The Immunology of Macrophage Activation Syndrome

Abstract

Synonymous with secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus (SLE). Clinical and laboratory features of MAS include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic coagulopathy, and liver dysfunction. Soluble interleukin-2 receptor alpha chain (sCD25) and sCD163 may be elevated, and histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining. A common hypothesis as to the pathophysiology of many cases of MAS proposes a defect in lymphocyte cytolytic activity. Specific heterozygous gene mutations in familial HLH-associated cytolytic pathway genes (e.g., PRF1, UNC13D) have been linked to a substantial subset of MAS patients. In addition, the pro-inflammatory cytokine environment, particularly IL-6, has been shown to decrease NK cell cytolytic function. The inability of NK cells and cytolytic CD8 T cells to lyse infected and otherwise activated antigen presenting cells results in prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a pro-inflammatory cytokine cascade. The cytokine storm results in activation of macrophages, causing hemophagocytosis, as well as contributing to multi-organ dysfunction. In addition to macrophages, dendritic cells likely play a critical role in antigen presentation to cytolytic lymphocytes, as well as contributing to cytokine expression. Several cytokines, including tumor necrosis factor, interferon-gamma, and numerous interleukins (i.e., IL-1, IL-6, IL-18, IL-33), have been implicated in the cytokine cascade. In addition to broadly immunosuppressive therapies, novel cytokine targeted treatments are being explored to dampen the overly active immune response that is responsible for much of the pathology seen in MAS.

Keywords: IL-1; IL-18; IL-6; NK cell; anakinra; cytokine storm; hemophagocytic lymphohistiocytosis; macrophage activation syndrome.

Figure 1

Pathways regulating macrophage function in MAS. 1. IFNγ binds the IFNγ receptor (IFNGR) and subsequently induces the phosphorylation of STAT1 by JAK1/2 in the cytoplasm. STAT1 dimer then binds to γ-interferon activation site (GAS) and enhances the transcription of interferon-stimulated genes (ISG), such as interferon regulatory factor 1 (IRF1). 2. STAT1 activation by IFNγ also induces macropinocytosis leading to the engulfment and degradation of red blood cells (RBC) in a process known as hemophagocytosis. 3. Hemophagocytosis is also mediated by the uptake of hemoglobin (Hb)-heptaglobin complex by CD163. The Hb-heptaglobin complex is degraded in the lysosome followed by catalysis of heme by heme oxygenase-1 (HO-1) to carbon dioxide (CO), bilverdin, and iron (Fe²⁺). Bilverdin is then converted to bilirubin by bilverdin reductase, and iron is bound to ferritin. 4. This process also leads to the production of IL-10 that through binding to IL-10 receptor induces STAT3 phosphorylation and the production of anti-inflammatory cytokines that counteract IFNγ signaling. 5. In a mouse model of MAS, serial injections of CpG induce the activation of toll-like receptor 9 (TLR9) in the macrophage endosome leading to the production of pro-inflammatory cytokines in a MyD88 and NFκB dependent manner.