NLRC4-Related Macrophage Activation Syndrome (NLRC4-MAS): A Novel Primary Autoinflammatory Syndrome Caused By Activating Mutations in NLRC4

Scott Canna¹, Adriana Almeida de Jesus², Sushanth Gouni¹, Stephen Brooks³, Kristien J. Zaal⁴, Bernadette Marrero⁵, Yin Liu⁶, Michael Dimattia⁷, Gina A. Montealegre Sanchez⁶, Hanna Kim⁶, Dawn C. Chapelle⁶, Nicole Plass⁶, Yan Huang⁶, Angelique Biancotto⁸, J. Alex Duncan⁹, Susanne Benseler¹⁰, John J. O'Shea¹, Alexei A. Grom¹¹, Zuoming Deng¹², Ronald Laxer¹³ and Raphaela Goldbach-Mansky¹⁴, ¹Molecular Immunology and Inflammation Branch, NIAMS/NIH, Bethesda, MD, ²Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ³NIAMS/NIH, Bethesda, MD, ⁴Light Imaging Section, NIAMS/NIH, Bethesda, MD, ⁵Translational Autoinflammatory Disease Section, NIAMS/NIH, Bethesda, MD, ⁶Translational Autoinflammatory Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ⁷Laboratory of Structural Biology, NIAMS/NIH, Bethesda, MD, ⁸Center for Human Immunology, Autoimmunity and Inflammation, NHLBI/NIH, Bethesda, MD, ⁹Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, ¹⁰Alberta Children's Hospital Research Institute/University of Calgary, Calgary, AB, Canada, ¹¹Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ¹²Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ¹³Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, ¹⁴Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease, Immunogenetics, macrophage activation syndrome and nod-like receptor (NLR)

Session Information

Title: Pediatric Rheumatology - Pathogenesis and Genetics

Session Type: Abstract Submissions (ACR)

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.

[1] Romberg N et al., Nature Genetics, Under Review

Disclosure:

S. Canna,
None;

A. Almeida de Jesus,
None;

S. Gouni,
None;

S. Brooks,
None;

K. J. Zaal,
None;

B. Marrero,
None;

Y. Liu,
None;

M. Dimattia,
None;

G. A. Montealegre Sanchez,
None;

H. Kim,
None;

D. C. Chapelle,
None;

N. Plass,
None;

Y. Huang,
None;

A. Biancotto,
None;

J. A. Duncan,
None;

S. Benseler,
None;

J. J. O’Shea,
None;

A. A. Grom,

Novartis Pharmaceutical Corporation,

Roche Pharmaceuticals,

Z. Deng,
None;

R. Laxer,
None;

R. Goldbach-Mansky,
None.

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