INFECTION & IMMUNITY
Division of Infectious Diseases,
Department of Internal Medicine,
The Catholic University of Korea
Choi Jung Hyun
Immunity
From Latin “immunitas”
- (especially immune to something) having a natural resistance to or
protected by inoculation from a particular disease.
- (especially immune from something) free, exempt or protected from it.
- (especially immune to something) unaffected by or not susceptible to it.
Immunological recognition
Immune effector function
Immune regulation
Immunological memory
Characteristics of Immunity
Epithelial cells vs. Blood cells
Innate immunity vs. Adaptive immunity
Antigen-presenters vs. Effectors
T cells vs. B cells
Cellular immunity vs. Humoral immunity
Composition of Immune System
Epithelial surfaces make up the 1st line of defense against infections
Epithelial injuries (catheterization) Mucosal injury (chemotherapy)
INFECTION !
Epithelial Cells
Blood Cells
Others
Kupffer cells
alveolar macrophages
mesangial cells gut lymphocytes
Invasion of Microbes
Damages by Microbes
Timetables of Immune Responses
Innate Immunity
Preformed effectors ?
Recognition of molecular pattern ?
Preformed Effectors
Complements - direct microbial lysis
- role in phagocytosis, cytokine/chemokine production, attraction of
leukocytes to infected sites
Mannose-binding lectin - pluripotent sugar-binding protien
- discriminate self and nonself sugar
- activate complement system
Fibronectin - cell-cell adhesion, enhance macrophage functions
Antibacterial proteins - -defensins, -defensins, cathelin, protegrin, granulsyin, histatin, secretory
leukoprotease inhibitor, probiotics
Phagocytes
Phagocytes
NK cell Macrophage Dendritic cell Neutrophils Eosinophils
For innate immunity
- phagocytose and kill bacteria
- produce antimicrobial peptides
- produce cytokines/chemokines
For adaptive immunity
- antigen presentation
Preformed Effectors
Recognition of Molecular Pattern
Toll-like receptors (TLRs)
Inflammasome
Peroxisome proliferating activator receptor (PPAR-)
More and more….
TLRs Chronicles
Peptidoglycan [G(+)] Lipoprotein Lipoarabinomannan LPS (Leptospira) LPS (Porphyromonas) GPI (T. cruzi) Zymosan (Yeasts)
LPS LTA HSP60 RSV F protein dsRNA Fragellin
Unmethylated CpG DNA
TLR6 TLR2 TLR1 CD14 TLR4 TLR3 TLR5 TLR9
MD2
Ligands for TLRs
TLRs
TLRs TLR signaling: Pro-inflammatory!!
Shock 2005;23:393 - 9
PPAR- signaling: Anti-inflammatory!!
PPAR-
Cytokines
Sepsis Cascades
Classic Pathway Alternative Pathway
Ag/Ab complex Pathogen surfaces
C1 C4 C2 C3 B D
C3 convertase
C4a, C3a, C5a C3b C5b, C6, C7, C8, C9
Mediator of inflammation
Phagocyte recruitment
Opsonization of pathogen
Remove immune complex
Membrane attack complex
lysis of pathogen or cells
Tissue factor + Factor VII
Tissue factor +
Factor VII
Factor X
Factor Xa
Factor IXa
Factor II Factor IIa
Fibrinogen
Fibrin
Extrinsic
Prothrombin Thrombin
Factor V
Factor IX
Prekallikrein
Kallikrein
Factor XIa Factor XI
Factor XII
Factor XIIa
Collagen/Glass/
Platelet
Intrinsic
Factor VIII
Arachidonic Acid-Phospholipids
Arachidonic Acid
PGH2
PGG2
LTA4 LTC4
TXA2
TXB2
PGI2 PGE2 PGF2a
6-keto PGF1a
LTB4 LTD4
LTE4
Phospholipase A2
Fatty acid Cyclooxygenase
5-Lipooxygenase
+H2O +H2O
Can you see it?
Adaptive Immunity
Transport of antigen ?
B cell and T cells ?
Clonal expansion and differentiation ?
Transporters of Antigen
Human leukocyte antigen (HLA)
- Human version of major
histocompatibility complex (MHC)
- Wide-ranging effects not only
because of system’s role in the
adaptive immune response, but
also because of its genetic
complexity
MHC
Class I - HLA-A, -B, -C… - intracellular organism 처리 - naive T cell을 cytotoxic T cell (CD8)로 분화
Class II - HLA-D (-DR, -DQ…) - extracellular organism 처리 - naive T cell을 helper T cell (CD4)로 분화
T cell receptor
- MHC class I molecules bearing viral peptides are recognized by CD-8 bearing cytotoxic T cells, which then kill the infected cells;
- MHC class II molecule bearing peptide derived from pathogens taken up into vesicles are recognized by CD-4 bearing TH1 or TH2 cells
T cell activation
Role of T cells
B cells
B cells & antibodies
Clonal expansion
Proliferation and differentiation of effector cells
Summary of Immune Reaction
Summary of Immune Reaction
Immunological Memory
Definition of Sepsis
From the Greek words sepsis meaning to decay and sepein meaning to putrefy.
Represents the body’s systemic immune response to severe infection, and is the result of a complex interaction between the host and the invading organisms resulting in the release of a myriad of inflammatory mediators and resulting in host damages.
Death by Sepsis
Nidus of infection Pneumonia, cellulitis, meningitis, UTI, cholangitis, abscess, peritonitis …
Organism proliferation & spread ; microorganism-derived mediators • Bacterial products (exotoxins) ; TSST-1, Toxin A • Structural components ; endotoxin (LPS), teichoic acid antigens
Activation of host defense systems Plasma components, neutrophil, monocyte/macrophage, endothelial cells
Endogenous mediator release Nitric oxide Arachidonic acid metabolites ;
Oxygen free radical prostaglandins, leukotrienes
Cytokines ; TNF, IL, IFN Complement : C5a
Platelet activating factor (PAF) Coagulation
Endorphins Kinins : bradykinin
Endothelial cell damage Organ dysfunction
Mortality by Sepsis
Infection
Sepsis
Severe sepsis
Septic shock
Am J Respir Crit Care Med 2003;168:77-84
Mortality by Sepsis
Mortality by Severe Sepsis
Microbiologic factors Virulence
Resistance to antimicrobials
Host factors Age
Genetic factors
Immune status
- HIV infection, cancer, transplantation, immunosuppressants…
Co-morbid illness - DM, CRF, chronic lung diseases…
Site of infection
Treatment associated
Antimicrobial factors Appropriateness
Timing
Affecting Factors to Death
LPS and other triggers
Release of 2ndary mediators cytokines, prostaglandins PAF, kinins Activation of coagulation Complement activation
Hypotension vasodilation myocardial depression Tissue damage hypoxia neutrophil migration ROIs proteolytic enzymes
Responding cells
Prevention of activation
Inhibition of mediators
Limit organ damage
Immunotherapy of Sepsis
Glucocorticoid in Sepsis ?
Br Med J, 2004;329:480-8
In conclusion, hydrocortisone (or equivalent) should be given to patients with septic shock immediately after they undergo an adrenocorticotropin hormone test, add a doe of 200-300 mg, and should be continued for 5-11 days, and only when absolute or relative adrenal insufficiency is present.
Glucocorticoid
N Engl J Med 2008;358:111-24
Conclusions
Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (Clinical Trials.gov number, NCT00147004.)
Glucocorticoid
N Engl J Med 2008;358:111-24
Survival at 28th day
Shock reversal
N Engl J Med 2008;358:111-24
JAMA 2010;303:341 - 8
Possible mechanisms of IVIG
Immunoglobulin
Immunoglobulin
Recombinant activated protein C
Only FDA approved immunomodulatory agent
2008 Surviving Sepsis Campaign recommended for the treatment of severe sepsis in patient with more than one organ dysfunction, an APACHE II score >25, or both.
2012 Surviving Sepsis Campaign
The results of the PROWESS SHOCK trial (1,696 patients) were released in late 2011, showing no benefit of rhAPC in patients with septic shock (mortality 26.4 % for rhAPC, 24.2 % placebo) with a relative risk of 1.09 and a P value of 0.31.
The drug was withdrawn from the market and is no longer available, negating any need for an SSC recommendation regarding its use.
Curr Opin Crit Care 2004;10:354-63
- rhGCSF, recombinant human granulocyte colony stimulating factor - MAB-T88, human monoclonal immunoglobulin M Ab directed at the enterobacterial common Ag - TFPI, tissue factor pathway inhibitor - LY315920Na/S-5960, selective inhibitor of 14-kDa group IIA secretory phospholipase A2 - rhPAF-AH, recombinant human platelet-activating factor acetylhydrolase - 546C88, nitric oxide synthase inhibitor
DSMB : data and safety monitoring board
Other Immunomodulators
Anti-inflammatory Is Matter!
Agent Study Outcomes
G-CSF RCT in patients with pneumonia and severe sepsis Increased WBC counts No reduction in mortality Well tolerated
G-CSF RCT in patients with multilobar pneumonia Increased WBC counts Reduction in mortality (trend) Well tolerated
GM-CSF RCT in patients with sepsis or septic shock and sepsis induced immunosuppression
Increased HLA-DR expression Restored cytokine secretion in monocytes Improved patients outcomes
GM-CSF, rIFN- (ongoing)
Effects of immunosuppression with GM-CSF or IFN- on immunoparalysis following human endotoxemia
Cytokine secretion by lymphocytes, HLA-DR expression, Monocyte/neutrophil function, Lymphocyte gene expression, volunteer responses
rIFN- RCT in trauma patients Increased HLA-DR expression Decreased severe infection (trend)
rIFN- RCT in patients with burns No improved patients outcome
rIFN- RCT in trauma patients Reduced infection related deaths
rIFN- (ongoing)
Effects of IFN- on sepsis-induced immuoparalysis Cytokine secretion by lymphocytes, HLA-DR and receptor expression (PD-1), Lymphocyte gene expression, Reversibility of monocyte dysfunction, Patients outcomes
Immunostimulation
Virulence 2013, Sep 25:5(1), Epub
Initial resuscitation and infection
issues
Initial resuscitation Diagnosis Antimicrobial therapy Source control
Hemodynamic support and adjunctive
therapy
Fluid therapy Vasopressors Inotropic therapy Corticosteroids
Other supportive therapy
Blood product administration Mechanical ventilation Sedation, analgesics, NM blockade Glucose control Renal replacement Bicarbonate therapy DVT prophylaxis Stress ulcer prophylaxis Nutrition
Surviving Sepsis Campaign Intensive Care Med 2013;39:165-228
Conclusion
Prevention and protection are the best way
Infection Control and Prevention
Vaccination