Advertisement

The Intersections of Autoinflammation and Cytokine Storm

  • Scott W. CannaEmail author
Chapter
  • 652 Downloads

Abstract

Autoinflammation is a category of human immune dysregulation best exemplified by inborn errors in genes important for innate immunity. Though overproduction of cytokines is a mechanistic feature of most autoinflammatory diseases, only a few have been associated with the phenotype of Cytokine Storm. Rarely, the most severe presentations of some canonical autoinflammatory diseases have featured cytokine storm. Innate immune activation is also part of the pathogenesis of canonical cytokine storm disorders, like hemophagocytic lymphohistiocytosis. More recently, biomarker, mechanistic, and early treatment studies in patients with Still’s disease, or with NLRC4 or XIAP mutations, have placed the inflammasome-activated cytokine IL-18 at the center of the intersection of autoinflammation and cytokine storm.

Keywords

Autoinflammatory Inflammasome Innate immunity IL-1 IL-18 IL-18 binding protein Pyroptosis Multiorgan dysfunction syndrome Type I interferon Type II interferon/IFN-γ 

References

  1. 1.
    Goldstein, B., Giroir, B., & Randolph, A. (2005). International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatric Critical Care Medicine, 6(1), 2–8.  https://doi.org/10.1097/01.PCC.0000149131.72248.E6CrossRefPubMedGoogle Scholar
  2. 2.
    Pras, E., Aksentijevich, I., Gruberg, L., Balow Jr., J. E., Prosen, L., Dean, M., et al. (1992). Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. The New England Journal of Medicine, 326(23), 1509–1513.  https://doi.org/10.1056/NEJM199206043262301CrossRefPubMedGoogle Scholar
  3. 3.
    McDermott, M. F., Aksentijevich, I., Galon, J., McDermott, E. M., Ogunkolade, B. W., Centola, M., et al. (1999). Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell, 97(1), 133–144.CrossRefGoogle Scholar
  4. 4.
    Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A., & Kolodner, R. D. (2001). Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genetics, 29(3), 301–305.  https://doi.org/10.1038/ng756CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Feldmann, J., Prieur, A. M., Quartier, P., Berquin, P., Certain, S., Cortis, E., et al. (2002). Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. American Journal of Human Genetics, 71(1), 198–203.CrossRefGoogle Scholar
  6. 6.
    Aksentijevich, I., Nowak, M., Mallah, M., Chae, J. J., Watford, W. T., Hofmann, S. R., et al. (2002). De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis and Rheumatism, 46(12), 3340–3348.  https://doi.org/10.1002/art.10688CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    de Jesus, A. A., Canna, S. W., Liu, Y., & Goldbach-Mansky, R. (2015). Molecular mechanisms in genetically defined autoinflammatory diseases: Disorders of amplified danger signaling. Annual Review of Immunology, 33, 823–874.  https://doi.org/10.1146/annurev-immunol-032414-112227CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Agostini, L., Martinon, F., Burns, K., McDermott, M. F., Hawkins, P. N., & Tschopp, J. (2004). NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity, 20(3), 319–325.CrossRefGoogle Scholar
  9. 9.
    Broz, P., & Dixit, V. M. (2016). Inflammasomes: Mechanism of assembly, regulation and signalling. Nature Reviews. Immunology, 16(7), 407–420.  https://doi.org/10.1038/nri.2016.58CrossRefPubMedGoogle Scholar
  10. 10.
    Park, Y. H., Wood, G., Kastner, D. L., & Chae, J. J. (2016). Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nature Immunology, 17(8), 914–921.  https://doi.org/10.1038/ni.3457CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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(10), 1140–1146.  https://doi.org/10.1038/ng.3089CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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(10), 1135–1139.  https://doi.org/10.1038/ng.3066CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldbach-Mansky, R., Dailey, N. J., Canna, S. W., Gelabert, A., Jones, J., Rubin, B. I., et al. (2006). Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. The New England Journal of Medicine, 355(6), 581–592.  https://doi.org/10.1056/NEJMoa055137CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hawkins, P. N., Lachmann, H. J., Aganna, E., & McDermott, M. F. (2004). Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis and Rheumatism, 50(2), 607–612.  https://doi.org/10.1002/art.20033CrossRefPubMedGoogle Scholar
  15. 15.
    Tsoukas, P., & Canna, S. W. (2017). No shortcuts: New findings reinforce why nuance is the rule in genetic autoinflammatory syndromes. Current Opinion in Rheumatology, 29(5), 506–515.  https://doi.org/10.1097/BOR.0000000000000422CrossRefPubMedGoogle Scholar
  16. 16.
    Manthiram, K., Zhou, Q., Aksentijevich, I., & Kastner, D. L. (2017). The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nature Immunology, 18(8), 832–842.  https://doi.org/10.1038/ni.3777CrossRefPubMedGoogle Scholar
  17. 17.
    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.  https://doi.org/10.1182/blood-2010-12-324533
  18. 18.
    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(4), 426–435.  https://doi.org/10.1182/blood-2015-07-659813CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jordan, M. B., Locatelli, F., Allen, C., de Benedetti, F., Grom, A., Ballabio, M., et al. (2015). Abstract: 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(23), LBA-3.CrossRefGoogle Scholar
  20. 20.
    Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., et al. (2007). Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American Journal of Human Genetics, 81(4), 713–725.  https://doi.org/10.1086/521373CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tungler, V., Konig, N., Gunther, C., Engel, K., Fiehn, C., Smitka, M., et al. (2016). Response to: ‘JAK inhibition in STING-associated interferonopathy’ by Crow et al. Annals of the Rheumatic Diseases, 75(12), e76.  https://doi.org/10.1136/annrheumdis-2016-210565CrossRefPubMedGoogle Scholar
  22. 22.
    Aksentijevich, I., Masters, S. L., Ferguson, P. J., Dancey, P., Frenkel, J., van Royen-Kerkhoff, A., et al. (2009). An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. The New England Journal of Medicine, 360(23), 2426–2437.  https://doi.org/10.1056/NEJMoa0807865CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mendonca, L. O., Malle, L., Donovan, F. X., Chandrasekharappa, S. C., Montealegre Sanchez, G. A., Garg, M., et al. (2017). Deficiency of interleukin-1 receptor antagonist (DIRA): Report of the first Indian patient and a novel deletion affecting IL1RN. Journal of Clinical Immunology, 37(5), 445–451.  https://doi.org/10.1007/s10875-017-0399-1CrossRefPubMedGoogle Scholar
  24. 24.
    Koc, B., Oktenli, C., Bulucu, F., Karadurmus, N., Sanisoglu, S. Y., & Gul, D. (2007). The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: A pilot study. The Journal of Rheumatology, 34(10), 2070–2075.PubMedGoogle Scholar
  25. 25.
    Rodrigue-Gervais, I. G., & Saleh, M. (2010). Genetics of inflammasome-associated disorders: A lesson in the guiding principals of inflammasome function. European Journal of Immunology, 40(3), 643–648.  https://doi.org/10.1002/eji.200940225CrossRefPubMedGoogle Scholar
  26. 26.
    Schulert, G. S., Zhang, M., Fall, N., Husami, A., Kissell, D., Hanosh, A., et al. (2016). Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. The Journal of Infectious Diseases, 213(7), 1180–1188.  https://doi.org/10.1093/infdis/jiv550CrossRefPubMedGoogle Scholar
  27. 27.
    Krebs, P., Crozat, K., Popkin, D., Oldstone, M. B., & Beutler, B. (2011). Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood, 117(24), 6582–6588.  https://doi.org/10.1182/blood-2011-01-329607CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zoller, E. E., Lykens, J. E., Terrell, C. E., Aliberti, J., Filipovich, A. H., Henson, P. M., et al. (2011). Hemophagocytosis causes a consumptive anemia of inflammation. The Journal of Experimental Medicine, 208(6), 1203–1214.  https://doi.org/10.1084/jem.20102538CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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(15), e88181.  https://doi.org/10.1172/jci.insight.88181CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sepulveda, F. E., Maschalidi, S., Vosshenrich, C. A., Garrigue, A., Kurowska, M., Menasche, G., et al. (2014). A novel immunoregulatory role for NK cell cytotoxicity in protection from HLH-like immunopathology in mice. Blood, 125(9), 1427–1434.  https://doi.org/10.1182/blood-2014-09-602946CrossRefPubMedGoogle Scholar
  31. 31.
    Ombrello, M. J., Remmers, E. F., Tachmazidou, I., Grom, A., Foell, D., Haas, J. P., et al. (2015). HLA-DRB1∗11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proceedings of the National Academy of Sciences of the United States of America, 112(52), 15970–15975.  https://doi.org/10.1073/pnas.1520779112CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    De Benedetti, F., Brunner, H. I., Ruperto, N., Kenwright, A., Wright, S., Calvo, I., et al. (2012). Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. The New England Journal of Medicine, 367(25), 2385–2395.  https://doi.org/10.1056/NEJMoa1112802CrossRefPubMedGoogle Scholar
  33. 33.
    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(25), 2396–2406.  https://doi.org/10.1056/NEJMoa1205099CrossRefPubMedGoogle Scholar
  34. 34.
    Ombrello, M. J., Arthur, V. L., Remmers, E. F., Hinks, A., Tachmazidou, I., Grom, A. A., et al. (2016). Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications. Annals of the Rheumatic Diseases, 76(5), 906–913.  https://doi.org/10.1136/annrheumdis-2016-210324CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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(2), 277–281.  https://doi.org/10.1016/j.clim.2015.06.005CrossRefPubMedGoogle Scholar
  36. 36.
    Girard, C., Rech, J., Brown, M., Allali, D., Roux-Lombard, P., Spertini, F., et al. (2016). Elevated serum levels of free interleukin-18 in adult-onset Still’s disease. Rheumatology (Oxford), 55(12), 2237–2247.  https://doi.org/10.1093/rheumatology/kew300CrossRefGoogle Scholar
  37. 37.
    Gabay, C., Fautrel, B., Rech, J., Spertini, F., Feist, E., Kotter, I., et al. (2018). Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease. Annals of the Rheumatic Diseases.  https://doi.org/10.1136/annrheumdis-2017-212608
  38. 38.
    Weiss, E. S., Girard-Guyonvarc’h, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., et al. (2018). Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood, 131(13), 1442–1455.  https://doi.org/10.1182/blood-2017-12-820852CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liang, J., Alfano, D. N., Squires, J. E., Riley, M. M., Parks, W. T., Kofler, J., et al. (2017). Novel NLRC4 mutation causes a syndrome of perinatal autoinflammation with hemophagocytic lymphohistiocytosis, hepatosplenomegaly, fetal thrombotic vasculopathy, and congenital anemia and ascites. Pediatric and Developmental Pathology, 20(6), 498–505.CrossRefGoogle Scholar
  40. 40.
    Moghaddas, F., Zeng, P., Zhang, Y., Schutzle, H., Brenner, S., Hofmann, S. R., et al. (2018). Autoinflammatory mutation in NLRC4 reveals an LRR-LRR oligomerization interface. The Journal of Allergy and Clinical Immunology.  https://doi.org/10.1016/j.jaci.2018.04.033
  41. 41.
    Canna, S. W., Girard, C., Malle, L., de Jesus, A., Romberg, N., Kelsen, J., et al. (2016). Life-threatening NLRC4-associated hyperinflammation successfully treated with Interleukin-18 inhibition. The Journal of Allergy and Clinical Immunology, 139(5), 1698–1701.  https://doi.org/10.1016/j.jaci.2016.10.022CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Bracaglia, C., Prencipe, G., Gatto, A., Pardeo, M., Lapeyre, G., Raganelli, L., et al. (2015). Anti interferon-gamma (IFN gamma) monoclonal antibody treatment in a child with NLRC4-related disease and severe hemophagocytic lymphohistiocytosis (HLH). Pediatric Blood & Cancer, 62, S123–S123.CrossRefGoogle Scholar
  43. 43.
    Bracaglia, C., de Graaf, K., Pires Marafon, D., Guilhot, F., Ferlin, W., Prencipe, G., et al. (2017). Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Annals of the Rheumatic Diseases, 76(1), 166–172.  https://doi.org/10.1136/annrheumdis-2015-209020CrossRefPubMedGoogle Scholar
  44. 44.
    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(13), 1430–1441.  https://doi.org/10.1182/blood-2017-06-789552CrossRefPubMedGoogle Scholar
  45. 45.
    Rigaud, S., Fondaneche, M. C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., et al. (2006). XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature, 444(7115), 110–114.  https://doi.org/10.1038/nature05257CrossRefPubMedGoogle Scholar
  46. 46.
    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(7), 1079–1082.  https://doi.org/10.1182/blood-2010-01-256099CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lawlor, K. E., Feltham, R., Yabal, M., Conos, S. A., Chen, K. W., Ziehe, S., et al. (2017). XIAP loss triggers RIPK3- and caspase-8-driven IL-1beta activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Reports, 20(3), 668–682.  https://doi.org/10.1016/j.celrep.2017.06.073CrossRefPubMedGoogle Scholar
  48. 48.
    Kenneth, N. S., & Duckett, C. S. (2012). IAP proteins: Regulators of cell migration and development. Current Opinion in Cell Biology, 24(6), 871–875.  https://doi.org/10.1016/j.ceb.2012.11.004CrossRefPubMedGoogle Scholar
  49. 49.
    Yabal, M., Muller, N., Adler, H., Knies, N., Gross, C. J., Damgaard, R. B., et al. (2014). XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Reports, 7(6), 1796–1808.  https://doi.org/10.1016/j.celrep.2014.05.008CrossRefPubMedGoogle Scholar
  50. 50.
    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.2013.09.007CrossRefPubMedGoogle Scholar
  51. 51.
    Gernez, Y., de Jesus, A. A., Alsaleem, H., Macaubas, C., Roy, A., Lovell, D., et al. (2019). Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 (CDC42) successfully treated with IL-1beta inhibition. The Journal of Allergy and Clinical Immunology, epub Jul 2.  https://doi.org/10.1016/j.jaci.2019.06.017
  52. 52.
    Speckmann, C., Lehmberg, K., Albert, M. H., Damgaard, R. B., Fritsch, M., Gyrd-Hansen, M., et al. (2013). X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clinical Immunology, 149(1), 133–141.  https://doi.org/10.1016/j.clim.2013.07.004CrossRefPubMedGoogle Scholar
  53. 53.
    Kitamura, A., Sasaki, Y., Abe, T., Kano, H., & Yasutomo, K. (2014). An inherited mutation in NLRC4 causes autoinflammation in human and mice. The Journal of Experimental Medicine, 211(12), 2385–2396.  https://doi.org/10.1084/jem.20141091CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Volker-Touw, C. M., de Koning, H. D., Giltay, J., de Kovel, C., van Kempen, T. S., Oberndorff, K., et al. (2016). Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype. The British Journal of Dermatology, 176(1), 244–248.  https://doi.org/10.1111/bjd.14757CrossRefPubMedGoogle Scholar
  55. 55.
    Kawasaki, Y., Oda, H., Ito, J., Niwa, A., Tanaka, T., Hijikata, A., et al. (2017). Identification of a high-frequency somatic NLRC4 mutation as a cause of autoinflammation by pluripotent cell-based phenotype dissection. Arthritis & Rheumatology, 69(2), 447–459.  https://doi.org/10.1002/art.39960CrossRefGoogle Scholar
  56. 56.
    de Jager, W., Vastert, S. J., Beekman, J. M., Wulffraat, N. M., Kuis, W., Coffer, P. J., et al. (2009). Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis and Rheumatism, 60(9), 2782–2793.  https://doi.org/10.1002/art.24750CrossRefPubMedGoogle Scholar
  57. 57.
    Put, K., Vandenhaute, J., Avau, A., van Nieuwenhuijze, A., Brisse, E., Dierckx, T., et al. (2017). Inflammatory gene expression profile and defective interferon-gamma and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients. Arthritis & Rheumatology, 69(1), 213–224.  https://doi.org/10.1002/art.39933CrossRefGoogle Scholar
  58. 58.
    Munoz, M., Eidenschenk, C., Ota, N., Wong, K., Lohmann, U., Kuhl, A. A., et al. (2015). Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity, 42(2), 321–331.  https://doi.org/10.1016/j.immuni.2015.01.011CrossRefPubMedGoogle Scholar
  59. 59.
    Nowarski, R., Jackson, R., Gagliani, N., de Zoete, M. R., Palm, N. W., Bailis, W., et al. (2015). Epithelial IL-18 equilibrium controls barrier function in colitis. Cell, 163(6), 1444–1456.  https://doi.org/10.1016/j.cell.2015.10.072CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Rauch, I., Deets, K. A., Ji, D. X., von Moltke, J., Tenthorey, J. L., Lee, A. Y., et al. (2017). NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity, 46(4), 649–659.  https://doi.org/10.1016/j.immuni.2017.03.016CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chudnovskiy, A., Mortha, A., Kana, V., Kennard, A., Ramirez, J. D., Rahman, A., et al. (2016). Host-protozoan interactions protect from mucosal infections through activation of the inflammasome. Cell, 167(2), 444–456.e414.  https://doi.org/10.1016/j.cell.2016.08.076CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    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(2), 275–281.  https://doi.org/10.1097/CCM.0000000000001402CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.RK Mellon Institute for Pediatric Research/Pediatric RheumatologyUniversity of Pittsburgh/UPMC Children’s Hospital of PittsburghPittsburghUSA

Personalised recommendations