Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis

Abstract

Purpose of review: Macrophage activation syndrome is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions.

Recent findings: The heterogeneity of clinical manifestations seen in patients with hyperinflammatory syndromes continues to grow as novel genetic and immunotherapeutic triggers of cytokine storm have been identified. Recent studies characterize unique cytokine and gene expression profiles from patients with different hyperinflammatory syndromes, whereas novel murine models begin to define networks of immune dysregulation thought to drive excessive inflammation in cytokine storm.

Summary: Emerging evidence suggests hypercytokinemia is the driving cause of immunopathology and morbidity/mortality in hyperinflammatory syndromes. Therefore, approaches to block cytokine function may be fruitful in treating hyperinflammatory syndromes with less toxicity than current therapies. However, not all hyperinflammatory syndromes result in the same pathogenic cytokine profile, implying that a personalized approach will be required for effective use of anticytokine therapies in the treatment of hyperinflammatory syndromes.

Figure 1. Self-perpetuating inflammatory cycles sustain enhanced systemic inflammation in hyperinflammatory syndromes

The working model of pathogenesis for hyperinflammatory diseases occurs from amplifying feed-forward inflammatory cycles leading to downstream immunopathology. In MAS, an autoinflammatory trigger likely mediated through pattern recognition receptor activation of innate immune cells leads to the release of proinflammatory mediators. Effector cells amplify this proinflammatory cytokine cascade leading to hypercytokinemia. The combination of proinflammatory cytokines and continued activation of pattern recognition receptors (PRRs) leads to synergistic activation of innate immune cells driving an enhanced immunopathologic cycle (29). In FHL, viral infections stimulate antigen-presenting cells to activate cytotoxic T cells to release tissue-damaging effector molecules. Due to defective cytotoxicity, uncontrolled viral replication propagates robust innate immune cell antigen presentation perpetuating a vicious cycle of self-sustaining and self-enhancing systemic inflammation (30).