You are here:
Autoinflammatory Pathogenesis Unit
Acute systemic inflammatory disorders are known by many names, including sepsis, systemic inflammatory response syndrome (SIRS), cytokine storm, and others. One subgroup is known as hemophagocytic disorders, named for their frequent association with activated macrophages that have engulfed other hematopoietic cells. Two clinically similar disorders constitute the hemophagocytic syndromes: Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS). Some patients with HLH carry loss-of-function mutations in genes critical for cytotoxic function, like perforin. Genetic deficiency of signaling lymphocytic activation molecule (SLAM )-associated protein (SAP) or X-linked inhibitor of apoptosis (XIAP) can also lead to HLH. Most cases of HLH and MAS occur in the context of infection (particularly Epstein-Barr Virus), malignancy, or rheumatic disease. Adult-onset Stillís disease (AOSD) and systemic Juvenile Idiopathic Arthritis (sJIA) are the rheumatic diseases most closely associated with MAS. Using careful evaluation of affected patients, human cell lines, and murine models, we aim to elucidate the pathogenic mechanisms that result in a distinct MAS phenotype. One distinction of the MAS phenotype is that patients who have had MAS usually have chronically and extremely elevated levels of serum Interleukin 18 (IL-18).
Using this approach, we recently identified that activating mutations in the intracellular innate-immune protein NLRC4 cause a monogenic, dominant form of MAS also associated with early-onset enterocolitis. This discovery serves as a platform to contrast the variety of contexts in which MAS can arise. It also enables us to study how activation of different inflammasomes (e.g. NLRP3, NLRC4, and Pyrin) can have different effects at the cellular and organismal levels. We are hopeful that this line of inquiry will shed light on the basic biology underpinning MAS, disorders at risk for MAS, and phenotypically distinct inflammasomopathies.
The broader goal of our group is to leverage monogenic forms of hyperinflammation (like NLRC4-MAS) to define distinct signatures that may be present in more common inflammatory states (like sepsis). This immunologic lumping and splitting will help us understand the host factors that determine the systemic response to inflammatory stimuli, and identify which patients will benefit from which targeted anti-inflammatory therapies.
Hemophagocyte seen in the spleen of a WT mice treated with TLR9 stimulation and IL-10 blockade. *=engulfed RBC (so-called ghost cell); #=engulfed leukocyte.
Spontaneous inflammasome formation is seen in monocyte-derived macrophages from an NLRC4-associated Macrophage Activation Syndrome (NLRC4-MAS) patient (bottom) as compared to a healthy control (top). Photo credit: Kristien Zaal, Ph.D., NIAMS Light Imaging Facility.
Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014 Oct;46(10):1140-6. doi: 10.1038/ng.3089. Epub 2014 Sep 14.
Canna SW, Costa-Reis P, Bernal WE, Chu N, Sullivan KE, Paessler ME, Behrens EM. Brief report: alternative activation of laser-captured murine hemophagocytes. Arthritis Rheumatol. 2014 Jun;66(6):1666-71.
Canna S, de Jesus AA, Deng Z, Gouni S, Marrero B, Brooks S, Dimattia M, Liu Y, Huang Y, Plass N, Chapelle DC, Montealegre G, Benseler S, Laxer RM, Goldbach-Mansky R. A157: Macrophage Activation Syndrome-like Illness Due to an Activating Mutation in NLRC4. Arthritis Rheumatol. 2014 Mar;66 Suppl 11:S203. doi: 10.1002/art.38583.
Canna SW, Costa-Reis P, Bernal WE, Chu N, Sullivan KE, Paessler ME, Behrens EM. Alternative activation of laser-captured murine hemophagocytes. Arthritis Rheumatol. 2014 Jan 27. doi: 10.1002/art.38379. [Epub ahead of print]
Canna SW, Wrobel J, Chu N, Kreiger PA, Paessler M, Behrens EM. Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice. Arthritis Rheum. 2013 Jul;65(7):1764-75. doi: 10.1002/art.37958.
Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012 Apr;59(2):329-44. doi: 10.1016/j.pcl.2012.03.002.
Canna SW, Behrens EM. Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes. Curr Opin Rheumatol. 2012 Jan;24(1):113-8. doi: 10.1097/BOR.0b013e32834dd37e.
Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, Kambayashi T, Koretzky GA.Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest. 2011 Jun;121(6):2264-77. doi: 10.1172/JCI43157.
Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. The New England Journal of Medicine 2006 Aug 10;355(6):581-92.See extended list of publications
Updated December 22, 2015