Immunity to infectious agents MD Class, 18-Aban-93 Presented by: Farshid Noorbakhsh MD PhD In the...

Immunity to infectious agents

MD Class, 18-Aban-93

Presented by: Farshid Noorbakhsh MD PhD

In the Name of God

Dr F Noorbakhsh, Dept Immunol, TUMS

Type of the microbe

Target organ

Localization(extra- or intracellular)

Type of Immune response


Protozoa (uni-cellular)

Metazoa (multi-cellular)

Type of the microbe

Bacteria

Viruses

Fungi

Parasites


Bacteria

Viruses

Fungi

Parasites

Bacteria

Viruses

Fungi

Parasites

Extracellular Intracellular


E. Coli, Pneumococci, Salmonella

Mycobacteria

None All

Candida Histoplasma

Helminths Plasmodium

Phagocytosed microbes Infected cell

Intra-vesicular Intra-cytosolic

Bacteria

Viruses

Fungi

ParasitesDr F Noorbakhsh, Dept Immunol, TUMS

E. Coli, Pneumococci, Salmonella

Mycobacteria

None All

Candida Histoplasma

Helminths Plasmodium


Bacteria

Viruses

Fungi

Parasites


I-Vesicular I-Cytosolic

All

Mycobacteria

PneumocystisHistoplasma

Plasmodium

Rickettsia,Chlamydia

Leishmania

Interstitial, blood, lymphepithelial

E.coli, Staph, Neisseria?

Candida

Helminths filaria

Staph, Strep, bacilli



I-Vesicular I-CytosolicInterstitial,

blood, lymphepithelial



Phagocytosed microbes

1- Intravesicular microbes; intracellular killing

Cathionic proteins (cathepsins) damages bacterial cell wall

Lysozyme peptidoglaycal hydrolysis

Lactoferrin deprives bacteria of iron

Proteases digest microbial proteins

Oxygen-independent killing


Activated macrophage

2- Activated phagocytes produce cytokines

TNF-α

Fever,

Anorexia,

Sickness behavior

Acute phase proteins (eg: CRP)

Neutrophil chemoattraction

Enhanced phagocytosis

Cytokine (IL1) production

Tumor cell lysis

TNF-α

TNF-α

TNF-α

TNF-α


Phagocytosed microbes

CD4+ T cells

MHC Class2

3- Intravesicular microbes’ antigens are presented

CD8+ T cells

Enhanced microbicidal activity

4- Intravesicular microbes, T cell activationIL-12

IFN-γ

NK cell

IL-12

IFN-γ CD40LCD40

Th1

CD28B7

IL-2

Enhanced protease activity, lower intravesicular pH ….

Th1

Th1

Th1

Th1

Th1

Production of ROS: O2-, OH-, H2O2, HClO-Oxygen-dependent killing

Defense against intravesicular microbesIL-12

IFN-γ

NK cell

IL-12

IFN-γ CD40LCD40

Th1

CD28B7

IL-2

2NK-mediated macrophage

activation

3Th1-mediated macrophage

activation

1Initial

intravesicular killing


IFN-γ

NK cell

IL-12

IFN-γ CD40LCD40

TH1

CD28B7

IL-2

What happens if mechanism “1” works?

2NK-mediated macrophage

activation

3Th1-mediated macrophage

activation

1Initial

intravesicular killing


IFN-γ

NK cell

IL-12

IFN-γ CD40LCD40

TH1

CD28B7

IL-2

What happens if mechanism “1” works?

Bacteria

Viruses

Fungi

Parasites



All

Mycobacteria


Plasmodium


Leishmania


E.coli, Staph, Neisseria?

Candida

Helminths filaria




Interferon response against virusesIntracellular microbes (intra-cytosolic)

Antiviral state Antiviral stateAntiviral state

IFNα/β IFNα/βIFNα/β


MHCI

Cytolysis by CD8+ lymphocytes

Intracellular microbes (intra-cytosolic)

CD8+ T cell

FAS FASL


CD8+ T cell

MHCI

Cytolysis by NK cells


Some viruses block MHCI expression

NK cell

Killer inhibitory receptor

MHCI


MHCI

Cytokine production by CD8+ or NK cells


MHCI

IFN-γIFN-γ

CD8+ T cell

NK cell


MHCI


MHCI

IFN-γIFN-γ

CD8+ T cell

CD8 T cell-mediated cell lysis

NK cell

NK-mediated cell lysis

IFNα/β

IFNα/β

Interferon response

IFNα/β

IL-12

CD4+

CD8+CTL

MHC Class 2MHC Class 1

IFN-g

IFN-g

Pre-CTL

Escaping vesicle

Cross-presentation of Ag

Bacteria

Viruses

Fungi

Parasites




Dr F Noorbakhsh, Dept Immunol, TUMSDr F Noorbakhsh, Dept Immunol, TUMS

CD4- m

ediated Mφ

activation

NK- m

ediated Mφ

activation

Initial intravesicular killing

CD8- m

ediated cell lysis

NK- m

ediated cell lysis

Interferon response


Now let’s look at immune defense against extracellular microbes!

Bacteria

Viruses

Fungi

Parasites



All

Mycobacteria


Plasmodium


Leishmania


E.coli, Staph, Neisseria

Candida

Helminths Filaria



Functions of different classes of antibodies

B CellsYYYYYYYYYY

YYY

Neutralization (mucosal)

YYYYYYYYY

F Noorbakhsh, Dept Immunology, TUMS

Neutralization(serum)

Opsonization & phagocytosis

Complement activation

Eos & mast cell degranulation

IgA IgG IgM IgE

Dr F Noorbakhsh, Dept Immunol, TUMSYY B

cell

YYYY YY YY Y YYYYY

NK/ PMNs

Antibody-dependent cell cytotoxicity(ADCC)


YY

B cell

YYYY YY YY Y Y

YYYY

Antibody-dependent cell cytotoxicity(ADCC)

NK/ PMNs

Effector mechanisms of humoral immunity

B CellsYYYYYYYYYY

YYY

Neutralization (mucosal)

YYYYYYYYY

F Noorbakhsh, Dept Immunology, TUMS

Neutralization(serum)

Opsonization & phagocytosis

Complement activation

Eos & mast cell degranulation ADCC

IgA IgG IgM IgE

IL-12

IFN-γ

IL-4

B Cells

YYYYYYYYYYYYY YYY YYY

IgG1IgG3IgG2

IL-4

IgE

TGF-β

IgA

TH1TH2

TH3

IL-10

Neutralization

Opsonization

Complement activationMucosal defense

IL-4

TH2

B Cells


IL-4

IgE


Mast cell Eosinophil

Defense against helminthsIL-4

TH2

B Cells


IL-4

IgE

IL-5

YY

YYY

YYYY YYY Y Y

Y YYY IgG4

IL-12

IFN-γ

IL-4

B Cells


IgG1IgG3IgG2

IL-4

IgEIgG4

TGF-β

IgA

TH1TH2

TH3

IL-10

IL-12

IFN-γ

IL-4

IL-4TGF-β

TH1TH2

TH3

TH17

IL-21,IL-23

TGF-β,IL-6

NeutrophilIL-17IL-22Antimicrobial peptides (AMPs) at epithelial

surfaces

IL-10

Bacteria

Viruses

Fungi

Parasites




Dr F Noorbakhsh, Dept Immunol, TUMSDr F Noorbakhsh, Dept Immunol, TUMS

Th17 IL22 epithelium AM

Ps

Th17 IL17 neutrophils

Th3 TGFβ B cell IgA

Th1 IFNγ B cell IgG

Th2 IL4 B cell IgE

CD4- m

ediated Mφ

activation

NK- m

ediated Mφ

activation

Initial intravesicular killing

CD8- m

ediated cell lysis

NK- m

ediated cell lysis

Interferon response

B CellYY

Y

Y Y Y

Y

B Cell

CD4 T cell

B CellY

Y

Y

Y Y Y YY

Help from T cells (cytokines)

CD4 T cell

Help from T cells (cytokines)

Weak help

Strong help

Happens during primary response

Happens during secondary response


Microbial evasion of immune response

Change in the immune

system

Change in the microbe


Inhibition of phagolysosome formation: M Tuberculosis, L Pneumophila

Inactivation of ROS: M Leprae (phenolic glycolipid)

Disruption of phagolysosome: Listeria (hemolysin)

Immune evasion in intracellular/intravesicular pathogens


MHCI

Immune evasion in Intracytosolic microbes

MHCI

IFN-γIFN-γ

CD8+ T cell

NK cell

IFNα/β IFNα/βIFNα/β


CD8+ T cell

Adenoviruses block MHCI expressionAdenovirus

Adenovirus blocks MHCI expression!!


Poxvirus blocks MHCI loading and produces decoy receptors

CD8+ T cell

Poxvirus blocks MHCI loading!!

Poxvirus

IFN-γPox virus produces decoy IFNγ receptors


NK cell

CMV generates an MHCI homologCMVCMV generates an

MHCI homolog!

CMV blocks MHCI

expression!!

TH1TH2

TH3

TH17

IL-12IL-4

IL-10

B cell

YYYYYYYYY

YYYYEBV

IL10 homolog IL10 homolog


CD4

CD4+

CD28B7

How HIV suppresses immune response?

CD4+

CD4

CD4+

CD28B7

HIV infects macrophages

Nef blocks MHCII expression!!

HIV infects CD4 T cells

Nef Nef

Nef blocks CD4 expression!!

Nef blocks CD28 expression!!

Finally, HIV kills CD4 cells!


Viruses have different ways of immune evasion!

Poxvirus

HIV

Adenovirus

EBV

CMV

Blocks MHCII, CD4, B7, kills CD4 T cells

Blocks MHCI expression

Blocks MHCI loading, produces decoy receptors

Expresses MHCI homolog (to block NK cells)

Expresses IL10 homolog

B CellsYYYYYYYYYY

YYYNeutralization

of AntigenOpsonization &

phagocytosisYYY

Complement activationADCC

YYYYYY

Immune evasion in extracellular pathogens

Resistance to phagocytosis

(pneumococcus)Inactivation of complement


Microbial evasion of immune response

Change in the immune

system

Change in the microbe


Genetic recombination

Change in microbial antigens

Antigenic drift/shift

Multiple antigenic variants

Antigenic variation during

life cycle


Immune evasion via multiple antigenic variants of microbes (serotypes).


Immune evasion via multiple antigenic variants of microbes (serotypes).


Immune Evasion via antigenic drift/shift.


Immune Evasion via antigenic drift/shift


Trypanosomes have a special way of escaping from immune response!

Sleeping sickness, caused by Trypanosoma brucei, Chagas disease, caused by Trypanosoma cruzi.

Achilles heel! What if he had multiple copies of the heel?!

Immune evasion via sequential DNA rearrangements of trypanosomal antigens

Plasmodium’s antigenic variation during life cycle

النجوم بمواقع اقسم ... فال


QUIZتولید- 1 به منجر روند زیر های مسیر از لمفوسیت IgGکدامیک بوسیله

دهد؟ Bهای می نشان درستی به را.aAPC IL2 Th1 IL4 B cell IgG.b APC IL12 Th1 IL4 B cell IgG.cAPC IL2 Th1 IFNγ B cell IgG.dAPC IL12 Th1 IFNγ B cell IgG

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نمیدهد؟ رخ سیتوزول فضای.e Interferon response.fNK-mediated cell lysis.gCD8-mediated cell lysis.hmacrophage activation by NK cells

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Immunity to infectious agents MD Class, 18-Aban-93 Presented by: Farshid Noorbakhsh MD PhD In the...

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