Immunopathogenesis of atherosclerosis

Abstract

Recent clinical studies indicate that the number of microbial infections (the "pathogen burden") critically determines the development and progression of atherosclerotic disease. Viruses or bacteria with a specific tropism for cells of the vascular wall may contribute to the initial vascular injury via direct cytopathic effects or via the induction of genuine autoimmune responses. Immunopathological processes such as molecular mimicry, epitope spreading, or bystander activation of self-reactive lymphocytes most likely fuel the chronic inflammatory process in the vascular wall. Recognition of atherogenesis as a pathogen-driven, immunopathological process makes this disease amenable to new treatment strategies such as vaccination or immunomodulation.

Childhood Infection and Endothelial Dysfunction

“…Chronic infection might also influence preexisting plaque by enhancing T-cell activation or other inflammatory responses that may participate in destabilization of the intimal cap. 22 Evidence is mounting for a variety of other potential agents, including other herpes viruses, influenza, other specific bacteria (eg, Micoplasma pneumoniae), and chronic infections with common bacterial agents (periodontal disease, chronic bronchitis, and chronic urinary tract infection, among others). 22 Future clinical trials are expected to elucidate further the pathophysiological relationship between chronic infection and atherosclerosis and to evaluate further the potential of a variety of treatment approaches, including antibiotics, during early childhood.…”

“…21,22 For the most part, these relationships are still just associations. Specific causative relationships on par with that determined between Helicobacter pylori and peptic ulcer disease have not yet been established.…”

A Microbial TLR2 Agonist Imparts Macrophage-Activating Ability to Apolipoprotein A-1

“…Chronic inflammation due to microbial infection within the arterial vessel walls is receiving increasing attention as one etiological factor in atherosclerosis (16,17). New epidemiological studies have implicated Helicobacter pylori (32), Chlamydia pneumoniae (33,34), Mycoplasma pneumoniae (35,36), and a number of oral bacteria such as Porphymonas gingivalis and Bacteroides forsythus (37,38) as contributors to atherosclerosis.…”

“…Experimental models using these organisms, such as P. gingivalis (39), show that they can indeed induce atherosclerotic inflammation, although the mechanism(s) by which they might promote this disease is not clear. It has been proposed recently that innate recognition by TLR2 in conjunction with either TLR1 or TLR6 of a wide range of microbial agonists is a potential inflammatory pathway whereby microbial moieties might be involved (17,40). In fact, Mullick et al (19) recently demonstrated that the systemic administration of the synthetic TLR2-using Pam 3 CSK 4 lipopeptide could greatly enhance atherosclerosis in a mouse model using the LDL receptor KO Ϫ/Ϫ mouse, and that disease was ablated when TLR2 was eliminated through use of Ldl Ϫ/Ϫ , TLR2 Ϫ/Ϫ mice.…”

“…These interactions may be beneficial to the host by promoting a rapid immune response to invading organisms or may trigger an acute inflammatory reaction as seen in toxic shock syndromes (4). TLR/endogenous interactions may also lead to autoimmunity (16,17), and chronic infections may promote asthma (18); in addition, there is increasing evidence that agonists from multiple microbial agents may be a contributing factor to the development of atherosclerosis (19,20).…”