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….

TLRsChronicles

Peptidoglycan [G(+)]LipoproteinLipoarabinomannanLPS (Leptospira)LPS (Porphyromonas)GPI (T. cruzi)Zymosan (Yeasts)

LPSLTA HSP60RSV F protein dsRNA Fragellin

UnmethylatedCpG DNA

TLR6 TLR2 TLR1 CD14 TLR4 TLR3 TLR5 TLR9

MD2

Ligands for TLRs

TLRs

TLRsTLR 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)로분화

Class II

- HLA-D (-DR, -DQ…)- extracellular organism 처리- naive T cell을 helper T cell (CD4)로분화

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 infectionPneumonia, 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 systemsPlasma components, neutrophil, monocyte/macrophage, endothelial cells

Endogenous mediator releaseNitric 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 factorsVirulence

Resistance to antimicrobials

Host factorsAge

Genetic factors

Immune status

- HIV infection, cancer, transplantation, immunosuppressants…

Co-morbid illness - DM, CRF, chronic lung diseases…

Site of infection

Treatment associated

Antimicrobial factorsAppropriateness

Timing

Affecting Factors to Death

LPS and other triggers

Release of 2ndary mediatorscytokines, prostaglandinsPAF, kinins

Activation of coagulationComplement activation

Hypotensionvasodilationmyocardial depression

Tissue damagehypoxianeutrophil migrationROIsproteolytic 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 rhAPCin 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 countsNo reduction in mortalityWell tolerated

G-CSF RCT in patients with multilobar pneumonia Increased WBC countsReduction in mortality (trend)Well tolerated

GM-CSF RCT in patients with sepsis or septic shock and sepsis induced immunosuppression

Increased HLA-DR expressionRestored cytokine secretion in monocytesImproved patients outcomes

GM-CSF, rIFN-(ongoing)

Effects of immunosuppression with GM-CSF or IFN- on immunoparalysis followinghuman endotoxemia

Cytokine secretion by lymphocytes, HLA-DR expression, Monocyte/neutrophil function, Lymphocyte gene expression, volunteer responses

rIFN- RCT in trauma patients Increased HLA-DR expressionDecreased 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

Pathogenesis of sepsis

Chaos itself !

Initial resuscitation and

infection issues

Initial resuscitationDiagnosisAntimicrobial therapySource control

Hemodynamic support and adjunctive

therapy

Fluid therapyVasopressorsInotropic therapyCorticosteroids

Other supportive therapy

Blood product administrationMechanical ventilationSedation, analgesics, NM blockadeGlucose controlRenal replacementBicarbonate therapyDVT prophylaxisStress ulcer prophylaxisNutrition

Surviving Sepsis CampaignIntensive Care Med 2013;39:165-228

Conclusion

Prevention and protection are the best way

Infection Control and Prevention

Vaccination