1. Immunity to infectious agents PharmD Class, 18-Ordibehesht-95 Presented by: F Noorbakhsh MD PhD In the Name of God

3. Dr F Noorbakhsh, Dept Immunol, TUMS

4. Destruction of Grande Armee

7. Dr F Noorbakhsh, Dept Immunol, TUMS

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

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

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

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

12. Phagocytosed microbes Infected cell Intra-vesicularIntra-cytosolic

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

14. 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

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

16. 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

17. 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

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

19. 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

20. 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

21. 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

22. 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?

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

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

25. 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

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

27. 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

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

29. 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

30. 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

31. 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

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

33. Mast cell Eosinophil Defense against helminths 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-4

34. IL-12 IFN-γ 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

35. IL-12 IFN-γ 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

36. 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

37. فلا اقسم بمواقع النجوم...

38. QUIZ 1- Which of the following is NOT considered a mechanism of immune response against intracytosolic viruses? 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