THE IMMUNE RESPONSES TO PATHOGENS

PATHOGENSViruses, Bacteria, Fungi

ParasitesUnicellular protozoaMulticellular worms

REQUIRES HIGH INITIAL DOSE FOR INFECTIONESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS

HUMAN BODY

VAST RESOURCE RICH ENVIRONMENT FOR PATHOGENSDEFENSE MECHANISMS

Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING Adaptive immunity

Diseases – Medical practice

DISEASEDISEASE Innate immunity fails to terminate infection

Pathogen spreading into lymphoid tissues and activation of adaptive immunity

Successful evasion and subversion of the immune Successful evasion and subversion of the immune system by pathogenssystem by pathogens

DIRECT

EXOTOXIN ENDOTOXIN CYTOPHATHIC

Streptococcus pyogenesStaphylococcus aureus

Corynebacterium diphteriaeClostridium tetani

Vibrio cholerae

Escherichia coliHaemophylus influenzae

Salmonella typhiShigella

Pseudomonas aeruginosaYersinia pestis

VariolaVaricella zosterHepatitis B virus

Polio virusMeasles virusInfluenza virus

Herpes simplex virus

TonsilitisScarlet fever

Toxic shock syndromeFood poisoning

DiphteriaTetanusCholera

Gram (-) sepsisMeningitisPneumonia

Typhoid feverBaccillary dysentery

Wound infectionPlague

Small poxChicken pox, shingles

HepatitisPoliomyelitis

MeaslesSubacute sclerosing

panencephalitisInfluenza, cold sores

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS

DISEASE

INDIRECT

IMMUNE COMPLEX ANTI-HOST ANTIBODY CELL-MEDIATED IMMUNITY

Hepatitis B virusMalaria

Strreptococcus pyogenesTreponema pallidumMost acute infections

Streptococcus pyogenesMycoplasma pneumoniae

Mycobacterium tuberculosisMycobacterium lepraeLymphocytic chorio-

meningitis virusBorrelia burgdorferi

Schistosoma mansoniHerpes simplex virus

Kidney diseaseVascular deposits

GlomerulonephritisKidney demage

in secondary syphilisTransient renal deposits

Rheumatic feverHemolytic anaemia

TuberculosisTuberculoid leprosyAseptic meningitis

Lyme arthritisSchistosomiasis

Herpes stromal keratitis

MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS

DISEASE

SITE OF REPLICATION

EXTRACELLULAR INTRACELLULAR

Interstitial spacesBlood, lymph

Bronchial,Gastrointestinal lumen

Epithelial surfaces Cytoplasmic Vesicular

VirusesBacteriaProtozoa

FungiWorms

Neisseria gonorrhoeaeWorms

MycoplasmaStreptococcuspneumoniae

Vibrio choleraeEscherichia coli

Candida albicansHelicobacter pylori

VirusesChlamydia ssp.Richettsia ssp.

Listeria monocytogenesProtozoa

MycobacteriaSalmonella typhimurium

Seishmania spp.Listeria ssp.

Trypanosoma spp.Legionella pneumophila

Cryptococcus neoformansHistoplasma

Yersinia pestis

IgA type antibodies Anti-microbial peptides

AntibodiesComplementPhagocytosis

Neutralization

Cytotoxic T cellsNK cells

T cell and NK cell-dependent

macrophage activation

PROTECTIVE IMMUNITY

MHCI

MHCII

MHCII

MHCII

B-sejt

PATHOGEN TYPE PROCESSING RESPONSE

Extracellular

Intravesicular

Cytosolic

Acidic vesicles

MHC II binding

CD4+ T cells

ANTIBODY PRODUCTIONNeutralizationComplement activationPhagocytosis

THE SITE OF PATHOGEN DEGRADATION DETERMINES THE TYPE OF IMMUNE RESPONSES

Acidic vesicles

MHC II binding

CD4+ T cells

KILLING BACTERIA IN VESICLES

Intracellular killing

Th1 NK

Cytoplasm

MHC I bindingMHC II binding

CD8+ T cellsCD4+ T cells

KILLING OF INFECTED CELL

Extracellular killing

ANTIBODY PRODUCTION

S. pneumoniae in the lung

EVASION OF THE IMMUNE RESPONSE TO STREPTOCOCCI

BB LymphoLymphocytecyte

12 h12 hrsrs

BaBaccteriumterium

6x106x101010 BaBaccteriteriaaTToxinoxin

CONSEQUENCES OF SKIN DAMAGECONSEQUENCES OF SKIN DAMAGE

INFLAMMATION IN CONNECTIVE TISSUEINFLAMMATION IN CONNECTIVE TISSUE

Fibrin mesh in fluid with PMN's at the area of acute inflammation. It is this fluid collection that produces the "tumor" or swelling aspect of acute inflammation.

IC

THE IMMUNE RESPONSE AGAINST EXTRACELLULAR BACTERIA

INNATE IMMUNITY

1 2 3 4 5

Plas

ma

leve

l

hours

LPS

TNF-α

IL-1βIL-6

T-INDEPENDENT

IgM antibody + Complement

Complement-mediated lysis

Bplasma

CR1CR3

Helper T-cell activation

IgM IgG switch

FcR

macrophage

Bacterial killing

MECHANISMS OF PROTECTION

INNATE IMMUNITYComplement activation

Gram (+) peptidoglycan alternative pathwayGram (-) LPS alternative pathway

Mannose + MBL lectin pathwayPhagocytosis

Antibody and complement mediated opsonization

Inflammation LPS TLR macrophage activationPeptidoglycan TLR macrophage activation

ACQUIRED IMMUNITYHumoral immune response

Targets: cell wall antigens and toxins

T-independent cell wall polysaccharideT-dependent bacterial protein isotype switch

inflammation macrophage activation

ANTIBODY MEDIATED EFFECTOR FUNCTIONS

SPECIFIC ANTIBODY

Bacterial toxin

Toxin receptor

Neutralization

Neutralization

Bacteria in interstitium Bacteria in plasma

Opsonization Complement activation

Phagocytosis Phagocytosis and lysis

COMPLEMENT

GENERAL SUPPRESSION OF THE IMMUNE RESPONSEGENERAL SUPPRESSION OF THE IMMUNE RESPONSE

SUBVERSION OF THE IMMUNE SYSTEM BY EXTRACELLULAR BACTERIA

Superantigens of staphylococci – staphylococcal enterotoxins (SE)

– toxic shock syndrom toxin-1 (TSST-1)

Simultaneous binding to MHC class II and TCR -chain irrespective of peptide binding specificity

Mimic specific antigenMimic specific antigen

Induce massive but ineffective T-cell activation and proliferation in the absence of specific peptide

2 – 20% of CD4+ T-cells, which are not specific for the bacteria but share V get activated and develop to effector T-lymphocytes

Over production of cytokines – IL-1, IL-2, TNF-α

Systemic toxicity – sepsis/septicemia

Suppression of adaptive immunity by

apoptosis

PROFESSIONAL APC

11

22

T cell

Sepsis/SepticemiaSepsis/Septicemia

TNF-TNF-αα→platelet activating factor by endothelial cells→clotting, blockage restricts plasma leakage & spread of infection

Infection of blood – SepsisInfection of blood – Sepsis

Systemic edema, decreased blood Systemic edema, decreased blood volume, collapse of vesselsvolume, collapse of vessels

Disseminated intravascular Disseminated intravascular coagulation, multiple organ failurecoagulation, multiple organ failure

OpsonizationOpsonization

ESCAPEESCAPE

High carbohydrate High carbohydrate variabilityvariability

Competition of strains Competition of strains

~90 serotypes~90 serotypes

Serotype-specific Ab Serotype-specific Ab responseresponse

EVASION MECHANISMS OF EXTRACELLULAR BACTERIA

Inhibition of complement-dependent cell lysis Str. pyogenes M-proteinM-proteinSialic acid rich capsule inhibits activation of the alternative complement pathway

Antigenic variantsNeisseria gonorrhoeae (pilinpilin)

Elimination of reactive oxygen speciesCatalase positive staphylococci

Degradation of IgA antibodiesNeisseria, H. influenzae

Proteins to increase adhesionBordetella pertussis

Inhibition of phagocytosisS.aureus, Str. pneumoniae,