Immunologic Alterations and the Pathogenesis of Organ Failure in the ICU

ABSTRACT

Rapid and marked alterations of innate and adaptive immunity typify the host response to systemic infection and acute inflammatory states. Immune dysfunction contributes to the development of organ failure in most patients with critical illness. The molecular mechanisms by which microbial pathogens and tissue injury activate myeloid cells and prime cellular and humoral immunity are increasingly understood. An early and effective immune response to microbial invasion is essential to mount an effective antimicrobial response. However, unchecked and nonresolving inflammation can induce diffuse vasodilation, increased capillary permeability, microvascular damage, coagulation activation, and organ dysfunction. Control of the inflammatory response to limit tissue damage, yet retain the antimicrobial responses in critically ill patients with severe infection, has been sought for decades. Anti-inflammatory approaches might be beneficial in some patients but detrimental in others. It is now clear that a state of sepsis-induced immune suppression can follow the immune activation phase of sepsis. In carefully selected patients, a better therapeutic strategy might be to provide immunoadjuvants to reconstitute immune function in intensive care unit (ICU) patients. Proresolving agents are also in development to terminate acute inflammatory reactions without immune suppression. This brief review summarizes the current understanding of the fundamental immune alterations in critical illness that lead to organ failure in critical illness.

KEYWORDS

Lipopolysaccharide - sepsis - septic shock - co-stimulatory signals - co-inhibitory signals - sepsis-induced immunosuppression

REFERENCES

• 1 Takeda K. Evolution and integration of innate immune recognition systems: the Toll-like receptors.  J Endotoxin Res. 2005;  11 (1) 51-55
• 2 van der Poll T, Opal S M. Host-pathogen interactions in sepsis.  Lancet Infect Dis. 2008;  8 (1) 32-43
• 3 Cinel I, Opal S M. Molecular biology of inflammation and sepsis: a primer.  Crit Care Med. 2009;  37 (1) 291-304
• 4 Davidson G H, Hamlat C A, Rivara F P, Koepsell T D, Jurkovich G J, Arbabi S. Long-term survival of adult trauma patients.  JAMA. 2011;  305 (10) 1001-1007
• 5 Netea M G, van der Meer J WM. Immunodeficiency and genetic defects of pattern-recognition receptors.  N Engl J Med. 2011;  364 (1) 60-70
• 6 Rathinam V AK, Jiang Z, Waggoner S N et al.. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.  Nat Immunol. 2010;  11 (5) 395-402
• 7 Goodridge H S, Marshall F A, Else K J et al.. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62.  J Immunol. 2005;  174 (1) 284-293
• 8 Coban C, Ishii K J, Kawai T et al.. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin.  J Exp Med. 2005;  201 (1) 19-25
• 9 Angus D C, Linde-Zwirble W T, Lidicker J, Clermont G, Carcillo J, Pinsky M R. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.  Crit Care Med. 2001;  29 (7) 1303-1310
• 10 Dellinger R P, Levy M M, Carlet J M International Surviving Sepsis Campaign Guidelines Committee et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.  Crit Care Med. 2008;  36 (1) 296-327
• 11 Opal S M. The host response to endotoxin, antilipopolysaccharide strategies, and the management of severe sepsis.  Int J Med Microbiol. 2007;  297 (5) 365-377
• 12 Martin G S, Mannino D M, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.  N Engl J Med. 2003;  348 (16) 1546-1554
• 13 Opal S M, Calandra T. Antibiotic usage and resistance: gaining or losing ground on infections in critically ill patients?.  JAMA. 2009;  302 (21) 2367-2368
• 14 Littman D R, Rudensky A Y. Th17 and regulatory T cells in mediating and restraining inflammation.  Cell. 2010;  140 (6) 845-858
• 15 Akira S, Takeda K. Toll-like receptor signalling.  Nat Rev Immunol. 2004;  4 (7) 499-511
• 16 Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling.  Nature. 2004;  430 (6996) 257-263
• 17 Nathan C, Ding A. Nonresolving inflammation.  Cell. 2010;  140 (6) 871-882
• 18 Sriskandan S, Ferguson M, Elliot V, Faulkner L, Cohen J. Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation.  J Antimicrob Chemother. 2006;  58 (1) 117-124
• 19 Levi M, Opal S M. Coagulation abnormalities in critically ill patients.  Crit Care. 2006;  10 (4) 222-228
• 20 Riewald M, Petrovan R J, Donner A, Mueller B M, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway.  Science. 2002;  296 (5574) 1880-1882
• 21 Coughlin S R. Thrombin signalling and protease-activated receptors.  Nature. 2000;  407 (6801) 258-264
• 22 Tressel S L, Kaneider N C, Kasuda S et al.. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis.  EMBO Mol Med. 2011;  3 (7) 370-384
• 23 Hotchkiss R S, Karl I E. The pathophysiology and treatment of sepsis.  N Engl J Med. 2003;  348 (2) 138-150
• 24 Hotchkiss R S, Coopersmith C M, McDunn J E, Ferguson T A. The sepsis seesaw: tilting toward immunosuppression.  Nat Med. 2009;  15 (5) 496-497
• 25 Hotchkiss R S, Nicholson D W. Apoptosis and caspases regulate death and inflammation in sepsis.  Nat Rev Immunol. 2006;  6 (11) 813-822
• 26 Hotchkiss R S, Opal S M. Immunotherapy for sepsis—a new approach against an ancient foe.  N Engl J Med. 2010;  363 (1) 87-89
• 27 Jiang H, Chess L. Regulation of immune responses by T cells.  N Engl J Med. 2006;  354 (11) 1166-1176
• 28 Kasten K R, Tschöp J, Adediran S G, Hildeman D A, Caldwell C C. T cells are potent early mediators of the host response to sepsis.  Shock. 2010;  34 (4) 327-336
• 29 Patrozou E, Opal S M. What is inflammation, what is sepsis, what is MODS?. In: Deutschman C S, Neligan P J, eds. Evidence-Based Practice of Critical Care. Philadelphia, PA: Saunders Elsevier; 2010: 151-157
• 30 Opal S M. New perspectives on immunomodulatory therapy for bacteraemia and sepsis.  Int J Antimicrob Agents. 2010;  36 (Suppl 2) S70-S73
• 31 Venet F, Bohé J, Debard A-L, Bienvenu J, Lepape A, Monneret G. Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock.  Crit Care Med. 2005;  33 (12) 2836-2840
• 32 Laudanski K, Miller-Graziano C, Xiao W et al.. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways.  Proc Natl Acad Sci U S A. 2006;  103 (42) 15564-15569
• 33 van de Veerdonk F L, Teirlinck A C, Kleinnijenhuis J et al.. Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1.  J Leukoc Biol. 2010;  88 (2) 227-232
• 34 Chen Z, O'Shea J J. Th17 cells: a new fate for differentiating helper T cells.  Immunol Res. 2008;  41 (2) 87-102
• 35 Chizzolini C, Chicheportiche R, Alvarez M et al.. Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion.  Blood. 2008;  112 (9) 3696-3703
• 36 Lavoie P M, Huang Q, Jolette E et al.. Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis.  J Infect Dis. 2010;  202 (11) 1754-1763
• 37 Kitazawa Y, Fujino M, Wang Q et al.. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4 + CD25 + regulatory T-cell activity to suppress alloimmune responses.  Transplantation. 2007;  83 (6) 774-782
• 38 Spite M, Serhan C N. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins.  Circ Res. 2010;  107 (10) 1170-1184
• 39 Serhan C N, Chiang N, Van Dyke T E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.  Nat Rev Immunol. 2008;  8 (5) 349-361
• 40 Serhan C N, Savill J. Resolution of inflammation: the beginning programs the end.  Nat Immunol. 2005;  6 (12) 1191-1197
• 41 Schwab J M, Chiang N, Arita M, Serhan C N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes.  Nature. 2007;  447 (7146) 869-874
• 42 Osuchowski M F, Welch K, Siddiqui J, Remick D G. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality.  J Immunol. 2006;  177 (3) 1967-1974
• 43 Meisel C, Schefold J C, Pschowski R 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 (7) 640-648
• 44 Trapnell B C. A novel biomarker-guided immunomodulatory approach for the therapy of sepsis.  Am J Respir Crit Care Med. 2009;  180 (7) 585-586
• 45 Dinarello C A. Anti-inflammatory agents: present and future.  Cell. 2010;  140 (6) 935-950
• 46 Kalil A C. A silent killer: cytomegalovirus infection in the nonimmunocompromised critically ill patient.  Crit Care Med. 2008;  36 (12) 3261-3264
• 47 Ziemann M, Sedemund-Adib B, Reiland P, Schmucker P, Hennig H. Increased mortality in long-term intensive care patients with active cytomegalovirus infection.  Crit Care Med. 2008;  36 (12) 3145-3150
• 48 Hutloff A, Dittrich A M, Beier K C et al.. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28.  Nature. 1999;  397 (6716) 263-266
• 49 Wang S, Zhu G, Chapoval A I et al.. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS.  Blood. 2000;  96 (8) 2808-2813
• 50 Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance.  Trends Immunol. 2006;  27 (4) 195-201
• 51 Keir M E, Butte M J, Freeman G J, Sharpe A H. PD-1 and its ligands in tolerance and immunity.  Annu Rev Immunol. 2008;  26 677-704
• 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 (15) 6303-6308
• 53 Brahmamdam P, Inoue S, Unsinger J, Chang K C, McDunn J E, Hotchkiss R S. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis.  J Leukoc Biol. 2010;  88 (2) 233-240
• 54 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 (15) 6303-6308
• 55 Albring J C, Sandau M M, Rapaport A S et al.. Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.  J Exp Med. 2010;  207 (12) 2551-2559
• 56 Watanabe N, Gavrieli M, Sedy J R et al.. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.  Nat Immunol. 2003;  4 (7) 670-679
• 57 Vendel A C, Calemine-Fenaux J, Izrael-Tomasevic A, Chauhan V, Arnott D, Eaton D LB. B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK.  J Immunol. 2009;  182 (3) 1509-1517
• 58 Hurchla M A, Sedy J R, Gavrieli M, Drake C G, Murphy T L, Murphy K MB. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly Induced in anergic CD4 + T cells.  J Immunol. 2005;  174 (6) 3377-3385
• 59 Sedy J R, Gavrieli M, Potter K G et al.. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator.  Nat Immunol. 2005;  6 (1) 90-98
• 60 Chemnitz J M, Lanfranco A R, Braunstein I, Riley J LB. B and T lymphocyte attenuator-mediated signal transduction provides a potent inhibitory signal to primary human CD4 T cells that can be initiated by multiple phosphotyrosine motifs.  J Immunol. 2006;  176 (11) 6603-6614
• 61 Wing K, Onishi Y, Prieto-Martin P et al.. CTLA-4 control over Foxp3 + regulatory T cell function.  Science. 2008;  322 (5899) 271-275
• 62 Zhu X, Marcus W D, Xu W et al.. Novel human interleukin-15 agonists.  J Immunol. 2009;  183 (6) 3598-3607
• 63 Hasegawa A, Iwasaka H, Hagiwara S, Asai N, Nishida T, Noguchi T. Alternate day calorie restriction improves systemic inflammation in a mouse model of sepsis induced by cecal ligation and puncture.  J Surg Res. 2010;  Dec 9. [Epub ahead of print]
• 64 Christaki E, Opal S M, Keith Jr J C et al.. Estrogen receptor beta agonism increases survival in experimentally induced sepsis and ameliorates the genomic sepsis signature: a pharmacogenomic study.  J Infect Dis. 2010;  201 (8) 1250-1257
• 65 Cohen I, Rider P, Carmi Y et al.. Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation.  Proc Natl Acad Sci U S A. 2010;  107 (6) 2574-2579
• 66 Chen C J, Kono H, Golenbock D, Reed G, Akira S, Rock K L. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells.  Nat Med. 2007;  13 (7) 851-856
• 67 Dinarello C A. Immunological and inflammatory functions of the interleukin-1 family.  Annu Rev Immunol. 2009;  27 519-550
• 68 Werman A, Werman-Venkert R, White R et al.. The precursor form of IL-1α is an intracrine proinflammatory activator of transcription.  Proc Natl Acad Sci U S A. 2004;  101 (8) 2434-2439
• 69 López R A, Zorzopulos J. Vaccine shortage for pandemic influenza: can it be solved?.  Vaccine. 2006;  24 (15) 2701
• 70 Zhao G, Jin H, Li J et al.. PyNTTTTGT prototype oligonucleotide IMT504, a novel effective adjuvant of the FMDV DNA vaccine.  Viral Immunol. 2009;  22 (2) 131-138