Convergent pathways of the hyperferritinemic syndromes

Abstract

Hyperferritinemia and pronounced hemophagocytosis help distinguish a subset of patients with a particularly inflammatory and deadly systemic inflammatory response syndrome. Two clinically similar disorders typify these hyperferritinemic syndromes: hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). HLH is canonically associated with a complete disturbance of perforin/granzyme-mediated cytotoxicity, whereas MAS occurs in the context of the related rheumatic diseases systemic juvenile idiopathic arthritis and adult-onset Still's disease, with associated IL-1 family cytokine activation. In practice, however, there are accumulating lines of evidence for innate immune dysregulation in HLH as well as partial impairments of cytotoxicity in MAS, and these mechanisms likely represent only a fraction of the host and environmental factors driving hyperferritinemic inflammation. Herein, we present new findings that highlight the pathogenic differences between HLH and MAS, two conditions that present with life-threatening hyperinflammation, hyperferritinemia and hemophagocytosis.

Fig. 1.

Convergent pathways of the hyperferritinemic syndromes HLH and MAS. In a typical immune response, infectious (often viral) triggers induce activation and expansion of specific CD8⁺ cytotoxic T Lymphocytes (CTLs). Both CD8+ CTLs and NK cells receive signals from antigen-presenting cells (APCs), leading to enhanced IFNγ production and cytolytic killing (red arrows). Contraction and resolution of the immune response also depend upon NK cell killing of activated lymphocytes. In HLH, impaired CTL function leads an inability to kill target cells and excessive IFNγ production. IFNγ has essential roles in activating macrophages, which produce high levels of inflammatory cytokines and further enhance the CTL response. Absent NK cell cytotoxicity further leads to inability to contract the immune response. During MAS, innate immune activation including excessive IL-18 production, drives activation and expansion of CTLs to overproduce IFNγ, which further stimulating macrophages to produce inflammatory cytokines. Partial genetic or acquired CTL and NK cell defects may augment this IFNγ response and similarly impair resolution of inflammation. In both HLH and MAS, this overwhelming immune activation leads to a systemic cytokine storm.