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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 SAP or 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 clarify the pathogenic factors that lead to a distinct MAS phenotype characterized by constitutively high levels of IL-18. Using this approach, we recently identified that activating mutations in the intracellular innate-immune sensor NLRC4 cause a monogenic, dominant form of MAS that is partially responsive to IL-1 inhibition. 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 (NLRP3 versus NLRC4, for example) 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.
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 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.
Canna S, Frankovich J, Higgins G, Narkewicz MR, Nash SR, Hollister JR, Soep JB, Dragone LL. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist. Pediatr Rheumatol Online J. 2009 Dec 22;7:21. doi: 10.1186/1546-0096-7-21.See extended list of publications
Updated September 18, 2014