Immune homeostasis (deregulation) in sepsis and septic shock


Authors: Karvunidis Thomas 1;  Lysák Daniel 2;  Chvojka Jiří 1;  Ledvinová Lenka 1;  Raděj Jaroslav 1;  Novák Ivan 1;  Matějovič Martin 1
Authors‘ workplace: JIP, I. interní klinika FN v Plzni a LF v Plzni, Univerzita Karlova v Praze 1;  Hematologicko-onkologické oddělení, Fakultní nemocnice v Plzni 2
Published in: Anest. intenziv. Med., 24, 2013, č. 4, s. 250-263
Category: Intensive Care Medicine - Original Paper

Overview

Sepsis and septic shock represent an important medical and socio-economic burden worldwide. The double-phased concept of significant immune homeostasis impairment in sepsis has generally been accepted. In this theory, the initial phase is characterized by enormous activation of immune system followed by the compen-satory phase resulting in profound immunosuppression. However, this paradigm has recently been challenged and the concept of simultaneous pro-inflammatory, anti-inflammatory and adaptive immunity suppressing response occurring early in sepsis has been introduced. These immune alterations leading to the failure to combat relatively avirulent, nosocomial and opportune pathogens, and prolonged multiorgan dysfunction seem to be a major cause of increased morbidity and mortality in critically ill patients. This review briefly summarizes the current concept of sepsis-induced immune deregulation and discusses diagnostic tools and emerging immune-based therapeutic interventions.

Keywords:
sepsis – immune response – immune deregulation – flow cytometry


Sources

1. Martin, G. S., Mannino, D. M., Eaton, S. et al. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med., 2003, 348, p. 1546–1554.

2. Annane, D., Bellissant, E., Cavaillon, J. M. Septic shock. Lancet, 2005, 365, p. 63–78.

3. Riedemann, N. C., Guo, R. F., Ward, P. A. Novel strategies for the treatment of sepsis. Nat. Med., 2003, 9, p. 517–524.

4. Boomer, J. S., To, K., Chang, K. C. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA, 2011, 306, p. 2594–2605.

5. Littman, D. R., Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell, 2010, 140, p. 845–858.

6. Cinel, I., Opal, S. M. Molecular biology of inflammation and sepsis: a primer. Crit. Care Med., 2009, 37, p. 291–304.

7. Netea, M. G., van der Meer, J. W. Immunodeficiency and genetic defects of pattern-recognition receptors. N. Engl. J. Med., 2011, 364, p. 60–70.

8. Opal, S. M. New perspectives on immunomodulatory therapy for bacteraemia and sepsis. Int. J. Antimicrob. Agents, 2010, 36 Suppl 2, p. S70–S73.

9. Larosa, S. P., Opal, S. M. Immune aspects of sepsis and hope for new therapeutics. Curr. Infect. Dis. Rep., 2012, 14, p. 474–483.

10. Van der, P. T., Opal, S. M. Host-pathogen interactions in sepsis. Lancet Infect. Dis., 2008, 8, p. 32–43.

11. Sursal, T., Stearns-Kurosawa, D. J., Itagaki, K. et al. Plasma bacterial and mitochondrial DNA distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates. Shock, 2013, 39, p. 55–62.

12. Gentile, L. F., Cuenca, A. G., Efron, P. A. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute. Care Surg., 2012, 72, p. 1491–1501.

13. Monneret, G., Lepape, A., Voirin, N. et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med., 2006, 32, p. 1175–1183.

14. Xiao, W., Mindrinos, M. N., Seok, J. et al. A genomic storm in critically injured humans. J. Exp. Med., 2011, 208, p. 2581–2590.

15. Calvano, S. E., Xiao, W., Richards, D. R. et al. A network-based analysis of systemic inflammation in humans. Nature, 2005, 437, p. 1032–1037.

16. Prucha, M., Ruryk, A., Boriss, H. et al. Expression profiling: toward an application in sepsis. Shock, 2004, 22, p. 29–33.

17. Johnson, S. B., Lissauer, M., Bochicchio, G. V. et al. Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann. Surg., 2007, 245, p. 611–621.

18. Tang, B. M., McLean, A. S., Dawes, I. W. et al. Gene-expression profiling of peripheral blood mononuclear cells in sepsis. Crit. Care Med., 2009, 37, p. 882–888.

19. Sprung, C. L., Sakr, Y., Vincent, J. L. et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely ill Patients (SOAP) study. Intensive Care Med., 2006, 32, p. 421–427.

20. Hotchkiss, R. S., Karl, I. E. The pathophysiology and treatment of sepsis. N. Engl. J. Med., 2003, 348, p. 138–150.

21. Gentile, L. F., Moldawer, L. L. DAMPs, PAMPs, and the Origins of SIRS in Bacterial Sepsis. Shock, 2013, 39, p. 113–114.

22. Bauer, M., Reinhart, K. Molecular diagnostics of sepsis--where are we today? Int. J. Med. Microbiol., 2010, 300, p. 411–413.

23. Wong, H. R. Clinical review: sepsis and septic shock – the potential of gene arrays. Crit Care, 2012, 16, p. 204.

24. Karvunidis, T., Mares, J., Thongboonkerd, V. et al. Recent progress of proteomics in critical illness. Shock, 2009, 31, p. 545–552.

25. Cohen, J. The immunopathogenesis of sepsis. Nature, 2002, 420, p. 885–891.

26. Hotchkiss, R. S., Swanson, P. E., Freeman, B. D. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med., 1999, 27, p. 1230–1251.

27. Hotchkiss, R. S., Chang, K. C., Swanson, P. E. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat. Immunol., 2000, 1, p. 496–501.

28. Hotchkiss, R. S., Tinsley, K. W., Swanson, P. E. et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J. Immunol., 2001, 166, p. 6952–6963.

29. Hotchkiss, R. S., Tinsley, K. W., Swanson, P. E. et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J. Immunol., 2002, 168, p. 2493–2500.

30. Nolan, A., Kobayashi, H., Naveed, B. et al. Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis. PLoS. One., 2009, 4, p. e6600.

31. Hotchkiss, R. S., Opal, S. Immunotherapy for sepsis–a new approach against an ancient foe. N. Engl. J. Med., 2010, 363, p. 87–89.

32. Guisset, O., Dilhuydy, M. S., Thiebaut, R. et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med., 2007, 33, p. 148–152.

33. Faivre, V., Lukaszewicz, A. C., Alves, A. et al. Accelerated in vitro differentiation of blood monocytes into dendritic cells in human sepsis. Clin. Exp. Immunol., 2007, 147, p. 426–439.

34. Nathan, C., Ding, A. Nonresolving inflammation. Cell, 2010, 140, p. 871–882.

35. Mantovani, A., Cassatella, M. A., Costantini, C. et al. Neutrophilsin the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol., 2011, 11, p. 519–531.

36. Urban, C. F., Ermert, D., Schmid, M. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS. Pathog., 2009, 5, p. e1000639.

37. Kovach, M. A., Standiford, T. J. The function of neutrophils in sepsis. Curr. Opin. Infect. Dis., 2012, 25, p. 321–327.

38. Karvunidis, T., Chvojka, J., Lysak, D. et al. Septic shock and chemotherapy – induced cytopenia: effects on microcirculation. Intensive Care Med., 2012, 38, p. 1336–1344.

39. Lipscomb, M. F., Masten, B. J. Dendritic cells: immune regulators in health and disease. Physiol Rev., 2002, 82, p. 97–130.

40. Zitvogel, L. Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J. Exp. Med., 2002, 195, p. F9–14.

41. Pene, F., Mira, J. P., Chiche, J. D. Nobel Prize laureates pave the way for therapeutic advances in sepsis. Intensive Care Med., 2012, 38, p. 183–185.

42. Patterson, S. Flexibility and cooperation among dendritic cells. Nat. Immunol., 2000, 1, p. 273–274.

43. Grimaldi, D., Louis, S., Pene, F. et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med., 2011, 37, p. 1438–1446.

44. Astiz, M., Saha, D., Lustbader, D. et al. Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. J. Lab Clin. Med., 1996, 128, p. 594–600.

45. Manjuck, J., Saha, D. C., Astiz, M. et al. Decreased response to recall antigens is associated with depressed costimulatory receptor expression in septic critically ill patients. J. Lab. Clin. Med., 2000, 135, p. 153–160.

46. Wolk, K., Docke, W. D., Von, B., V. et al. Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood, 2000, 96, p. 218–223.

47. Fumeaux, T., Pugin, J. Is the measurement of monocytesHLA-DR expression useful in patients with sepsis? Intensive Care Med., 2006, 32, p. 1106–1108.

48. Tschoeke, S. K., Moldawer, L. L. Human leukocyte antigen expression in sepsis: what have we learned? Crit. Care Med., 2005, 33, p. 236–237.

49. Trimmel, H., Luschin, U., Kohrer, K. et al. Clinical outcome of critically ill patients cannot be defined by cutoff values of monocyte human leukocyte antigen-DR expression. Shock, 2012, 37, p. 140–144.

50. Okazaki, T., Honjo, T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol., 2006, 27, p. 195–201.

51. Keir, M. E., Butte, M. J., Freeman, G. J. et al. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol., 2008, 26, p. 677–704.

52. Huang, X., Venet, F., Wang, Y. L. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl. Acad. Sci. U. S. A, 2009, 106, p. 6303–6308.

53. Holub, M., Kluckova, Z., Beneda, B. et al. Changes in lymphocyte subpopulations and CD3+/DR+ expression in sepsis. Clin. Microbiol. Infect., 2000, 6, p. 657–660.

54. Holub, M., Kluckova, Z., Helcl, M. et al. Lymphocyte subset numbers depend on the bacterial origin of sepsis. Clin. Microbiol. Infect., 2003, 9, p. 202–211.

55. Ochoa, J. B., Makarenkova, V. T lymphocytes. Crit. Care Med., 2005, 33, p. S510–S513.

56. Curfs, J. H., Meis, J. F., Hoogkamp-Korstanje, J. A. A primer on cytokines: sources, receptors, effects, and inducers. Clin. Microbiol. Rev., 1997, 10, p. 742–780.

57. Hotchkiss, R. S., Osmon, S. B., Chang, K. C. et al. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J. Immunol., 2005, 174, p. 5110–5118.

58. Felmet, K. A., Hall, M. W., Clark, R. S. et al. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J. Immunol., 2005, 174, p. 3765–3772.

59. Kasten, K. R., Tschop, J., Adediran, S. G. et al. T cells are potent early mediators of the host response to sepsis. Shock, 2010, 34, p. 327–336.

60. Swan, R., Chung, C. S., Albina, J. et al. Polymicrobial sepsis enhances clearance of apoptotic immune cells by splenic macrophages. Surgery, 2007, 142, p. 253–261.

61. Pachot, A., Monneret, G., Voirin, N. et al. Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin. Immunol., 2005, 114, p. 61–69.

62. Korn, T., Bettelli, E., Oukka, M. et al. IL-17 and Th17 Cells. Annu. Rev. Immunol., 2009, 27, p. 485–517.

63. Zhu, J., Paul, W. E. Heterogeneity and plasticity of T helper cells. Cell Res., 2010, 20, p. 4–12.

64. Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol., 2004, 22, p. 531–562.

65. Feuerer, M., Shen, Y., Littman, D. R. et al. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity, 2009, 31, p. 654–664.

66. Sitkovsky, M. V. T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol., 2009, 30, p. 102–108.

67. Souza-Fonseca-Guimaraes, F., Dib-Conquy, M., Cavaillon, J. M.Natural killer (NK) cells in antibacterial innate immunity: angels or devils? Mol. Med., 2012, 18, p. 270–285.

68. Vivier, E., Raulet, D. H., Moretta, A. et al. Innate or adaptive immunity? The example of natural killer cells. Science, 2011, 331, p. 44–49.

69. Forel, J. M., Chiche, L., Thomas, G. et al. Phenotype and functions of natural killer cells in critically-ill septic patients. PLoS. One., 2012, 7, p. e50446.

70. Boomer, J. S., Shuherk-Shaffer, J., Hotchkiss, R. S. et al.A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit. Care, 2012, 16, p. R112.

71. McDunn, J. E., Hotchkiss, R. S. Leukocyte phenotyping to stratify septic shock patients. Crit Care, 2009, 13, p. 127.

72. Gregoire, C., Chasson, L., Luci, C. et al. The trafficking of natural killer cells. Immunol. Rev., 2007, 220, p. 169–182.

73. Etogo, A. O., Nunez, J., Lin, C. Y. et al. NK but not CD1-restricted NKT cells facilitate systemic inflammation during polymicrobial intra-abdominal sepsis. J. Immunol., 2008, 180, p. 6334–6345.

74. Herzig, D. S., Driver, B. R., Fang, G. et al. Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock. Am. J. Respir. Crit. Care Med., 2012, 185, p. 291–300.

75. Monserrat, J., de, P. R., Reyes, E. et al. Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients. Crit Care, 2009, 13, p. R26.

76. Andaluz-Ojeda, D., Iglesias, V., Bobillo, F. et al. Early natural killer cell counts in blood predict mortality in severe sepsis. Crit. Care, 2011, 15, p. R243.

77. de Pablo, R., Monserrat, J., Torrijos, C. et al. The predictive role of early activation of natural killer cells in septic shock. Crit Care, 2012, 16, p. 413.

78. Roark, C. L., French, J. D., Taylor, M. A. et al. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J. Immunol., 2007, 179, p. 5576–5583.

79. Han, G., Geng, S., Li, Y. et al. gammadeltaT-cell function in sepsis is modulated by C5a receptor signalling. Immunology, 2011, 133, p. 340–349.

80. Cheng, L., Cui, Y., Shao, H. et al. Mouse gammadelta T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells. J. Neuroimmunol., 2008, 203, p. 3–11.

81. Sinha, P., Clements, V. K., Bunt, S. K. et al. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol., 2007, 179, p. 977–983.

82. Gabrilovich, D. I., Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol., 2009, 9, p. 162–174.

83. Ochoa, A. C., Zea, A. H., Hernandez, C. et al. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res., 2007, 13, p. 721s–726s.

84. Cuenca, A. G., Moldawer, L. L. Myeloid-derived suppressor cells in sepsis: friend or foe? Intensive Care Med., 2012, 38, p. 928–930.

85. Brudecki, L., Ferguson, D. A., McCall, C. E. et al. Myeloid-derived suppressor cells evolve during sepsis and can enhance or attenuate the systemic inflammatory response. Infect. Immun., 2012, 80, p. 2026–2034.

86. Derive, M., Bouazza, Y., Alauzet, C. et al. Myeloid-derived suppressor cells control microbial sepsis. Intensive Care Med., 2012, 38, p. 1040–1049.

87. Sansonetti, P. J. The innate signaling of dangers and the dangers of innate signaling. Nat. Immunol., 2006, 7, p. 1237–1242.

88. Monneret, G., Venet, F., Pachot, A. et al. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol. Med., 2008, 14, p. 64–78.

89. Carrette, F., Surh, C. D. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin. Immunol., 2012, 24, p. 209–217.

90. Kasten, K. R., Tschop, J., Goetzman, H. S. et al. T-cell activation differentially mediates the host response to sepsis. Shock, 2010, 34, p. 377–383.

91. Rendon, J. L., Choudhry, M. A. Th17 cells: critical mediators of host responses to burn injury and sepsis. J. Leukoc. Biol., 2012, 92, p. 529–538.

92. Iwakura, Y., Ishigame, H., Saijo, S. et al. Functional specialization of interleukin-17 family members. Immunity, 2011, 34, p. 149–162.

93. Nakada, T. A., Russell, J. A., Boyd, J. H. et al. IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis. Crit. Care, 2011, 15, p. R254.

94. Oboki, K., Ohno, T., Kajiwara, N. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl. Acad. Sci. U. S. A, 2010, 107, p. 18581–18586.

95. ves-Filho, J. C., Sonego, F., Souto, F. O. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med., 2010, 16, p. 708–712.

96. Mirchandani, A. S., Salmond, R. J., Liew, F. Y. Interleukin-33 and the function of innate lymphoid cells. Trends Immunol., 2012, 33, p. 389–396.

97. Bianchi, M. E., Manfredi, A. A. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol. Rev., 2007, 220, p. 35–46.

98. Sunden-Cullberg, J., Norrby-Teglund, A., Rouhiainen, A. et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med., 2005, 33, p. 564–573.

99. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol., 2007, 81, p. 1–5.

100. Hotchkiss, R. S. Immunotherapy for Sepsis — A New Approach against an Ancient Foe. N. Engl. J. Med., 2010, 363, p. 87–89

Labels
Anaesthesiology, Resuscitation and Inten Intensive Care Medicine
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account