Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Abstract

Macrophage activation syndrome (MAS) is a life-threatening complication of pediatric rheumatic diseases, occurring most commonly in children with systemic juvenile idiopathic arthritis (SJIA). Despite several classes of currently available treatment options for SJIA, including biologic agents targeting IL-1 or IL-6, there remain severe cases suffering from refractory disease and recurrent MAS. The phenotype of MAS is similar to hemophagocytic lymphohistiocytosis (HLH), but the underlying pathophysiology of MAS complicating SJIA or other disorders has not been fully clarified. These facts make it challenging to develop and utilize animal models to study MAS. To date, there is no “perfect” model replicating MAS, but several models do demonstrate aspects of SJIA and/or MAS. In this review, we examine the proposed animal models of SJIA and MAS, focusing on how they reflect these disorders, what we have learned from the models, and potential future research questions. As we better understand the key features of each, animal models can be powerful tools to further define the pathophysiology of SJIA and MAS, and develop new treatment targets and strategies.

CXCL9 inhibition does not ameliorate disease in murine models of both primary and secondary hemophagocytic lymphohistiocytosis

“…CpG induced splenomegaly and elevated levels of serum IFN-γ were consistent with previously described data when compared to non-MAS mice (Fig. 1 c) 5 , 29 , 35 , 37 . sIL2r was equally elevated in both groups when compared to non-MAS mice (mean 515.7 pg/mL, SEM ± 56.62, n = 12, data not shown).…”

“…Both groups were infected with LCMV to induce FHL and were sacrificed at 8 days post infection when features of disease are present but prior to progressing to high rate of mortality 4 . Similar to human disease, the murine model of FHL produces a much more severe phenotype compared to MAS with severe hypercytokinemia, weight loss/mortality, hepatitis and cytopenias 4 , 5 , 25 , 29 , 31 , 32 , 35 , 38 , 39 . Therefore, we hypothesized that the role of CXCL9 in the pathogenesis of prf1 −/− HLH will be more apparent.…”

“…The MAS murine model mimics human disease that is associated with abnormal TLR signaling in patients with Systemic Juvenile Idiopathic Arthritis 29,33,34 . Repeated stimulation of TLR9 produces similar features to MAS with elevated circulating IFN-γ, cytopenia, hepatosplenomegaly and hepatitis 5,28,29,33,35 . As oppose to murine FHL, the MAS model has both a type I and type II interferon response due to TLR9 stimulation resulting in an immune response of both innate and adaptive compartments with a milder contribution of T cells and an overall milder phenotype with mice universally not succumbing to TLR9 repeated stimulation and exhibiting milder features of HLH physiology 28,29,35 .…”

“…Repeated stimulation of TLR9 produces similar features to MAS with elevated circulating IFN-γ, cytopenia, hepatosplenomegaly and hepatitis 5,28,29,33,35 . As oppose to murine FHL, the MAS model has both a type I and type II interferon response due to TLR9 stimulation resulting in an immune response of both innate and adaptive compartments with a milder contribution of T cells and an overall milder phenotype with mice universally not succumbing to TLR9 repeated stimulation and exhibiting milder features of HLH physiology 28,29,35 . However, prior work has shown that IFN-γ is required for disease progression, whereas Type I interferon is dispensible 29,36 .…”

Peripheral Blood Single-Cell Sequencing Uncovers Common and Specific Immune Aberrations in Fibrotic Lung Diseases

“…Additionally, Tγδ cells were decreased in FHP patients’ BAL fluid, suggesting possible migration to lung tissues [42, 43]. CD56bright NK cells were reduced in FHP compared to controls and IPF, consistent with systemic inflammation-associated diseases [44–47]. Within B cells, FHP patients showed increased naïve B cells and decreased memory B cells, resembling dysregulation seen in rheumatoid arthritis-ILD [48, 49].…”