Abstract
Sepsis, now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, initiates a complex interplay of host processes. Several lines of clinical evidence show that patients with severe sepsis not only exhibited an exaggerated inflammation but also exhibited multiple defects in adaptive immunity. Data suggest that a subgroup of septic patients with severe immune alterations is at high risk of death or nosocomial infection and therefore could benefit from adjunctive immune stimulating therapies. This finding has been termed the persistent inflammation/immunosuppression and catabolism syndrome. The immediate inflammatory response is presumed to be predominantly driven by danger signals produced by pathogens, which bind to innate immune receptors activating a complex intracellular signaling system that leads to the expression of several common gene classes that are involved in inflammation, adaptive immunity, and cellular metabolism, but pathophysiology of immunosuppression is not completely understood. This review details the mediators in sepsis linking to innate and adaptive immune systems to explain part of pathophysiology of this severe condition.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10. https://doi.org/10.1001/jama.2016.0287.
Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.
Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 2001;16(2):83–96.
Ayala A, Chaudry IH. Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis. Shock. 1996;6(Suppl 1):S27–38.
Opal SM, Huber CE. Bench-to-bedside review: Toll-like receptors and their role in septic shock. Crit Care. 2002;6(2):125–36.
Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ. HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1768–73.
Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8(10):776–87. https://doi.org/10.1038/nri2402.
Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13(3):260–8. https://doi.org/10.1016/S1473-3099(13)70001-X.
Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000;343(1):37–49.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.
Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol. 2004;40:861–8.
Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–80.
Motta V, Soares F, Sun T, Philpott DJ. NOD-like receptors: versatile cytosolic sentinels. Physiol Rev. 2015;95(1):149–78. https://doi.org/10.1152/physrev.00009.2014.
Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R. The Nod-like receptor (NLR) family: a tale of similarities and differences. PLoS One. 2008;3(4):e2119. https://doi.org/10.1371/journal.pone.0002119.
Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314(5801):994–7.
Paz S, Sun Q, Nakhaei P, Romieu-Mourez R, Goubau D, Julkunen I, et al. Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway. Cell Mol Biol (Noisy-le-grand). 2006;52(1):17–28.
Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005;23:821–52.
Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun. 2010;2(5):439–45. https://doi.org/10.1159/000317194.
Ramnath R, Weing S, He M, Sun J, Zhang H, Bawa M, Bhatia M. Inflammatory mediators in sepsis: cytokines, chemokines, adhesion molecules and gases. J. Organ Dysfunction. 2006;2:80–92.
Bierhaus A, Nawroth PP. Modulation of the vascular endothelium during infection—the role of NF-kappa B activation. Contrib Microbiol. 2003;10:86–105.
Parikh SM. Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence. 2013;4(6):517–24. https://doi.org/10.4161/viru.24906.
Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. 2000;343(2):108–17. https://doi.org/10.1056/NEJM200007133430207.
Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013;93(3):329–42. https://doi.org/10.1189/jlb.0912437.
Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008;83(3):523–35.
Wiersinga WJ. Current insights in sepsis: from pathogenesis to new treatment targets. Curr Opin Crit Care. 2011;17(5):480–6. https://doi.org/10.1097/MCC.0b013e32834a4aeb.
Hotchkiss RS, Opal S. Immunotherapy for sepsis--a new approach against an ancient foe. N Engl J Med. 2010;363(1):87–9. https://doi.org/10.1056/NEJMcibr1004371.
Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;24(7):1125–8.
Bone RC. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med. 1996;24:163–72.
Remick D, Manohar P, Bolgos G, Rodriguez J, Moldawer L, Wollenberg G. Blockade of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal ligation and puncture. Shock. 1995;4(2):89–95.
Eskandari MK, Bolgos G, Miller C, Nguyen DT, DeForge LE, Remick DG. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J Immunol. 1992;148(9):2724–30.
Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177(3):1967–74.
Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, et al. Inflammation and host response to injury large-scale collaborative research program. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–90. https://doi.org/10.1084/jem.20111354.
Gentile LF, Cuenca AG, Efron PA, Ang D, Bihorac A, McKinley BA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491–501. https://doi.org/10.1097/TA.0b013e318256e000.
Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One. 2014;9(2):e98819. https://doi.org/10.1371/journal.pone.0098819.
Drifte G, Dunn-Siegrist I, Tissières P, Pugin J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med. 2013;41(3):820–32. https://doi.org/10.1097/CCM.0b013e318274647d.
Hashiba M, Huq A, Tomino A, Hirakawa A, Hattori T, Miyabe H, et al. Neutrophil extracellular traps in patients with sepsis. J Surg Res. 2015;194(1):248–54. https://doi.org/10.1016/j.jss.2014.09.033.
Hynninen M, Pettilä V, Takkunen O, Orko R, Jansson SE, Kuusela P, et al. Predictive value of monocyte histocompatibility leukocyte antigen-DR expression and plasma interleukin-4 and -10 levels in critically ill patients with sepsis. Shock. 2003;20(1):1–4.
Munoz C, Carlet J, Fitting C, Misset B, Blériot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88(5):1747–54. https://doi.org/10.1172/JCI115493.
Nierhaus A, Montag B, Timmler N, Frings DP, Gutensohn K, Jung R, et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003;29(4):646–51.
Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3(6):678–81.
Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte-macrophage colony stimulating factor to reverse sepsis-associated immunosuppression: a double blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–8. https://doi.org/10.1164/rccm.200903-0363OC.
Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, 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(15):6303–8. https://doi.org/10.1073/pnas.0809422106.
Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–605. https://doi.org/10.1001/jama.2011.1829.
Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42(5):383–91. https://doi.org/10.1097/SHK.0000000000000234.
Coopersmith CM, Amiot DM 2nd, Stromberg PE, Dunne WM, Davis CG, Osborne DF, et al. Antibiotics improve survival and alter the inflammatory profile in a murine model of sepsis from Pseudomonas aeruginosa pneumonia. Shock. 2003;19(5):408–14.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64.
Fehérvari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest. 2004;114(9):1209–17.
Scumpia PO, Delano MJ, Kelly KM, O'Malley KA, Efron PA, McAuliffe PF, et al. Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol. 2006;177(11):7943–9.
Wisnoski N, Chung CS, Chen Y, Huang X, Ayala A. The contribution of CD4+ CD25+ T-regulatory-cells to immune suppression in sepsis. Shock. 2007;27(3):251–7. https://doi.org/10.1097/01.shk.0000239780.33398.e4.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media LLC
About this chapter
Cite this chapter
Fonseca-Ruiz, N.J. (2018). Immunity in Sepsis. In: Ortiz-Ruiz, G., Dueñas-Castell, C. (eds) Sepsis. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7334-7_3
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7334-7_3
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-7332-3
Online ISBN: 978-1-4939-7334-7
eBook Packages: MedicineMedicine (R0)