1. The Immune Responses to Infectious Disease 950616

2. Three Levels of Defense Epithelial surface barriers: Clearance and nonspecific host defenses at skin and mucosal surfaces Epithelial barriers Antibacterial factors (fatty acids, antibactericidal peptides, lysozymes, phospholipase A2) Mucociliary activity Normal flora Adherence blocking molecules The innate immune responses The acquired immune responses

3. The Immune Systems An organization of cells and molecules with specialized roles in defending against infection. The innate immune responses The acquired immune responses Innate and acquired responses usually work together to eliminate pathogens. Immunobiology Fig. 2.1

4. The innate immune responses occur to the same extent No changes after infection Lack immunologic memory The cellular components phagocytic cells: neutrophils, monocytes, and macrophages cells that release inflammatory mediators: basophils, mast cells, and eosinophils natural killer cells The molecular components Complement acute-phase proteins cytokines such as the interferons. Specialized cells, called antigen-presenting cells Macrophage, dendritic cells, B-cells display the antigen to lymphocytes To generate the adaptive immune response

5. Macrophages Derived from blood-borne monocytes Immune Recognition: discriminate between foreign and self molecules. Receptors for carbohydrates : such as mannose Toll-like receptors Receptors for antibodies and complement the coating of microorganisms enhances phagocytosis. Phagocytosis The engulfed microorganisms toxic intracellular molecules, including superoxide anion, hydroxyl radicals, hypochlorous acid, nitric oxide, antimicrobial cationic proteins and peptides, and lysozyme. remove the bodys own dead or dying cells. Figure 2.5.

6. Toll-like Receptors (TLR) A mammalian homologue of the drosophila Toll , identified in 1997 TLR family 11 members in humans A leucine-rich repeat (LRR) domain in extracelluar domain A Toll/IL-1 receptor (TIR) domain in intracellular domain

7. TLR and Their Ligands Nature Immunology 2: 675, 2001

8. Signalling pathways by TLRs in vertebrates & Drosophila. Toll-like receptors in the induction of the innate immune response Alan Aderem & Richard J. Ulevitch NATURE | 2000 | VOL 406 | 782-787

9. NF-B activation pathways NF-B family, I-B family, IKK complex, Signaling components A key player in controlling both innate and adaptive immunity Nature Reviews: Immunology, Volume 2, October 2002, pp725-734

10. NF-B proteins TD: C-terminal non-homologous transactivation domain strongly RHD: structurally conserved N-terminal Rel- activate transcription from NFB- homology domain : dimerization, nuclear- binding sites in target genes localization (N) and DNA binding domains (p65) ANK: Ankyrin Leucine- RELB: no homodimer repeats: protein- zipper protein motif(LZ) interaction GRR: glycine- (NF-B1) P50 homodimer: rich region transcriptional repressor Required for (NF-B2) processing Main activated form of NFB: heterodimer of p65 and (p50 or p52) Transcription of RELB, c-REL and p105: regulated by NF B Nature Reviews: Immunology, Volume 2, October 2002, pp725-734

11. IB Proteins Ankyrin repeats: 33-amino-acid motif: protein-protein interaction IB retain NFB in the cytoplasm By masking NLSs on NFB subunits IB:Nuclear-export signal(NES) at N terminus (also IB, but not IB) IB:degraded rapidly; NFB response element in its promoter; intrinsic NLS; displace NFB from DNA binding sites; NES post-induction repression of NFB function IB:less sensitive to degradation; not NFB inducible; no NES; not displace NFB from DNA binding sites Nature Reviews: Immunology, Volume 2, October 2002, pp725-734

12. A model of how NF-B phosphorylation regulates its transactivation function Nature Reviews: Immunology, Volume 2, October 2002, pp725-734

13. Toll-like receptors: critical proteins linking innate and acquired immunity

14. Granulocytes (polymorphonuclear leukocytes, PMN) Neutrophils Phagocytic cell Most numerous and most important cellular component of innate immune response Eosinophils only weakly phagocytic kill parasites mainly by releasing cationic proteins and reactive oxygen metabolites into the extracellular fluid. secrete leukotrienes, prostaglandins, and various cytokines.

15. Granulocytes (polymorphonuclear leukocytes, PMN) Basophils and mast cells possess high-affinity receptors for IgE (FcR) become coated with IgE antibodies. secrete inflammatory mediators such as histamine, prostaglandins, and leukotrienes. important in atopic allergies such as eczema, hay fever, and asthma, in which allergen binding to the IgE cross-links the FcR.

16. Interferons are antiviral proteins produced by cells in response to viral infection Interferons and induce resistance to viral replication in uninfected cells by activating genes that cause the destruction of mRNA and inhibit the translation of viral and some host proteins. induce MHC class I expression enhancing their resistance to NK cells; induce increased synthesis of MHC class I molecules in cells that are newly infected by virus more susceptible to killing by CD8 cytotoxic T cells activate NK cells, which then kill virus-infected cells selectively.

17. Erythrocytes and Platelets Have complement receptors Play an important part in the clearance of immune complexes consisting of antigen, antibody, and components of the complement system.

18. Natural killer cells destroy infected and malignant cells. recognize their targets in one of two ways. Killer-activating receptors and killer-inhibitory receptors Fc receptors that bind IgG (FcR) IgG- coated target cells: antibody-dependent cellular cytotoxicity.

19. A System Used by Natural Killer Cells to Recognize Normal Cells and Cells That Lack Major-Histocompatibility Complex Class I Surface Molecules NEJM, 2000, 343(1), p37

20. interdigitating dendritic cell Cells of this type, which include Langerhans cells in skin, constantly but quietly endocytose extracellular antigens. Pattern-recognition receptors on dendritic cells the lipopolysaccharide receptor, the mannose receptor Toll-like receptor

21. MHC molecules class I : HLA-A, B, and C class II : HLA-DP, DQ, and DR present the peptides to the T-cell receptor on the surface of helper T cells. Dendritic cells are particularly efficient at initiating (priming) immune responses : activate so called naive T cells

22. Activated dendritic cells up-regulate the expression of B7 costimulatory molecules provide the signals necessary for lymphocyte activation in addition to those provided through the antigen receptor. Activated dendritic cells migrate to the local draining lymph node, The antigen is processed intracellularly into short peptides by means of proteolytic cleavage before it is presented by major- histocompatibility-complex (MHC) molecules on the surface of dendritic cells.

23. Function of Interdigitating Dendritic Cells NEJM, 2000, 343(1), p37

24. Soluble Factors in Innate Defense Complement Acute-phase proteins Cytokines

25. Complement first identified as a heat-labile principle in serum that complemented antibodies in the killing of bacteria. a system of more than 30 proteins in plasma and on cell surfaces. Complement proteins > 3g/L in plasma 15 % of the globulin fraction. The nomenclature of complement follows the historical order of discovery of the proteins

26. NEJM, 2001, 344(14), p1058

27. NEJM, 2001, 344(14), p1058

28. The Waste-Disposal Hypothesis for SLE NEJM, 2001. Vol. 344, No. 15, P 1140

29. Acute Phase Proteins enhance resistance to infection promote the repair of damaged tissue Plasma levels change rapidly in response to infection, inflammation, and tissue injury. C-reactive protein Clinical Use serum amyloid A protein Mannan-binding lectin ESR CRP proteinase inhibitors coagulation proteins fibrinogen

30. C-reactive protein A member of the pentraxin protein family A multipronged pathogen-recognition molecule Binds to the phosphorylcholine portion of certain bacterial and fungal cell-wall lipopolysaccharides Opsonize pathogen Activate the complement cascade by binding to C1q

31. Cytokines act as messengers both within the immune system and between the immune system and other systems of the body, forming an integrated network that is highly involved in the regulation of immune responses.

32. Figure 2.31 Figure 2.39

33. The Acute Inflammatory Response NEJM, 2000, 343(1), p37

34. Figure 2.37. The release of TNF- by macrophages induces local protective effects, but TNF- can have damaging effects when released systemically.

35. The acquired immune responses Improve on repeated exposure to a given infection. The proliferation of antigen-specific B and T cells occurs when the surface receptors of these cells bind to antigen. B cells secrete immunoglobulins, the antigen-specific antibodies responsible for eliminating extracellular microorganisms. T cells help B cells to make antibody eradicate intracellular pathogens by activating macrophages and by killing virally infected cells.

36. Diversity of Antigen Receptors. NEJM, 2000, 343(1), p37

37. Figure 9.19. Each human immuno-globulin isotype has specialized functions and a unique distribution

38. Recognition of Epitopes by B Cells. NEJM, 2000, 343(1), p37

39. The Germinal Center. NEJM, 2000, 343(2), p109

40. Positive and Negative Selection in the Thymus. NEJM, 2000, 343(1), p37

41. Langerhans' cells can take up antigen in the skin and migrate to lymphoid organs where they present it to T cells Antigen-presenting cells Initiate Adaptive Immune Responses

42. IL-12 IL-4 IL18

43. Figure 8.29. The polarization of T cells during specific antigen recognition allows effector molecules to be focused on the antigen-bearing target cell microtubule- organizing center (MTOC)

44. Figure 8.36. Cytotoxic effector proteins released by cytotoxic T cells Figure 8.37. Perforin released from the lytic granules of cytotoxic T cells can insert into the target cell membrane to form pores

45. Figure 8.42. The immune response to intracellular bacteria is coordinated by activated TH1 cells

46. An Overview of Lymphocyte Responses. NEJM, 2000, 343(2), p109

47. Role of Antibodies NEJM, 2000, 343(1), p37 IgA antibody-dependent cellular cytotoxicity.

48. NEJM, 2000, 343(2), p109

49. NEJM, 2000, 343(2), p109