Transcript NK cell

THE IMMUNE RESPONSE TO PARASITES
Unicelllular protozoa
Leishmania major
Plasmodium – malaria
Trypanosoma (sleeping disease, Chagas disease)
SPREADING BY BITES
Multicellular invertebrates
Helminths – Intestinal worms
Ascaris, Cestoda (gut), Trichinella (muscle), Filaria (lymph)
Tape worm Diphyllobothrium latum
9m in length, lives in small intestine
B12 deficiency (magaloblastic anaemia)
Blood, liver, lung flukes
COMPLEX LIFE CYCLE
THE IMMUNE RESPONSE TO THE SINGLE CELL
PARAZITE LEISHMANIA
Dead parazites
NO,
IL-12
O2-,H2O2,OH-
IL-2
TNF
Active radicals
CLEARS THE
INFECTION
Th1
MACROPHAGE
IFNγ
lipophosphoglycane
IL-2
IL-10
Leishmania major
CR4
CR3
IL-4
DOES NOT CLEAR
THE INFECTION
Th2
MACROPHAGE
MECHANISMS OF DELAYED TYPE HYPERSENSITIVITY
ACTIVATION OF
CELLS
RECRUITMENT OF
CELLS
Activation of macrophages,
increased release of
inflammatory mediators
IL-2
IFNγ
TH 1
IL-3
GM-CSF
TNFβ
Local tissue destruction
Increased expression of
adhesion molecules on local
blood vessels
Chemokines
Increased production of
neutrophils and monocytes in
the bone marrow
DEFENSE MECHANISMS AGAINST HELMINTHS
HOST ENVIRONMENT is accepted, resistant to complement and phagocytes
BIG – no phagocytosis
RESISTANT – to reactive radicals and enzymes of macrophages and
neutrophils
IgE – mediated protection
IgE-mediated antibody dependent cellular cytotoxicity ADCC
EFFECTOR CELLS: mast cells, basophils, and eosinophils
 inflammatory mediators
 vasodilation  recruitment of inflammatory cells  fluid outflow
 smooth muscle cell contraction  mechanical removal
Schistosoma mansoni
Delayed Type Hypersensitivity - DTH
Fibrosis around the eggs in the liver
Chronic inflammation – Fibrotic connective tissue
Inhibits the venous circulation of the liver
IgE – MEDIATED CELLULAR CYTOTOXICITY
Death of worm
Shistosoma
IgE
FcεRI
Granules
Eosinophil granulocyte
THE IMMUNE RESPONSE TO MULTICELLULAR WORMS
Can not be ingested by phagocytes
Plasma cell IgE
IL-3
IL-4
mediators
Th2
ECF
NCF
Mast cell
Permeability 
Eosinophil
B
B
IL-4, IL-5
BLOOD
IgE
Neutrophil
IgG
Th2
C'
LYMPH NODE
C3a, C5a
Monocyte
Schistosoma mansoni
Activated eosinophils bind to IgE-coated parasites via the high affinity FcεRII
and release their toxic contents onto the worm
Other effector cells bind to IgG-coated parasites
ESCAPE MECHANISMS OF PARASITES
Poor antigenicity
Variations in surface structure – gene conversion
Alternating expression
Trypanosoma
Priviledged sites isolated from the immune system (cyst)
Intracellular Leishmania, Toxoplasma
Inhibition of phagosome and lysosome fusion
Toxoplasma
Antigen masking by bound self proteins
Complement (DAF) like structures
THE IMMUNE RESPONSE TO VIRUSES
INFECTION WITH LYMPHOCYTE CHORIOMENINGITIS
VIRUS (LCMV)
LCMV
LCMV
T T
T
Mouse dyes
Mouse healthy
No thymus
LCMV
Mouse dyes
THE IMMUNE RESPONSE TO VIRUSES
VIRUSES – obligatory parasites
ENTRY TO HOST CELL – receptor – mediated internalization
LIFE CYCLE – Acute, latent, chronic, slow infection
PROTECTION
INNATE IMMUNITY – Type I interferons – inhibition of virus replication
– NK cells
ADAPTIVE IMMUNITY
Antibodies
– neutralization
– opsonisation
Cytotoxic reactions
– complement – mediated lysis
– NK cell – ADCC
– virus – specific CD8+ effectors
VIRUSES REPLICATE WITHIN HOST CELLS AND ARE
HIDDEN FROM ANTIBODIES
Virus
Antibodies
DNA
Replication
Viral proteins
Transcrition
+
Translation
New viral particles
Antibodies
THE IMMUNE RESPONSE TO VIRUSES
neutralization
Inhibition of viral spread
Phagocytosis
IFNαβ
Neutralization
IgA
opsonization
KILLING
Mucosal surface
Killing of infected
cells by cytotoxic
reactions
Complement-mediated lysis
C'
Killing by virus-specific
cytotoxic T cells
Tc cell
NK cell-mediated antibodydependent cytotoxicity (ADCC)
NK cell
KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS
IFNα/β, IL-12
Cytotoxic T cells
Antibody
level/activity
NK cells
Complement
vírustiter
VIRUS TITER
1
2
3
4
5
6
7
8
9
10 11 12
13
na pok
days
RECOGNITION OF TARGET CELLS BY NATURAL KILLER
CELLS
Target
MHC+
Target
MHC-
Target
Ag
MHC class I
KAR
KIR
KAR
NK
KIR – Killer Inhibitory Receptor
Recognition of MHC class I
KAR – Killer Activatory Receptor
FcRIII
CD16
KIR
NK
NK
Antibody-mediated NK-cell killing
LINKED RECOGNITION OF VIRAL ANTIGENS
BY CD4+ AND CD8+ T LYMPHOCYTES
TNF
IFN
CD40
CD40L
CD40
APC
Apoptotic cell
CD4+
TH1
CD40L
MHCII
IL-12
M
H
CI
Ag
B
Survival
IL2
IL4
IFN
CD8+
Tc
INDIRECT ANTIGEN
PRESENTATION
THE ROLE OF CD4+ AND CD8+ T CELLS IN VIRAL
INFECTIONS
• CD4
• CD8
– Killing potential
• Perforin, granzymes
• Acts before virus progeny
– Anti-viral cyto- & chemokines
HBV
MIP-1,, RANTES HIV
• TNF-, IFN-
•
• Blocks virus progeny
– APC conditioning
• CD40-CD40L (pathogens)
• IL-12  Th1
• IL-15  CTL memory
– Anti-viral cytokines
• TNF-, IFN-
– Growth factors
• IL-2
– Negative regulation
• AICD, Fas-FasL
ESCAPE MECHANISMS OF VIRUSES

High variability of surface antigens

Integration to the host cell genome

Infection of „privileged” locations

Inhibition of antigen presentation (HSV – TAP, HCMV- MHC-I)

Production of cytokin receptor homologes (HCMV- chemokine, poxvírus- IFN)

Immunosupresszive cytokine production (EBV - IL-10 homológ)

Infection of immunocompetent cells
CHRONIC INFLAMMATION
Chronic inflammation is more difficult to
understand, because it is so variable. Seen here is
chronic endometritis with lymphocytes and plasma
cells in the endometrial stroma. In general, the
inflammatory infiltrate of chronic inflammation
consists mainly of mononuclear cells:
lymphocytes, plasma cells, and macrophages.
Certain etiologic agents such as viruses are
more likely to lead to chronic inflammation,
as seen here in the lung of a patient with
influenza A. Note also that the inflammatory
infiltrates of chronic inflammation are more
likely to be interstitial (within tissues) rather
than exudative (above surfaces or in spaces)
like acute inflammation.