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

Type of the microbe Target organ Localization (extra- or intracellular) Type of Immune response Dr F Noorbakhsh, Dept Immunol, TUMS

Protozoa (uni-cellular) Metazoa (multi-cellular) Type of the microbe Bacteria Viruses Fungi Parasites Dr F Noorbakhsh, Dept Immunol, TUMS

Bacteria Viruses Fungi Parasites Dr F Noorbakhsh, Dept Immunol, TUMS

Bacteria Viruses Fungi Parasites ExtracellularIntracellular Dr F Noorbakhsh, Dept Immunol, TUMS E. Coli, Pneumococci, Salmonella Mycobacteria NoneAll CandidaHistoplasma HelminthsPlasmodium

Phagocytosed microbes Infected cell Intra-vesicularIntra-cytosolic

Bacteria Viruses Fungi Parasites Dr F Noorbakhsh, Dept Immunol, TUMS E. Coli, Pneumococci, Salmonella Mycobacteria NoneAll CandidaHistoplasma HelminthsPlasmodium Extracellular Intracellular

Bacteria Viruses Fungi Parasites Extracellular Intracellular I-VesicularI-Cytosolic All Mycobacteria Pneumocystis Histoplasma Plasmodium Rickettsia, Chlamydia Leishmania Interstitial, blood, lymph epithelial E.coli, Staph, Neisseria? Candida Helminthsfilaria Staph, Strep, bacilli Dr F Noorbakhsh, Dept Immunol, TUMS

Extracellular Intracellular I-VesicularI-Cytosolic Interstitial, blood, lymph epithelial Dr F Noorbakhsh, Dept Immunol, TUMS

Phagocytosed microbes 1- Intravesicular microbes; intracellular killing Dr F Noorbakhsh, Dept Immunol, TUMS 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 Dr F Noorbakhsh, Dept Immunol, TUMS TNF-α Fever, Anorexia, Sickness behavior Acute phase proteins (eg: CRP) Neutrophil chemoattraction Enhanced phagocytosis Cytokine (IL1) production Tumor cell lysis TNF-α

Phagocytosed microbes CD4+ T cells MHC Class2 3- Intravesicular microbes’ antigens are presented Dr F Noorbakhsh, Dept Immunol, TUMS CD8+ T cells

Enhanced microbicidal activity 4- Intravesicular microbes, T cell activation IL-12 IFN-γ NK cell IL-12 IFN-γ CD40L CD40 Th1 CD28 B7 IL-2 Enhanced protease activity, lower intravesicular pH …. Th1 Production of ROS: O2-, OH-, H2O2, HClO- Oxygen-dependent killing

Defense against intravesicular microbes IL-12 IFN-γ NK cell IL-12 IFN-γ CD40L CD40 Th1 CD28 B7 IL-2 2 NK-mediated macrophage activation 3 Th1-mediated macrophage activation 1 Initial intravesicular killing

Defense against intravesicular microbes IL-12 IFN-γ NK cell IL-12 IFN-γ CD40L CD40 TH1 CD28 B7 IL-2 What happens if mechanism “1” works? 2 NK-mediated macrophage activation 3 Th1-mediated macrophage activation 1 Initial intravesicular killing

Defense against intravesicular microbes IL-12 IFN-γ NK cell IL-12 IFN-γ CD40L CD40 TH1 CD28 B7 IL-2 What happens if mechanism “1” works?

Bacteria Viruses Fungi Parasites Extracellular Intracellular I-VesicularI-Cytosolic All Mycobacteria Pneumocystis Histoplasma Plasmodium Rickettsia, Chlamydia Leishmania Interstitial, blood, lymph epithelial E.coli, Staph, Neisseria? Candida Helminthsfilaria Staph, Strep, bacilli Dr F Noorbakhsh, Dept Immunol, TUMS

Interferon response against viruses Intracellular microbes (intra-cytosolic) Dr F Noorbakhsh, Dept Immunol, TUMS Antiviral state IFNα/β

MHCI Cytolysis by CD8+ lymphocytes Intracellular microbes (intra-cytosolic) Dr F Noorbakhsh, Dept Immunol, TUMS CD8+ T cell FASFASL

CD8+ T cell MHCI Cytolysis by NK cells Intracellular microbes (intra-cytosolic) Dr F Noorbakhsh, Dept Immunol, TUMS Some viruses block MHCI expression NK cell Killer inhibitory receptor MHCI

Cytokine production by CD8+ or NK cells Intracellular microbes (intra-cytosolic) Dr F Noorbakhsh, Dept Immunol, TUMS MHCI IFN-γ CD8+ T cell NK cell

MHCI Intracellular microbes (intra-cytosolic) Dr F Noorbakhsh, Dept Immunol, TUMS MHCI IFN-γ CD8+ T cell CD8 T cell- mediated cell lysis NK cell NK-mediated cell lysis IFNα/ β Interferon response IFNα/β

IL-12 CD4+ CD8+ CTL MHC Class 2 MHC Class 1 IFN-g Pre- CTL Escaping vesicle Cross-presentation of Ag

Bacteria Viruses Fungi Parasites Extracellular Intracellular I-VesicularI-Cytosolic Interstitial, blood, lymph epithelial Dr F Noorbakhsh, Dept Immunol, TUMS CD4- mediated M φ activation NK- mediated M φ activation Initial intravesicular killing CD8- mediated cell lysis NK- mediated cell lysis Interferon response

Now let’s look at immune defense against extracellular microbes! Dr F Noorbakhsh, Dept Immunol, TUMS

Bacteria Viruses Fungi Parasites Extracellular Intracellular I-VesicularI-Cytosolic All Mycobacteria Pneumocystis Histoplasma Plasmodium Rickettsia, Chlamydia Leishmania Interstitial, blood, lymph epithelial E.coli, Staph, Neisseria Candida Helminths Filaria Staph, Strep, bacilli Dr F Noorbakhsh, Dept Immunol, TUMS

Functions of different classes of antibodies B Cells Y YY Y Y Y Y Y Y Y Y YY Neutralization (mucosal) Y YY Y YY Y YY F Noorbakhsh, Dept Immunology, TUMS Neutralization (serum) Opsonization & phagocytosis Complement activation Eos & mast cell degranulation IgA IgG IgMIgE

YY B cell Y Y Y Y Y Y Y Y Y Y YYYY NK/ PMNs Antibody-dependent cell cytotoxicity (ADCC) Dr F Noorbakhsh, Dept Immunol, TUMS

YY B cell Y Y Y Y Y Y Y Y Y Y YYYY Antibody-dependent cell cytotoxicity (ADCC) NK/ PMNs Dr F Noorbakhsh, Dept Immunol, TUMS

Effector mechanisms of humoral immunity B Cells Y YY Y Y Y Y Y Y Y Y YY Neutralization (mucosal) Y YY Y YY Y YY F Noorbakhsh, Dept Immunology, TUMS Neutralization (serum) Opsonization & phagocytosis Complement activation Eos & mast cell degranulation ADCC IgA IgG IgMIgE

IL-12 IFN-γ IL-4 B Cells Y YY Y Y Y Y Y Y Y Y YY Y YY Y YY IgG1 IgG3 IgG2 IL-4 IgE TGF-β IgA TH1 TH2 TH3 IL-10 Neutralization Opsonization Complement activation Mucosal defense

IL-4 TH2 B Cells Y YY Y Y Y Y Y Y Y Y YY Y YY Y YY IL-4 IgE

Mast cell Eosinophil Defense against helminths IL-4 TH2 B Cells Y YY Y Y Y Y Y Y Y Y YY Y YY Y YY IL-4 IgE IL-5 Dr F Noorbakhsh, Dept Immunol, TUMS Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y IgG4

IL-12 IFN-γ IL-4 B Cells Y YY Y Y Y Y Y Y Y Y YY Y YY Y YY IgG1 IgG3 IgG2 IL-4 IgE IgG4 TGF-β IgA TH1 TH2 TH3 IL-10

IL-12 IFN-γ IL-4 B Cells Y YY Y Y Y Y Y Y Y Y YY Y YY Y YY IgG1 IgG3 IL-4 IgE TGF-β IgA TH1 TH2 TH3 TH17 IL-21, IL-23 TGF-β, IL-6 Neutrophil IL-17IL-22 Antimicrobial peptides (AMPs) at epithelial surfaces IL-10

Bacteria Viruses Fungi Parasites Extracellular Intracellular I-VesicularI-Cytosolic Interstitial, blood, lymph epithelial Dr F Noorbakhsh, Dept Immunol, TUMS Th17  IL22  epithelium  AMPs Th17  IL17  neutrophils Th3  TGF β  B cell  IgA Th1  IFN γ  B cell  IgG Th2  IL4  B cell  IgE CD4- mediated M φ activation NK- mediated M φ activation Initial intravesicular killing CD8- mediated cell lysis NK- mediated cell lysis Interferon response

B Cell Y Y Y Y Y Y Y CD4 T cell B Cell Y Y Y Y Y Y Y Y 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

Dr F Noorbakhsh, Dept Immunol, TUMS Microbial evasion of immune response Change in the immune system Change in the microbe

Dr F Noorbakhsh, Dept Immunol, TUMS 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 Dr F Noorbakhsh, Dept Immunol, TUMS MHCI IFN-γ CD8+ T cell NK cell IFNα/β

CD8+ T cell Dr F Noorbakhsh, Dept Immunol, TUMS Adenoviruses block MHCI expression Adenovirus Adenovirus blocks MHCI expression!!

Dr F Noorbakhsh, Dept Immunol, TUMS Poxvirus blocks MHCI loading and produces decoy receptors CD8+ T cell Poxvirus blocks MHCI loading!! Poxvirus IFN-γ Pox virus produces decoy IFNγ receptors

Dr F Noorbakhsh, Dept Immunol, TUMS NK cell CMV generates an MHCI homolog CMV CMV generates an MHCI homolog! CMV blocks MHCI expression!!

TH1 TH2 TH3 TH17 IL-12IL-4 IL-10 B cell Y YY Y Y Y Y Y Y Y Y YY EBV IL10 homolog

CD4 CD4+ CD28 B7 How HIV suppresses immune response? Dr F Noorbakhsh, Dept Immunol, TUMS CD4+

CD4 CD4+ CD28 B7 HIV infects macrophages Nef blocks MHCII expression!! HIV infects CD4 T cells Nef Nef blocks CD4 expression!! Nef blocks CD28 expression!! Finally, HIV kills CD4 cells!

Viruses have different ways of immune evasion! Dr F Noorbakhsh, Dept Immunol, TUMS 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 Cells Y YY Y Y Y Y Y Y Y Y YY Neutralization of Antigen Opsonization & phagocytosis Y YY Complement activation ADCC Y YY Y YY Immune evasion in extracellular pathogens Resistance to phagocytosis (pneumococcus) Inactivation of complement

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

Immune evasion via multiple antigenic variants of microbes (serotypes). Dr F Noorbakhsh, Dept Immunol, TUMS

Immune evasion via multiple antigenic variants of microbes (serotypes). Dr F Noorbakhsh, Dept Immunol, TUMS

Immune Evasion via antigenic drift/shift. Dr F Noorbakhsh, Dept Immunol, TUMS

Immune Evasion via antigenic drift/shift Dr F Noorbakhsh, Dept Immunol, TUMS

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

فلا اقسم بمواقع النجوم...

QUIZ 1- کدامیک از مسیر های زیر روند منجر به تولید IgG بوسیله لمفوسیت های B را به درستی نشان می دهد؟ a.APC  IL2  Th1  IL4  B cell  IgG b. APC  IL12  Th1  IL4  B cell  IgG c.APC  IL2  Th1  IFNγ  B cell  IgG d.APC  IL12  Th1  IFNγ  B cell  IgG 2- کدامیک از روند های دفاعی زیر معمولا در مورد ویروسهای واقع در فضای سیتوزول رخ نمیدهد؟ a. Interferon response b.NK-mediated cell lysis c.CD8-mediated cell lysis d.macrophage activation by NK cells Dr F Noorbakhsh, Dept Immunol, TUMS