaques, and their frequency significantly
subset of ACS patients, helper T-cell dysregulation might affect increases the risk of ACS, particularly in patients with diabetes. 16-18
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the biological outcome of the immune response and contribute CD4 CD28 T cells from ACS patients show several abnormali-
to plaque destabilization through multiple damaging pathways ties such as the ability to mediate endothelial cytotoxicity by
(Fig. 69.3). triggering the NK stimulatory receptor KIR2DS2, killer Ig-like
T cells physiologically drive B-cell hypersomatic mutation, receptor 2DS2 (KIR2DS2) in the absence of T-cell receptor (TCR)
isotype switch, and affinity maturation in the germinal centers activation and higher levels of costimulatory receptors, e.g., OX40
of lymphoid organs and also in extranodal sites in autoimmune and 4–1BB.
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diseases . Indeed, coronary atherosclerotic plaques obtained by
endoluminal directional atherectomy are sites of B lymphocyte Th17 Cells
proliferation in patients with ACS, strongly suggesting the local Th17 cells are characterized by the expression of retinoid orphan
presence of an activating or recruiting antigen in these lesions receptor (ROR)-γt, the master regulator transcription factor
(Table 69.3). responsible for the production of IL-17.
Although the precise role of IL-17 in atherosclerosis and ACS
T-helper 1 (Th1) Cells remains controversial, experimental studies in mice have
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The importance of Th1 and IFN-γ in atherosclerosis progression provided direct evidence that IL-17 is predominantly proath-
and in plaque destabilization is confirmed by numerous studies erogenic. Indeed, in combination with IFN-γ, IL-17 induces a
proinflammatory response in vascular smooth muscle cells. On
the other hand, Th17 cells are involved in wound healing and
exert powerful fibrogenic activity. These cells activated in the
TABLE 69.3 Potential role of Infection in context of the atherosclerotic plaque promote the formation of
atherosclerosis and thrombosis thick collagen fibers that can resist the mechanical assault exerted
Infectious Organisms Implicated by hemodynamic forces. This is due to the capacity of the IL-17
Viruses to promote procollagen expression.
Herpes viruses (e.g., cytomegalovirus)
Bacteria Regulatory T Cells
Chlamydia pneumonia In atherosclerosis, the role of regulatory T cells (Treg) is well
Helicobacter pylori appreciated. Indeed, this T-cell subpopulation inhibits athero-
Porphyromonas gingivalis?
sclerosis development and progression by suppressing effector
Mechanism(s) by Which Infections May Contribute T-cell responses. A defective Treg compartment has been
to atherothrombosis demonstrated in the peripheral blood of ACS; these patients
Direct infection of the vascular wall with endothelial injury, show low levels of circulating Treg, a reduced suppressive efficiency
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inflammatory cell recruitment, and activation (Chlamydia of Treg, and an increased Treg susceptibility to apoptosis. In a
pneumoniae, herpes virus, cytomegalovirus) small study, Treg have been identified as the major T-cell subset
Immune-mediated vascular injury through molecular mimicry in aspirated coronary thrombus adjacent to the culprit lesion
(Chlamydia pneumoniae) in patients with ACS, associated with a restricted TCR diversity
Remote infections with systemic activation of the inflammatory
response (Helicobacter pylori, Porphyromonas gingivalis) in thrombus-resident T cells; this suggests an increased antigen-
specific Treg redistribution between the peripheral blood and