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Cytokines in Cytokine Storm Syndrome

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Cytokine Storm Syndrome

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

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    PubMed  Google Scholar 

  17. Kelly, A., & Ramanan, A. V. (2008). A case of macrophage activation syndrome successfully treated with anakinra. Nature Clinical Practice. Rheumatology, 4, 615–620.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

  42. 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.

    Article  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Edward M. Behrens

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  1. Edward M. Behrens
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Correspondence to Edward M. Behrens .

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Editors and Affiliations

  1. UAB School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Randy Q. Cron

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edward M. Behrens

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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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