Transcript 1. dia - immunology.unideb.hu

THE IMMUNE RESPONSES TO PATHOGENS
PATHOGENS
Viruses, Bacteria, Fungi
Parasites
Unicellular protozoa
Multicellular worms
REQUIRES HIGH INITIAL DOSE FOR INFECTION
ESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS
HUMAN BODY
VAST RESOURCE RICH ENVIRONMENT FOR PATHOGENS
DEFENSE MECHANISMS
Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING
Adaptive immunity
Diseases – Medical practice
DISEASE Innate immunity fails to terminate infection
Pathogen spreading into lymphoid tissues and
activation of adaptive immunity
Successful evasion and subversion of the immune
system by pathogens
MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS
DIRECT
EXOTOXIN
ENDOTOXIN
CYTOPHATHIC
Streptococcus pyogenes
Staphylococcus aureus
Corynebacterium diphteriae
Clostridium tetani
Vibrio cholerae
Escherichia coli
Haemophylus influenzae
Salmonella typhi
Shigella
Pseudomonas aeruginosa
Yersinia pestis
Variola
Varicella zoster
Hepatitis B virus
Polio virus
Measles virus
Influenza virus
Herpes simplex virus
DISEASE
Tonsilitis
Scarlet fever
Toxic shock syndrome
Food poisoning
Diphteria
Tetanus
Cholera
Gram (-) sepsis
Meningitis
Pneumonia
Typhoid fever
Baccillary dysentery
Wound infection
Plague
Small pox
Chicken pox, shingles
Hepatitis
Poliomyelitis
Measles
Subacute sclerosing
panencephalitis
Influenza, cold sores
MECHANISMS OF TISSUE DEMAGE INDUCED BY PATHOGENS
INDIRECT
IMMUNE COMPLEX
Hepatitis B virus
Malaria
Strreptococcus pyogenes
Treponema pallidum
Most acute infections
ANTI-HOST ANTIBODY
CELL-MEDIATED IMMUNITY
Streptococcus pyogenes
Mycoplasma pneumoniae
Mycobacterium tuberculosis
Mycobacterium leprae
Lymphocytic choriomeningitis virus
Borrelia burgdorferi
Schistosoma mansoni
Herpes simplex virus
DISEASE
Kidney disease
Vascular deposits
Glomerulonephritis
Kidney demage
in secondary syphilis
Transient renal deposits
Rheumatic fever
Hemolytic anaemia
Tuberculosis
Tuberculoid leprosy
Aseptic meningitis
Lyme arthritis
Schistosomiasis
Herpes stromal keratitis
SITE OF REPLICATION
EXTRACELLULAR
Interstitial spaces
Blood, lymph
Bronchial,
Gastrointestinal lumen
Viruses
Bacteria
Protozoa
Fungi
Worms
INTRACELLULAR
Epithelial surfaces
Neisseria gonorrhoeae
Worms
Mycoplasma
Streptococcus
pneumoniae
Vibrio cholerae
Escherichia coli
Candida albicans
Helicobacter pylori
Cytoplasmic
Viruses
Chlamydia ssp.
Richettsia ssp.
Listeria monocytogenes
Protozoa
Vesicular
Mycobacteria
Salmonella typhimurium
Seishmania spp.
Listeria ssp.
Trypanosoma spp.
Legionella pneumophila
Cryptococcus neoformans
Histoplasma
Yersinia pestis
PROTECTIVE IMMUNITY
Antibodies
Complement
Phagocytosis
Neutralization
IgA type antibodies
Anti-microbial peptides
Cytotoxic T cells
NK cells
T cell and NK celldependent
macrophage activation
THE SITE OF PATHOGEN DEGRADATION DETERMINES THE TYPE OF IMMUNE
RESPONSES
PATHOGEN TYPE
PROCESSING
RESPONSE
Extracellular
ANTIBODY PRODUCTION
Acidic vesicles
MHCII
Neutralization
Complement activation
Phagocytosis
MHC II binding
CD4+ T cells
B-se jt
Intravesicular
MHCII
Acidic vesicles
KILLING BACTERIA IN VESICLES
MHC II binding
Intracellular killing
CD4+ T cells
Th1
Cytosolic
MHCI
Cytoplasm
MHC I binding
MHC II binding
CD8+ T cells
CD4+ T cells
MHCII
NK
KILLING OF INFECTED CELL
Extracellular killing
ANTIBODY PRODUCTION
EVASION OF THE IMMUNE RESPONSE TO STREPTOCOCCI
B Lymphocyte
Bacterium
12 hrs
6x1010 Bacteria
Toxin
S. pneumoniae in the lung
CONSEQUENCES OF SKIN DAMAGE
INFLAMMATION 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.
THE IMMUNE RESPONSE AGAINST EXTRACELLULAR BACTERIA
Complement-mediated lysis
T-INDEPENDENT
IgM antibody + Complement
Bacterial killing
plasma
CR1
CR3 macrophage
B
LPS
FcR
Plasma level
TNF-α
IL-1β
IC
IL-6
INNATE IMMUNITY
1
2
3
4
5
hours
Helper T-cell activation
IgM  IgG switch
MECHANISMS OF PROTECTION
INNATE IMMUNITY
Complement activation
Gram (+) peptidoglycan

Gram (-)
LPS
Mannose + MBL
alternative pathway

alternative pathway

lectin pathway
Phagocytosis
Antibody and complement mediated opsonization
Inflammation
LPS
Peptidoglycan


TLR macrophage activation
TLR macrophage activation
ACQUIRED IMMUNITY
Humoral immune response
Targets: cell wall antigens and toxins
T-independent
T-dependent
 cell wall polysaccharide
 bacterial protein
 isotype switch
 inflammation
 macrophage activation
ANTIBODY MEDIATED EFFECTOR FUNCTIONS
SPECIFIC ANTIBODY
Bacteria in interstitium
Bacterial toxin
Bacteria in plasma
Toxin
receptor
Neutralization
Opsonization
Complement activation
COMPLEMENT
Neutralization
Phagocytosis
Phagocytosis and lysis
GENERAL SUPPRESSION OF THE IMMUNE RESPONSE
SUBVERSION OF THE IMMUNE SYSTEM BY EXTRACELLULAR BACTERIA
Superantigens of staphylococci – staphylococcal enterotoxins (SE)
PROFESSIONAL APC
2
2
– toxic shock syndrom toxin-1 (TSST-1)
Simultaneous binding to MHC class II and TCR -chain
irrespective of peptide binding specificity
Mimic specific antigen
1

1

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
T cell
Systemic toxicity – sepsis/septicemia
Suppression of adaptive immunity by
apoptosis
Sepsis/Septicemia
TNF-α→platelet activating factor by
endothelial cells→clotting, blockage
restricts plasma leakage & spread of
infection
Infection of blood – Sepsis
Systemic edema, decreased blood
volume, collapse of vessels
Disseminated intravascular
coagulation, multiple organ failure
ESCAPE
High carbohydrate
variability
Competition of strains
~90 serotypes
Serotype-specific Ab
response
Opsonization
EVASION MECHANISMS OF EXTRACELLULAR BACTERIA
Proteins to increase adhesion
Bordetella pertussis
Inhibition of phagocytosis
S.aureus, Str. pneumoniae,
Antigenic variants
Neisseria gonorrhoeae (pilin)
Inhibition of complement-dependent cell lysis
Str. pyogenes M-protein
Sialic acid rich capsule inhibits activation of the alternative complement pathway
Elimination of reactive oxygen species
Catalase positive staphylococci
Degradation of IgA antibodies
Neisseria, H. influenzae