LAUSR

Acute rheumatic fever (ARF) is a consequence of an autoimmune response to infection with the Gram-positive bacteria Streptococcus pyogenes or group A Streptococcus (GAS).1 ARF afflicts ≈.5 million people every year, and both environmental and genetic factors contribute to the etiology of ARF and its chronic sequelae, rheumatic heart disease (RHD).2 ARF/RHD is more prevalent in developing countries and is mainly associated with poverty and other determinants of poor health, which facilitates rapid transmission of GAS. Although rare, ARF also persists in some developed countries, especially in disadvantaged communities.3 GAS infection causes a variety of diseases ranging from pharyngitis to severe life-threatening conditions such as necrotizing fasciitis and toxic shock syndrome. GAS activates both the innate and adaptive immune systems and elicits a potent inflammatory response that helps to restrict bacterial replication and dissemination. ARF develops as postinfectious sequelae to acute inflammation in genetically predisposed individuals and is manifested as a systemic inflammatory autoimmune reaction 2 to 4 weeks after the pharyngeal infection.1 Whereas the contributions of both humoraland cell-mediated immune responses in pathogenesis of ARF are well studied, the role of the innate immune system has not been explored in detail.2 Moreover, the immune and inflammatory pathways that link GAS to the progression of ARF to RHD are also poorly understood. In this issue of Circulation, Kim et al4 report a dysregulated interleukin (IL)1β—granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine axis in patients with ARF as a potential mechanism that drives the development of RHD on recurrent GAS infections. GAS induced persistent production of IL-1β and enhanced production of GM-CSF in peripheral blood mononuclear cells (PBMCs) from patients with ARF. A strong positive correlation between the levels of IL-1β and GM-CSF suggests a role for IL-1β in promoting the expression of GM-CSF in these cells. GAS also drives the expansion of GM-CSFand interferon γ-expressing Th1 CD4+ T cells; these pathogenic CD4+ T cells on trafficking to the heart can cause progressive heart valve dysfunction. Indeed, the level of IP-10/CXCL10, a potent Th1 chemoattractant, was found to be elevated in the systemic circulation of patients with ARF.4 These findings collectively imply IL-1β-dependent expansion followed by IP-10-mediated recruitment of interferon γand GM-CSF-expressing Th1 CD4+ T cells as a causative factor triggering chronic autoimmune valvulitis in patients with ARF. Overall, the study by Kim et al4 delineates a convincing sequence of immunologic events that promotes the development of cardiac dysfunction and RHD. However, the mechanism by which GAS induces persistent IL-1β production in PBMCs from patients with ARF, which is the primary event initiating this cascade, remains elusive. © 2018 American Heart Association, Inc.