Page 977 - Clinical Immunology_ Principles and Practice ( PDFDrive )

944 Part seven Organ-Specific Inflammatory Disease

TABLE 69.4 Pathogenical Mechanisms, Diagnosis, and Potential tailored therapy of acute
Coronary syndromes
Mechanism Diagnosis Potential therapeutic target
Plaque fissure with 1. Innate immunity Hs-CRP levels Immunosuppression (cyclosporine, tacrolimus,
systemic inflammation Early neutrophil activation T-cell phenotyping sirolimus, AZT, imatinib)
Inflammatory macrophages Functional imaging TCR signaling regulation (synthetic CD31-
Platelet activation (TLRs) derived peptide, PTPN22 inhibitor)
2. Adaptive immunity IL-1β antagonists (anakinra, canakinumab,
null
+
CD4 CD28 T-cell expansion rilonacept)
Treg imbalance Treg expansion, anti-CD3-Ab (mice)
Th17 cells Vaccines
B cells High-dose statins
Plaque fissure without 1. Sympathetic nervous system activation Anatomical imaging Statins
systemic inflammation 2. Changes in plaque composition PLA 2 inhibitors
Enhancement of cholesterol Efflux/impairment
of foam cells formation (3-
hydroxyanthranilic acid)
Plaque erosion 1. PMN producing MPO MPO levels Antithrombotic drugs
2. Hyaluronan/CD44 interaction Functional imaging
3. TLR2 activation and endothelial injury
4. Acute local hemodynamic changes
Functional alterations 1. Epicardial coronary spasm (enhanced Functional tests of vasomotility Nitrates
Rho kinase activity) Rho kinase activity Calcium antagonists
2. Microvascular spasm Rho kinase inhibitors
AZT, azathioprine; Hs-CRP, high-sensitivity C-reactive protein; IL-1β, interleukin-1β; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; PLA2, phospholipase A2TCR; PMN,
polymorphonuclear neutrophil; PTPN22, protein tyrosine phosphatase non–receptor type 22; TCR, T-cell receptor; Th17, T-helper cell-17; TLRs, toll-like receptors.

An unmet need in this patient subset is a specific antiinflam- a thinner cap compared with plaque fissure occurring at rest,
matory treatment. 31,32 Indeed, TCR activation signaling offers indicating greater susceptibility to biomechanical forces. The
several targets for immunosuppressive therapy such as cyclo- development of micro-OCT that enables imaging of coronary
sporine, tacrolimus, sirolimus, azathioprine, and imatinib artery microstructure on a scale comparable to that of histopathol-
mesylate. These drugs prevent T-cell activation and reduce ogy might shed some new light on the role played by cholesterol
hyperreactivity of the adaptive immune system and development crystallization. Inflammasome activation due to cholesterol
of autoimmunity. A synthetic CD31-derived peptide, able to crystals has been discussed as a potential mechanism.
engage a truncated extracellular CD31 fragment expressed by T
cells that apparently lack CD31, has an immunosuppressive effect Plaque Erosion
in vivo through restoration of the CD31 inhibitory pathway. The In plaque erosion, MPO is an important bystander and might
development of a novel series of inhibitors of PTPN22 might even play a pathogenic role. Molecular imaging techniques can
contribute to a better understanding of the role of this phosphatase visualize MPO in atherosclerotic plaques in carotid arteries;
in the immune dysregulation of ACS patients. these methods are more difficult, however, in coronary circula-
Another intervention target might be restoring the balance tion. Elevated plasma concentration of MPO might represent
between effector T cells and Treg cells. Adoptive transfer of ex an important biomarker for the identification of this subset
6
vivo expanded Treg might be considered. Of note, in mice of patients. In patients with plaque erosion, the mechanism
anti-CD3 antibody treatment induced rapid regression of of inflammation is probably an intense local thrombogenic
established atherosclerosis by reducing CD4 T cells and increasing stimulus. Thus potent antithrombotic treatment, based perhaps
33
the proportion of Treg. Additionally, it has been shown that on double antiaggregation and an oral anticoagulant, might be
the tryptophan metabolite 3-hydroxyanthranilic acid has immune the treatment of choice, but this approach must be tested in
regulatory properties that can be used to decrease atherosclerosis prospective studies.
in mice by regulating T cell–dependent inflammation and lowering
plasma lipids. Finally, the identification of antigens that trigger Functional Alterations of Coronary Circulation
adaptive immunity may open the way for specific vaccinations. Clinical history and 24- to 72-hr ambulatory ECG monitoring
Notably, strengthening antiviral immunity in at-risk patients, are usually sufficient to achieve the diagnosis of vasospastic
e.g., by vaccination against influenza, has been associated with angina, whereas the use of provocative tests of coronary artery
reduction in cardiovascular events, demonstrating the value of spasm (e.g., intravenous ergonovine, intracoronary ergonovine,
host protection through health maintenance. 34 or acetylcholine administration) is required in about 10% of
patients. Rho kinase activity in circulating neutrophils is increased
Plaque Fissure Without Systemic Inflammation and might represent a useful biomarker for diagnosis and disease
Clinical history of extreme emotional disturbance or intense activity assessment. Although nitrates and calcium antagonists
physical exertion might help to identify this subset of patients. are helpful in patients with vasospastic angina, further efforts
Anatomical (more than functional) features of the atherosclerotic are needed to identify the molecular alterations responsible for
plaque are important in determining coronary instability. Thus smooth muscle cell hyperreactivity because a sizable proportion
noninvasive imaging of stress-related plaque fissure might reveal of these patients are refractory to standard doses of vasodilator.