title: Complement and atherosclerosis-united to the point of no return?
abstract: Atherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of oxidized low-density lipoprotein (LDL) in the arterial intima and its interaction with components of both innate and adaptive immunity. This article reviews the role of the complement system in the context of a different concept on atherogenesis. Arguments are forwarded in support of the contention that enzymatic and not oxidative modification of LDL is the prerequisite for transforming the lipoprotein into a moiety that is recognized by the innate immune system. In a departure from general wisdom, it is proposed that these processes are initially not pathological. To the contrary, they are physiological and meaningful because only thus can the stranded lipoprotein with its insoluble cargo, cholesterol, be removed from tissues. It is contended that histopathologically defined initial foam cell formation develops without inflammation and is reversible. Atherosclerosis as a disease evolves only when the cholesterol removal machinery is overloaded and it then represents a special type of immunopathological process primarily involving immune effectors of the innate rather than the adaptive immune system. This sets it apart from classical immunopathological reactions that are all based on dysfunctional adaptive immunity. But as with all other diseases of known origin, a defined molecular trigger, enzymatically modified-LDL (eLDL), exists whose intimal accumulation is required to initiate the pathologic process. And as with other diseases, the course of atherosclerosis will then be influenced by myriad genetic, endogenous, and environmental factors that by themselves, however, will not cause the disease. This simple concept is completely in line with general clinical experience and with the results of major clinical trials that have been conducted during the past decades.
authors.affiliation: Department of Laboratory Medicine, Robert Bosch-Hospital, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D050197:Atherosclerosis / Q000209:etiology* / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003167:Complement Activation; D003165:Complement System Proteins / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*
chemical_list: D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D003165:Complement System Proteins; D002097:C-Reactive Protein; D002784:Cholesterol