The orchestra of Toll-like receptors and their potential role in frequently occurring rheumatic conditions.

In the early 1990s, Janeway discussed the theory that an immune response could not occur unless antigen-presenting cells (APCs) were first activated, which he called “the immunologist’s dirty little secret.” Then, in the coup that caused the immunology community to finally take notice, and following the seminal study by Lemaitre et al (1), Janeway discovered the crucial role of pattern-recognition receptors (PRRs), which recognized evolutionary conserved molecules on infectious nonself organisms (2). Toll-like receptors (TLRs) belong to the PRR family, which was first shown to recognize microbial components, known as pathogenassociated patterns. TLRs are constitutively expressed by numerous immune cells and are designed to detect and eliminate invading pathogens by activating both innate and adaptive immune responses. Accumulating evidence indicates a role of TLRs in the recognition of “host-derived” agonists (so-called endogenous ligands or alarmins), which might be involved in various autoimmune and/or autoinflammatory syndromes. Examples of such endogenous TLR ligands are Hsp60, Hsp70, gp96, small HspB8, hyaluronic acid, and fibronectin, which are all released upon cell stress and are found in various tissues during inflammation (discussed below). TLRs are of interest to immunologists because of their important role in the initiation of immune responses. Because evidence seems to implicate innate immunity in a wide variety of rheumatic conditions that are seen in the clinical practices of rheumatologists, the question is whether TLRs deserve more of the rheumatologist’s attention as well. The role of TLR agonists in animal models of arthritis has been explored and is consistent with Janeway’s “dirty little secret.” In this light, the use of Freund’s complete adjuvant to boost arthritis has lost its magic with the discovery of TLR binding to constituents of this “miracle potion.” In this review, we discuss how recent advances in TLRassociated research have enhanced our understanding of the role of this receptor family in frequently occurring rheumatic conditions and how continued exploration of their role is likely to change the types of therapy available to battle these chronic diseases.