Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation.
The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.
DeGraba
Thomas J
TJ
Clinical Stroke Research Unit, National Naval Medical Center, Bethesda, Md, USA. tjdegraba@bethesda.med.navy.mil
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000942:Antigens, Bacterial; D001161:Arteriosclerosis / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D001424:Bacterial Infections / Q000276:immunology; D004730:Endothelium, Vascular / Q000502:physiology; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation; D018836:Inflammation Mediators; D008264:Macrophages / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011110:Polymorphism, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors; D020521:Stroke / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013927:Thrombosis
D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D000942:Antigens, Bacterial; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D010975:Platelet Aggregation Inhibitors; D016693:Receptors, Antigen, T-Cell, alpha-beta