Background/Purpose: Macrophage Activation Syndrome (MAS) is a life-threatening systemic inflammatory complication of many rheumatic diseases and its causes are unknown. While genetic defects causing impaired cytotoxicity result in a similar entity called primary Hemophagocytic Lymphohistiocytosis (HLH), MAS has no known primary genetic cause.

Methods: We performed detailed clinical, genetic, and immunologic evaluation of a patient with early onset, recurrent MAS-like disease including whole exome sequencing, serum cytokine analysis, and whole blood transcriptional profiling. We also tested monocyte and macrophage inflammasome activation, cytokine production, and cell death. We also evaluated the inflammatory effects of this mutation in a transduced monocytic cell line.

Results: We identified a 7 year-old female with recurrent MAS-like episodes, including pancytopenia and hyperferritinemia, since 2 months of age. Genetic testing identified a de novo threonine to serine conversion in NLRC4, a cytosolic danger sensor, Nod-like Receptor (NLR), and component of the NLRC4 inflammasome. The patient’s serum and transcriptional profiles were distinct from NOMID and similar to MAS-prone diseases, with high, constitutive IL-18 elevation. Patient monocytes and monocyte-derived macrophages showed over-production of IL-1β and IL-18, enhanced cell death, and spontaneous ASC aggregate formation. These findings were reproduced in THP1 monocytes constitutively expressing mutant NLRC4. The patient has weaned from steroids and colchicine and has been flare-free after six months of IL-1 receptor antagonist (anakinra) therapy.


Conclusion: Like mutations in NOD2 causing Blau Syndrome and in NLRP3 causing the cryopyrinopathies, activating mutations in the nucleotide-binding region of NLRC4 cause a novel “inflammasomopathy”. However, NLRC4 mutations uniquely manifest as recurrent MAS. Strengthening the NLRC4-MAS association, our findings have been independently corroborated in an unrelated kindred[1]. Ongoing investigation of NLRC4-MAS to determine its unique inflammatory characteristics will shed light on the pathogenesis of MAS and related systemic inflammatory disorders.