Regulating Protective Immunity in Atherosclerosis

Abstract

Atherosclerosis is a disease characterized by chronic inflammation. Looking back it is almost embarrassing how long it took for us to realize that the presence of these innate immune responses also was associated with activation of adaptive immunity. The first hints of an involvement of adaptive immunity in atherosclerosis came from studies performed by Goran Hansson and his coworkers about 20 years ago demonstrating the presence of activated T cells and expression of class II molecules in atherosclerotic plaques.1 This finding provoked an intense interest in the role of immunity in atherosclerosis, and it is now generally recognized that adaptive immune responses have a key role in determining the balance between disease progression and regression.2 It also focused attention on the immune system as a target for prevention and treatment of cardiovascular disease. Mice with defective adaptive immunity, such as SCID and Rag-1, develop less atherosclerosis indicating that adaptive immune responses are primarily proatherogenic. Oxidized LDL has been identified as one of the most important autoantigens in atherosclerosis.3 A large fraction of the T cells present in atherosclerotic plaques are specific for oxidized LDL,4 and oxidized LDL IgG is prevalent in the circulation of both humans and atherosclerosis-prone animals. However, studies evaluating the role of immune responses against oxidized LDL by immunizing animals with in vitro oxidized LDL unexpectedly revealed a protective effect.5,6 Although it still remains to be established whether naturally occurring autoimmune responses against oxidized LDL also have atheroprotective effects, these observations suggest the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis. However, manipulating the immune system in complex diseases does not come without risk, and if the development of an immunomodulatory therapy for atherosclerosis is to become successful it will require detailed characterization of both disease-related and protective immune responses. The …