Abstract
As the eponymous mediators of the cytokine storm syndrome, cytokines are a pleomorphic and diverse set of soluble molecules that activate or suppress immune functions in a wide variety of ways. The relevant cytokines for each CSS are likely a result of differing combinations of environmental triggers and host susceptibilities. Because cytokines or their receptors may be specifically targeted by biologic therapeutics, understanding which cytokines are relevant for disease initiation and propagation for each unique CSS is of major clinical importance. This chapter reviews what is known about the role of cytokines across the spectrum of CSS.
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References
Jordan, M. B., Hildeman, D., Kappler, J., & Marrack, P. (2004). An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood, 104, 735–743.
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.
Takada, H., Takahata, Y., Nomura, A., Ohga, S., Mizuno, Y., & Hara, T. (2003). Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis. Clinical and Experimental Immunology, 133, 448–453.
Maruoka, H., Inoue, D., Takiuchi, Y., Nagano, S., Arima, H., Tabata, S., et al. (2014). IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome. Annals of Hematology, 93, 393–401.
Behrens, E. M., Canna, S. W., Slade, K., Rao, S., Kreiger, P. A., Paessler, M., et al. (2011). Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. The Journal of Clinical Investigation, 121, 2264–2277.
Prencipe, G., Caiello, I., Pascarella, A., Grom, A. A., Bracaglia, C., Chatel, L., et al. (2018). Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. The Journal of Allergy and Clinical Immunology, 141, 1439–1449.
Buatois, V., Chatel, L., Cons, L., Lory, S., Richard, F., Guilhot, F., et al. (2017). Use of a mouse model to identify a blood biomarker for IFNgamma activity in pediatric secondary hemophagocytic lymphohistiocytosis. Translational Research, 180, 37–52 e32.
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.
Villanueva, J., Lee, S., Giannini, E. H., Graham, T. B., Passo, M. H., Filipovich, A., et al. (2005). Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Research & Therapy, 7, R30–R37.
Put, K., Vandenhaute, J., Avau, A., Van Nieuwenhuijze, A., Brisse, E., Dierckx, T., et al. (2016). Inflammatory gene expression profile and defective IFN-gamma and granzyme K in natural killer cells of systemic juvenile idiopathic arthritis patients. Arthritis & Rhematology, 69(1), 213–224.
Jordan, M., Locatelli, F., Allen, C., De Benedetti, F., Grom, A. A., Ballabio, M., et al. (2015). A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFNγ) monoclonal antibody (mAb), NI-0501: First results from a pilot phase 2 study in children with primary HLH. Blood, 126, LBA–LB3.
Canna, S. W., Wrobel, J., Chu, N., Kreiger, P. A., Paessler, M., & Behrens, E. M. (2013). Interferon-gamma mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice. Arthritis and Rheumatism, 65, 1764–1775.
Staines-Boone, A. T., Deswarte, C., Venegas Montoya, E., Sanchez-Sanchez, L. M., Garcia Campos, J. A., Muniz-Ronquillo, T., et al. (2017). Multifocal recurrent osteomyelitis and hemophagocytic lymphohistiocytosis in a boy with partial dominant IFN-gammaR1 deficiency: Case report and review of the literature. Frontiers in Pediatrics, 5, 75.
Tesi, B., Sieni, E., Neves, C., Romano, F., Cetica, V., Cordeiro, A. I., et al. (2015). Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-gamma receptor deficiency. The Journal of Allergy and Clinical Immunology, 135, 1638–1641.
Miettunen, P. M., Narendran, A., Jayanthan, A., Behrens, E. M., & Cron, R. Q. (2011). Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: Case series with 12 patients. Rheumatology (Oxford), 50, 417–419.
Behrens, E. M., Kreiger, P. A., Cherian, S., & Cron, R. Q. (2006). Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. The Journal of Rheumatology, 33, 2081–2084.
Kelly, A., & Ramanan, A. V. (2008). A case of macrophage activation syndrome successfully treated with anakinra. Nature Clinical Practice. Rheumatology, 4, 615–620.
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.
Ruperto, N., Brunner, H. I., Quartier, P., Constantin, T., Wulffraat, N., Horneff, G., et al. (2012). Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. The New England Journal of Medicine, 367, 2396–2406.
Quartier, P., Allantaz, F., Cimaz, R., Pillet, P., Messiaen, C., Bardin, C., et al. (2011). A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Annals of the Rheumatic Diseases, 70, 747–754.
Nigrovic, P. A., Mannion, M., Prince, F. H., Zeft, A., Rabinovich, C. E., van Rossum, M. A., et al. (2011). Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series. Arthritis and Rheumatism, 63, 545–555.
Grom, A. A., Ilowite, N. T., Pascual, V., Brunner, H. I., Martini, A., Lovell, D., et al. (2016). Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis & Rhematology, 68, 218–228.
Shakoory, B., Carcillo, J. A., Chatham, W. W., Amdur, R. L., Zhao, H., Dinarello, C. A., et al. (2016). Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a prior phase III trial. Critical Care Medicine, 44, 275–281.
Shimizu, M., Nakagishi, Y., Inoue, N., Mizuta, M., Ko, G., Saikawa, Y., et al. (2015). Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clinical Immunology, 160, 277–281.
Girard-Guyonvarc’h, C., Palomo, J., Martin, P., Rodriguez, E., Troccaz, S., Palmer, G., et al. (2018). Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood, 131, 1430–1441.
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.
Canna, S. W., Girard, C., Malle, L., de Jesus, A., Romberg, N., Kelsen, J., et al. (2017). Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. The Journal of Allergy and Clinical Immunology, 139(5), 1698–1701.
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, 74–78.
Chiossone, L., Audonnet, S., Chetaille, B., Chasson, L., Farnarier, C., Berda-Haddad, Y., et al. (2012). Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Frontiers in Immunology, 3, 239.
Rood, J. E., Rao, S., Paessler, M., Kreiger, P. A., Chu, N., Stelekati, E., et al. (2016). ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood, 127, 426–435.
Shimizu, M., Nakagishi, Y., Kasai, K., Yamasaki, Y., Miyoshi, M., Takei, S., et al. (2012). Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The diagnostic significance of interleukin-18 and interleukin-6. Cytokine, 58, 287–294.
Shimizu, M., Yokoyama, T., Yamada, K., Kaneda, H., Wada, H., Wada, T., et al. (2010). Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis. Rheumatology (Oxford), 49, 1645–1653.
Strippoli, R., Carvello, F., Scianaro, R., De Pasquale, L., Vivarelli, M., Petrini, S., et al. (2012). Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: Implication for the pathogenesis of macrophage activation syndrome. Arthritis and Rheumatism, 64, 1680–1688.
Cifaldi, L., Prencipe, G., Caiello, I., Bracaglia, C., Locatelli, F., De Benedetti, F., et al. (2015). Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome. Arthritis & Rhematology, 67, 3037–3046.
Strippoli, R., Caiello, I., & De Benedetti, F. (2013). Reaching the threshold: A multilayer pathogenesis of macrophage activation syndrome. The Journal of Rheumatology, 40, 761–767.
Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., et al. (2013). Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. The New England Journal of Medicine, 368, 1509–1518.
Teachey, D. T., Rheingold, S. R., Maude, S. L., Zugmaier, G., Barrett, D. M., Seif, A. E., et al. (2013). Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood, 121, 5154–5157.
Abraham, E., Wunderink, R., Silverman, H., Perl, T. M., Nasraway, S., Levy, H., et al. (1995). Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA, 273, 934–941.
Clark, M. A., Plank, L. D., Connolly, A. B., Streat, S. J., Hill, A. A., Gupta, R., et al. (1998). Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis—a randomized, clinical trial. Critical Care Medicine, 26, 1650–1659.
Maeshima, K., Ishii, K., Iwakura, M., Akamine, M., Hamasaki, H., Abe, I., et al. (2012). Adult-onset Still’s disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept. Modern Rheumatology, 22, 137–141.
Makay, B., Yilmaz, S., Turkyilmaz, Z., Unal, N., Oren, H., & Unsal, E. (2008). Etanercept for therapy-resistant macrophage activation syndrome. Pediatric Blood & Cancer, 50, 419–421.
Stern, A., Riley, R., & Buckley, L. (2001). Worsening of macrophage activation syndrome in a patient with adult onset Still’s disease after initiation of etanercept therapy. Journal of Clinical Rheumatology, 7, 252–256.
Xu, X. J., Tang, Y. M., Song, H., Yang, S. L., Xu, W. Q., Zhao, N., et al. (2012). Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. The Journal of Pediatrics, 160, 984–990.e981.
Ohyagi, H., Onai, N., Sato, T., Yotsumoto, S., Liu, J., Akiba, H., et al. (2013). Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity, 39, 584–598.
Schaer, D. J., Schaer, C. A., Schoedon, G., Imhof, A., & Kurrer, M. O. (2006). Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. European Journal of Haematology, 77, 432–436.
Wunderlich, M., Stockman, C., Devarajan, M., Ravishankar, N., Sexton, C., Kumar, A. R., et al. (2016). A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti-IL-6R treatment. JCI Insight, 1, e88181.
Milner, J. D., Orekov, T., Ward, J. M., Cheng, L., Torres-Velez, F., Junttila, I., et al. (2010). Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation. Blood, 116, 2476–2483.
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Behrens, E.M. (2019). Cytokines in Cytokine Storm Syndrome. In: Cron, R., Behrens, E. (eds) Cytokine Storm Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-22094-5_12
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DOI: https://doi.org/10.1007/978-3-030-22094-5_12
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