Abstract
Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far the most common in systemic juvenile idiopathic arthritis (sJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure see in MAS. Whole-exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with sJIA-associated MAS, demonstrated increased “burden” of rare protein altering variants affecting the cytolytic pathway compared to healthy controls. These observations suggest that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state their presence partially reduces cytolytic activity that may lead to increased cytokine production. In patients with gain-of-function mutations in the NLRC4 gene, MAS-like clinical presentation seems to be induced by a macrophage-intrinsic defect in the absence of primary cytotoxic abnormalities suggesting that in the future the search for pathogenic variants in SJIA/MAS should be extended beyond the cytolytic pathway and include macrophage activation pathways as well.
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References
Grom, A. A., Horne, A. C., & De Benedetti, F. (2016). Macrophage activation syndrome in the era of biologic therapy: Clues to pathogenesis and impact on diagnostic approaches. Nature Reviews. Rheumatology, 12, 259–268.
Mouy, R., Stephan, J. L., Pillet, P., et al. (1996). Efficacy of cyclosporine a in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases. The Journal of Pediatrics, 129, 750–754.
Jordan, M. B., Allen, C. E., Weitzman, S., et al. (2011). How I treat hemophagocytic lymphohistiocytosis. Blood, 118, 4041–4052.
Henter, J. I., Horne, A., Arico, M., Egeler, R. M., Filipovich, A. H., et al. (2007). HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer, 48, 124–131.
Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., et al. (1999). Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science, 286, 1957–1959.
Feldmann, J., Callebaut, I., Raposo, G., et al. (2003). Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell, 115, 461–473.
zur Stadt, U., Schmidt, S., Diler, A. S., et al. (2005). Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Human Molecular Genetics, 14, 827–834.
zur Stadt, U., Rohr, J., Seifert, W., et al. (2009). Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to Syntaxin 11. American Journal of Human Genetics, 85, 482–492.
Zhang, K. J., Jordan, M. B., Marsh, R., et al. (2011). Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood, 118, 5794–5798.
Jenkins, M. R., Rudd-Schmidt, J. A., Lopez, J. A., Ramsbottom, K. M., Mannering, S. I., Andrews, D. M., et al. (2015). Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. The Journal of Experimental Medicine, 212, 307–317.
Heeg, M., Ammann, S., Klemann, C., Panning, M., Falcone, V., Hengel, H., et al. (2018). Is an infectious trigger always required for primary hemophagocytic lymphohistiocytosis? Lessons from in utero and neonatal disease. Pediatric Blood & Cancer, 65, e27344. https://doi.org/10.1002/pbc.27344
Kagi, D., Odermatt, B., & Mak, T. W. (1999). Homeostatic regulation of CD8 T cells by perforin. European Journal of Immunology, 29, 3262–3272.
Menasche, G., Feldmann, J., Fischer, A., & de Saint Basile, G. (2005). Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunological Reviews, 203, 165–179.
Lykens, J. E., Terrell, C. E., Zoller, E. E., Risma, K., & Jordan, M. B. (2011). Perforin is a critical physiologic regulator of T-cell activation. Blood, 118, 618–626.
Barbosa, M. D., Nguyen, Q. A., Tchernev, V. T., Ashley, J. A., Detter, J. C., Blaydes, S. M., et al. (1996). Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature, 382, 262–265.
Menasche, G., Pastural, E., Feldmann, J., Certain, S., Ersoy, F., Dupuis, S., et al. (2000). Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nature Genetics, 25, 173–176.
Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., et al. (1998). Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genetics, 20, 129–135.
Marsh, R. A., Madden, L., Kitchen, B. J., Mody, R., McClimon, B., Jordan, M. B., et al. (2010). XIAP deficiency: A unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood, 116, 1079–1082.
Wada, T., Kanegane, H., Ohta, K., Katoh, F., Imamura, T., Nakazawa, Y., et al. (2014). Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency. Cytokine, 65(1), 74–78. https://doi.org/10.1016/j.cyto.2013.09.007
Chirieleison, S. M., Marsh, R. A., Kumar, P., Rathkey, J. K., Dubyak, G. R., & Abbott, D. W. (2017). Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease. The Journal of Biological Chemistry, 292(23), 9666–9679. https://doi.org/10.1074/jbc.M117.781500
Grom, A. A., Villanueva, J., Lee, S., Goldmuntz, E. A., Passo, M. H., & Filipovich, A. (2003). Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. The Journal of Pediatrics, 142, 292–296.
Vastert, S. J., van Wijk, R., D’Urbano, L. E., de Vooght, K. M., de Jager, W., Ravelli, A., et al. (2010). Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford), 49, 441–449.
Kaufman, K. M., Linghu, B., Szustakowski, J. D., Husami, A., Yang, F., Zhang, K., et al. (2014). Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis and Rheumatism, 66, 3486–3495.
Behrens, E. M., Beukelman, T., Paessler, M., & Cron, R. Q. (2007). Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. The Journal of Rheumatology, 34, 1133–1138.
Bleesing, J., Prada, A., Siegel, D. M., Villanueva, J., Olson, J., Ilowite, N. T., et al. (2007). The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis and Rheumatism, 56, 965–971.
Bracaglia, C., Sieni, E., Da Ros, M., De Fusco, C., Micalizzi, C., Cetica, V., et al. (2014). Mutations of familial hemophagocytic lymphohistiocytosis related genes and abnormalities of cytotoxicity function tests in patients with macrophage activation syndrome (MAS) occurring in systemic juvenile idiopathic arthritis. Pediatric Rheumatology, 12(Suppl 1), P53.
Zhang, M., Behrens, E. M., Atkinson, T. P., Shakoory, B., Grom, A. A., & Cron, R. Q. (2014). Genetic defects in cytolysis in macrophage activation syndrome. Current Rheumatology Reports, 16, 439–446.
Jessen, B., Kogl, T., Sepulveda, F. E., de Saint Basile, G., Aichele, P., & Ehl, S. (2013). Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice. Frontiers in Immunology, 4, 448.
Spessott, W. A., Sanmillan, M. L., McCormick, M. E., Patel, N., Villanueva, J., Zhang, K., et al. (2015). Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood, 125, 1566–1577.
Zhang, M., Bracaglia, C., Prencipe, G., Bemrich-Stolz, C. J., Beukelman, T., Dimmitt, R. A., et al. (2016). A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. Journal of Immunology, 196, 2492–2503.
Zhang, K., Biroscak, J., Glass, D. N., Thompson, S., Finkel, T., Murray, P., et al. (2008). Macrophage activation syndrome in systemic juvenile idiopathic arthritis is associated with MUNC13D gene polymorphisms. Arthritis and Rheumatism, 58, 2892–2896.
Bruno, G., Cannella, S., Trizzino, A., Mosa, C., Faruggia, P., Guggino, G., et al. (2012). PRF1 A91V mutation associated with MUNC13-4 polymorphisms predispose to haemophagocytic lymphohistiocytosis. Journal of Clinical Immunology, 32(Suppl 1), 631.
Schulert, G., Zhang, M., Husami, A., Fall, N., Brunner, H., Zhang, K., et al. (2018). Novel NC13D intronic variant disrupting a NFkB enhancer in a patient with recurrent macrophage activation syndrome and systemic JIA. Arthritis Rheumatol 70(6), 963–970.
Cichocki, F., Schlums, H., Li, H., et al. (2014). Transcriptional regulation of MUNC13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with primary immunodeficiency. The Journal of Experimental Medicine, 211, 1079–1091.
Canna, S. W., de Jesus, A. A., Gouni, S., Brooks, S. R., Marrero, B., Liu, Y., et al. (2014). An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nature Genetics, 46, 1140–1146.
Romberg, N., Al Moussawi, K., Nelson-Williams, C., Stiegler, A. L., Loring, E., Choi, M., et al. (2014). Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nature Genetics, 46, 1135–1139.
Yanagimachi, M., Naruto, T., Miyamae, T., Hara, T., Kikuchi, M., Hara, R., et al. (2011). Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. The Journal of Rheumatology, 38, 769–774.
Bracaglia, C., Kathy de Graaf, K., Marafon, D. P., D’Ario, G., Guilhot, F., Ferlin, W., et al. (2017). Elevated circulating levels of interferon-γ and interferon- induced chemokines characterize patients with macrophage activation syndrome complicating systemic JIA. Annals of the Rheumatic Diseases, 76, 166–172.
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Grom, A.A. (2019). Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. In: Cron, R., Behrens, E. (eds) Cytokine Storm Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-22094-5_8
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DOI: https://doi.org/10.1007/978-3-030-22094-5_8
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