Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions

Abstract

Systemic juvenile idiopathic arthritis (sJIA) has long been recognized as unique among childhood arthritides, because of its distinctive clinical and epidemiological features, including an association with macrophage activation syndrome. Here, we summarize research into sJIA pathogenesis. The triggers of disease are unknown, although infections are suspects. Once initiated, sJIA seems to be driven by innate proinflammatory cytokines. Endogenous Toll-like receptor ligands, including S100 proteins, probably synergize with cytokines to perpetuate inflammation. These and other findings support the hypothesis that sJIA is an autoinflammatory condition. Indeed, IL-1 is implicated as a pivotal cytokine, but the source of excess IL-1 activity remains obscure and the role of IL-1 in chronic arthritis is less clear. Another hypothesis is that a form of hemophagocytic lymphohistiocytosis underlies sJIA, with varying degrees of its expression across the spectrum of disease. Alternatively, sJIA with MAS might be a genetically distinct subtype. Yet another hypothesis proposes that inadequate downregulation of immune activation is central to sJIA, supporting evidence for which includes 'alternative activation' of monocyte and macrophages and possible deficiencies in IL-10 and T regulatory cells. Some altered immune phenotypes persist during clinically inactive disease, which suggests that this stage might represent compensated inflammation. Despite much progress being made, many questions remain, providing fertile ground for future research.

Figure 1

Perpetuation of innate immune responses in sJIA. Innate immune pathways activated in sJIA are normally triggered by the recognition of pathogen-associated molecular patterns by TLRs expressed on innate immune cells, but can also be triggered by endogenous ligands in inflammatory conditions. These intracellular pathways lead to activation of the transcription factor NFκB, which is translocated into the nucleus where it upregulates expression of genes encoding several proinflammatory cytokines. These cytokines initiate the inflammatory cascade through their effects on the hypothalamus, bone marrow, liver and vascular endothelial cells. Activated vascular endothelial cells act as a procoagulant surface and are likely to contribute to the coagulopathy of sJIA.107 Antibodies against endothelial cells reportedly occur in sJIA,108 although the relevance of this latter finding is unclear. The cytokines also drive joint inflammation, by stimulating osteoclast-mediated bone resorption, osteoblast apoptosis, inhibition of chondrocyte proteoglycan synthesis and synoviocyte secretion of enzymes that degrade matrix and cartilage. Since signaling through IL-1R and IL-18R shares the downstream portion of the TLR4 signaling pathway, IL-1 and IL-18 provide positive feedback loops that further contribute to perpetuation of the inflammatory responses in sJIA. Abbreviations: IL-1R, IL-1 receptor; IL-18R, IL-18 receptor; M-CSF, macrophage colony-stimulating factor; NFκB, nuclear factor κB; sJIA, systemic juvenile idiopathic arthritis; TLR, Toll-like receptor; TNF, tumor necrosis factor; WBC, white blood cell.

Figure 2

Secretion of IL-1β by monocytes in inflammatory diseases. Ligation of pattern recognition receptors, such as TLRs, induces expression of inactive pro-IL-1β; its cleavage by caspase-1 leads to mature IL-1β and secretion.109 Activation of caspase-1 requires assembly of the inflammasome, a multimolecular complex that includes NALP3 (cryopyrin) and the adaptor protein ASC.110 Exogenous ATP triggers the receptor P2X7 and its associated pore, pannexin-1, inducing a strong redox response (generation of ROS followed by upregulation of antioxidant systems) and facilitating assembly/activation of the inflammasome. TLR signaling also stimulates ROS generation and release of endogenous ATP, resulting in autocrine stimulation. NLRP3 mutant monocytes (from patients with cryopyrin-associated periodic syndromes) have altered basal and TLR-stimulated redox states, causing increased and abnormally fast secretion of LPS-stimulated IL-1β. IL-1 secretion is not increased further by ATP, seemingly due to depletion of this pathway after LPS alone.27,45,111 sJIA monocytes do not share this overall phenotype,45 but are resistant to ATP-enhanced IL-1 secretion.37 Anakinra treatment results in increased P2X7 transcripts in sJIA blood cells,37 suggesting that excess IL-1 activity leads to suppression of P2X7. IL-18 processing and secretion is similar to that of IL-1; however, pro-IL-18 is constitutively produced by monocytes. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; DAMP, damage-associated molecular pattern molecule; IL, interleukin; LPS, lipopolysaccharide; PAMP, pathogen-associated molecular pattern molecule; P2X7, P2X purinoceptor 7; ROS, reactive oxygen species; sJIA, systemic juvenile idiopathic arthritis; TLR, Toll-like receptor.

Figure 3

A possible positive feedback cycle involving IL-1β and S100 proteins contributes to perpetuation of chronic inflammation in sJIA. Various pro-inflammatory stimuli, including IL-1β, lead to activation of monocytes and neutrophils. The activation of these cells is accompanied by increased secretion of S100 proteins, including S100-A8, S100-A9 and S100-A12. The proteins S100-A8 and S100-A9, which are markedly elevated in sJIA, form a complex called calprotectin that can serve as an endogenous agonist of TLR4 and trigger TLR signaling pathways, leading to activation of the transcription factor NFκB. Translocation of activated NFκB into the nucleus upregulates expression of IL-1β. In turn, increased IL-1β leads to further secretion of S100 proteins. In addition, S100-A8–S100-A9 complexes activate endothelial cells and also bind the integrin receptor CD11b/CD18 on phagocytes and stimulate their transendothelial migration into tissues.112,113 Abbreviations: IL, interleukin; M-CSF, macrophage colony-stimulating factor; NFκB, nuclear factor κB; TNF, tumor necrosis factor.