Evil humors take their toll as innate immunity makes gouty joints TREM‐ble

Abstract

Acute gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular tophaceous deposits of monosodium urate monohydrate (MSU) crystals. Full-blown acute gouty arthritis is dependent on the influx into the joint space of neutrophils, a cell type normally absent from this locus. Hence, the clinical term “gout,” classically described in the 5th century BC by Hippocrates, was derived in a remarkably prescient manner from the Latin word “gutta,” which literally means “drop.” Specifically, gout was named to reflect the notion of “evil humors” aberrantly seeping into affected joints. Recent advances have revealed the uncanny link between this ancient disease and innate immune inflammatory responses that are phylogenetically primeval. Innate immunity provides a first line of defense against infection via primitive responses that are nonspecific and broad in spectrum (1). Unlike adaptive immune responses, stereotypic innate immune “early induced” responses do not directly induce immunologic memory or lasting protective immunity, consistent in acute gout with the recurrent paroxysmal nature of the disease and the primary role in pathogenesis of “professional phagocytes.” Central to rapid innate immune inflammatory and killing responses is the remarkable capacity of all eukaryotic organisms to recognize the same constituents of microbes (termed pathogenassociated molecular patterns [PAMPs]). Seminal identification of Toll and Toll-like receptors (TLRs) that recognize PAMPs in Drosophila indicates that human innate immune mechanisms for discrimination of nonself PAMPs such as lipopolysaccharide (LPS) and peptidoglycan from self are phylogenetically primordial. The majority of encounters with microorganisms expressing PAMPs do not result in disease, but breaching of tissue barriers by pathogens can stimulate innate immune alternative complement pathway activation, the expression of chemokines and certain other inflammatory cytokines, and uptake of the pathogen by resident and recruited professional phagocytes in a rapid effort to eliminate the noxious agent.