2011 Nobel Prize in Physiology or Medicine

Beutler for their discoveries of the role of Toll-like receptors (TLRs) in innate immunity and to Dr Ralph M. Steinman for his discovery of dendritic cells and their role in adaptive immunity.These discoveries have had a tremendous impact on our field.A recent article by Chtarbanova and Imler in the Arteriosclerosis, Thrombosis, and Vascular Biology series "History of Discovery" recounted the discovery of TLRs. 1 Dr Charles Janeway initially postulated the existence of innate immune pattern-recognition receptors that detect molecular structures ubiquitously shared among pathogens that allow bridging between the innate and adaptive immune systems. 2 A role for the Toll gene in the innate immune system of the fly Drosophila melanogaster was first described in 1996 by the Hoffman laboratory.3 The first mammalian Toll homolog was reported by the Janeway laboratory a year later.4 In 1998, the Beutler laboratory identified TLR4 as the elusive mammalian receptor that detects bacterial lipopolysaccharide.5 In a subsequent study by Akira's group, knockout mice were generated to confirm that TLR4 recognizes lipopolysaccharide from Gram-negative bacteria, whereas TLR2 recognizes protein components of the Gram-positive bacterial cell wall.6,7 These studies support Janeway's original hypothesis of the importance of pattern-recognition receptors in the innate immune response.8 Given the known role of innate immunity in the pathogenesis of atherosclerosis and other vascular diseases, it was not surprising that TLRs were shown to affect atherosclerosis.Early studies demonstrated TLR1, TLR2, and TLR4 expression in both murine and human atherosclerotic plaques.9,10 Subsequent studies showed that TLR1/interleukin-1 receptor, TLR2, TLR3, and TLR4 were involved in atherosclerosis in murine models.[11][12][13][14][15][16][17] Interestingly, administration of either exogenous TLR ligands or the pathogens themselves accelerated atherosclerosis.13,18 However, endogenous ligands, such as oxidized lipids, can also bind to TLRs and inadvertently activate the innate immune system enhancing atherosclerosis.In addition, receptor complexes consisting of dif-