Macrophage activation syndrome: advances towards understanding pathogenesis

Abstract

Purpose of review: Macrophage activation syndrome (MAS), a major cause of morbidity and mortality in pediatric rheumatology, is most strongly associated with systemic juvenile idiopathic arthritis (SJIA). There are no validated diagnostic criteria and early diagnosis is difficult. This review summarizes the progress in understanding of MAS pathophysiology that may help define specific diagnostic biomarkers.

Recent findings: MAS is similar to the autosomal recessive disorders collectively known as familial hemophagocytic lymphohistiocytosis (FHLH), all associated with various genetic defects affecting the cytolytic pathway. Cytolytic function is profoundly depressed in SJIA with MAS as well. This immunologic abnormality distinguishes SJIA from other rheumatic diseases and is caused by both genetic and acquired factors. Phenotypic characterization of hemophagocytic macrophages has been another focus of research. These macrophages express CD163, a scavenger receptor that binds hemoglobin-haptoglobin complexes, and initiate pathways important for adaptation to oxidative stress induced by free iron. Expansion of these macrophages is seen in more than 30% of SJIA patients perhaps representing early stages of MAS. Recent gene expression studies linked expansion of these macrophages to distinct signatures.

Summary: Recent advances in understanding of pathophysiologic conditions that favor expansion of hemophagocytic macrophages provide a source of new MAS biomarkers with applicability to clinical practice.

Figure 1. Proposed mechanisms that may lead to increased predisposition to macrophage activation syndrome in systemic juvenile idiopathic arthritis

In active systemic juvenile idiopathic arthritis (SJIA), expression of the markers of the alternative pathway of macrophage differentiation parallels expression of negative regulators of innate immune responses including SOCS3 and IL-10. SOCS3 interacts with JAK/STAT signaling pathways leading to decreased responsiveness of monocytes/macrophages to IFN-γ. Altered responsiveness to IFN-γ combined with the presence of IL-10 may skew differentiation of monocytes towards the scavenger macrophages, which exhibit increased phagocytic activity and are CD163⁺. The presence of cytolytic dysfunction in SJIA patients that appears to be caused by both genetic and acquired factors may be another contributing factor.