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.

Keywords: Animal model; Cytokine storm syndromes; Hemophagocytic lymphohistiocytosis; Lung disease; Still’s spectrum.

Fig. 1

Temporal overview of mouse models of SJIA and MAS. A Repeated TLR-9 stimulation model. B IL-6 transgenic mice with TLR stimulation model. C IFN-γ knockout mice with CFA stimulation model. D IL1RN − / − and Tsc2-knock out models. E NSGS mice with xenograft models. F CD40 stimulated mice model. WT: wild type, i.p.: Intraperitoneal injection, IL-18BP: Interleukin-18-binding protein, KO: knock out, Tg: transgenic, IFN-γ: interferon gamma, CFA: Freund’s complete adjuvant, s.c.: subcutaneous injection, UCB: umbilical cord blood, hHSC: human hematopoietic stem cells