Unicelllular protozoa

Leishmania majorPlasmodium – malariaTrypanosoma (sleeping disease, Chagas disease)

SPREADING BY BITES

THE IMMUNE RESPONSE TO PARASITES

Multicellular invertebratesHelminths – Intestinal wormsAscaris, Cestoda (gut), Trichinella (muscle), Filaria (lymph)Tape worm Diphyllobothrium latum

9m in length, lives in small intestineB12 deficiency (magaloblastic anaemia)

Blood, liver, lung flukes

COMPLEX LIFE CYCLE

THE IMMUNE RESPONSE TO THE SINGLE CELL PARAZITE LEISHMANIA

Dead parazitesIL-12

TNFIL-2

Th1

Th2

IL-2 IL-10

IL-4

IFNγ

Leishmania major

MACROPHAGE

NO, O2-,H2O2,OH-

CR3CR4

lipophosphoglycane

CLEARS THE INFECTION

DOES NOT CLEAR THE INFECTION

MACROPHAGE

Active radicals

T 1H

IL-3GM-CSF

IL-2

Increased production of neutrophils and monocytes in

the bone marrow

IFNγ

TNFβ

Chemokines

RECRUITMENT OF CELLS

ACTIVATION OF CELLS

Activation of macrophages, increased release of

inflammatory mediators

Local tissue destructionIncreased expression of

adhesion molecules on local blood vessels

MECHANISMS OF DELAYED TYPE HYPERSENSITIVITY

DEFENSE MECHANISMS AGAINST HELMINTHS

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

HOST ENVIRONMENT is accepted, resistant to complement and phagocytes

BIG – no phagocytosis

RESISTANT – to reactive radicals and enzymes of macrophages and

neutrophils

Schistosoma mansoni Delayed Type Hypersensitivity - DTHFibrosis around the eggs in the liver Chronic inflammation – Fibrotic connective tissueInhibits the venous circulation of the liver

IgE – MEDIATED CELLULAR CYTOTOXICITY

Shistosoma

Eosinophil granulocyte

IgE

FcεRI

Death of worm

Granules

ECFNCF

C'

THE IMMUNE RESPONSE TO MULTICELLULAR WORMS

Can not be ingested by phagocytes

C3a, C5a Monocyte

Neutrophil

Eosinophil

Mast cellIL-3IL-4

Plasma cell IgE

mediators

B

B

Th2

Th2

IL-4, IL-5

LYMPH NODE

IgE IgG

BLOOD

Schistosoma mansoniActivated eosinophils bind to IgE-coated parasites via the high affinity FcεRII

and release their toxic contents onto the wormOther effector cells bind to IgG-coated parasites

Permeability

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

LCMVLCMV

MMouse healthyouse healthy

MMouse douse dyyeses

NNo thymuso thymusTT TTTT

LCMVLCMV

LCMVLCMV

INFECTION WITH LYMPHOCYTE CHORIOMENINGITIS VIRUS (LCMV)

Mouse dyesMouse 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

VirusVirus

Replication

NeNeww vviriraall particles particles

Translation

Transcrition++

Antibodies

VIRUSES REPLICATE WITHIN HOST CELLS AND ARE HIDDEN FROM ANTIBODIES

DNADNA

Viral proteins

Antibodies

C'

THE IMMUNE RESPONSE TO VIRUSES

IgA

Mucosal surface

Neutralization

Killing of infected cells by cytotoxic

reactions

Complement-mediated lysis

NK cell-mediated antibody-dependent cytotoxicity (ADCC)

Killing by virus-specific cytotoxic T cells

IFNαβ

Inhibition of viral spreadneutralization

Phagocytosis

opsonization

NK cellTc cell

KILLING

napok

vírus-titer

2 4 6 8 101 3 5 7 9 1211 13

KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS

Complement

AntibodyCytotoxic T cellsNK cells

IFNα/β, IL-12

days

lev

el/a

cti

vity

VIRUS TITER

RECOGNITION OF TARGET CELLS BY NATURAL KILLER CELLS

Antibody-mediated NK-cell killing

Ag

FcRIII CD16

Target

NKNK

KAR KIR

TargetMHC-

KAR KIR

KIR – Killer Inhibitory Receptor Recognition of MHC class I

KAR – Killer Activatory Receptor

NK

TargetMHC+

MHC class I

APC

CD40

M HC II

TNFIFN

CD8+

Tc

IL-12

CD4+

T 1H CD40LCD40L

Survival IL2 IL4 IFN

CD40 B

Ag

Apoptotic cell

LINKED RECOGNITION OF VIRAL ANTIGENS BY CD4+ AND CD8+ T LYMPHOCYTES

M HC I

INDIRECT ANTIGEN PRESENTATION

THE ROLE OF CD4+ AND CD8+ T CELLS IN VIRAL INFECTIONS

• CD8– Killing potential

• Perforin, granzymes

• Acts before virus progeny

– Anti-viral cyto- & chemokines

• TNF-, IFN- HBV• MIP-1,, RANTES HIV• Blocks virus progeny

• CD4– 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

                                 

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.

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.