Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease

Abstract

Systemic juvenile idiopathic arthritis (JIA) and adult-onset Still's disease (AOSD) are systemic inflammatory disorders that manifest as high-spiking fever, joint pain, evanescent skin rash, and organomegaly. Their pathogenesis is unclear, but inflammation is triggered by activation of the innate immune system with aberrant production of proinflammatory cytokines. Along with extrinsic factors, intrinsic pathways can trigger an unexpected immune response. Damage-associated molecular patterns (DAMPs) induce the activation of innate immune cells, leading to sterile inflammation in systemic JIA and AOSD. These endogenous proteins interact with Toll-like receptors (TLRs), which are pattern recognition receptors, and mediate immune signaling following stimulation by pathogen-associated molecular patterns and DAMPs. Several DAMPs, such as S100 proteins, play a role in the development or severity of systemic JIA and AOSD, in which their interactions with TLRs are altered. Also, the expression levels of genes encoding DAMPs contribute to the susceptibility to systemic JIA and AOSD. Herein, we review reports that TLR and DAMP signaling initiates and/or maintains the inflammatory response in systemic JIA and AOSD, and their correlations with the clinical characteristics of those diseases. In addition, we assess their utility as biomarkers or therapeutics for systemic JIA and AOSD.

The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis

“…To determine the immunosuppressive function of SoJIA-driven PBCECs, we investigated the monocyte responsiveness to lipopolysaccharide (LPS) in the presence or absence of PBCECs obtained from patients with SoJIA. We focused on the effect of CECs on monocytes but not lymphocytes, as SoJIA is an autoinflammatory disease involving excessive hypercytokinemia triggered by the activation of the innate immune system 35 , 36 . PBCECs were procured in combination with magnetic microbeads and fluorescent cell sorting from patient’s PBMCs to obtain a > 96% purity population (Fig.…”

“…Toll-like receptor (TLR)-2 mediated inflammation also led to stress erythropoiesis through Myd88-dependent signaling 48 , 49 , suggesting the involvement of innate immune signaling. In this line, the expansion of PBCECs in SoJIA and KD, pediatric autoinflammatory diseases deeply involved in the innate immune response 35 , 50 , may reflect this stress erythropoiesis. The positive correlation between erythropoietin levels and the amount of PBCECs also suggests the potential contribution of stress erythropoiesis to the expansion of CECs in autoinflammatory diseases.…”

Signals and Mechanisms Regulating Monocyte and Macrophage Activation in the Pathogenesis of Juvenile Idiopathic Arthritis

“…Increased TLR2 and TLR4 expression was found on ERA peripheral blood mononuclear cells (PBMCs) and SF Mos [ 71 ], and an increased TLR/IL-1R signature and TLR2 expression were revealed by analyzing gene expression in PBMCs from patients with sJIA [ 72 , 73 ]. Endogenous TLR ligands, such as S100A8/A9 (calprotectin), S100A12, high mobility group box 1, and serum amyloid A, are significantly elevated in JIA cases, particularly in sJIA [ 74 , 75 , 76 ], and are likely to lead to disease progression [ 77 ]. Specifically, the binding of TLR4 with S100A8/A9 on Mos/Mφs was found to induce the transcription of chemokine IFNγ inducible protein 10 (IP-10)/CXCL10 via TRIF signaling [ 78 ].…”

Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One?

“…It seems clear that polymorphisms in single genes do not cause sJIA, however, most confirmed genetic associations involve pro- or anti-inflammatory cytokine genes [ 56 ]. In addition, environmental factors and several DAMPs seem to play a role in the development or severity of systemic JIA and AOSD [ 58 ]. The concentration of S100 proteins (S100A8/A9) correlates with response to treatment and disease activity in SJIA patients [ 59 ], and HMGB1 [ 60 ] and SAA [ 61 ] serum levels are elevated in JIA and AOSD patients, and downregulated after disease resolution.…”