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Host Defenses

Host Defenses. Anne Nicholson-Weller. Innate (Natural, Non-Specific) Immunity VS Adaptive Immunity. Why is the distinction between Innate Immunity and Adaptive Immunity relevant for Clinical Medicine?. Vaccines Inflammation Autoimmunity. Innate vs Adaptive Immunity. Innate Adaptive.

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Host Defenses

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  1. Host Defenses Anne Nicholson-Weller

  2. Innate (Natural, Non-Specific) Immunity VS Adaptive Immunity

  3. Why is the distinction between Innate Immunity and Adaptive Immunity relevant for Clinical Medicine? Vaccines Inflammation Autoimmunity

  4. Innate vs Adaptive Immunity InnateAdaptive Origin: Genes: Recognize: Function: Invertebrates Sharks Germ line, Periphery, no mutations mutations Patterns Details Immediate 7-10 days

  5. Time Frame and Relative Capacity of Innate vs. Adaptive Immunity A D A P T I V E Log kill Acute phase reactants C’ NK PMN Barrier 0 4 8 10 Hours Days Years

  6. Innate Immunity Fluid phase proteins that recognize Pathogen Associated Molecular Patterns Examples:  Defensins--small intestine  Defensins--skin and respiratory epithelium Natural antibody Complement

  7. Natural Antibody Made by B1 type B cells B1 cells line cavities Have restricted VH recombination Usually are CD5+ When transformed = CML

  8. Functions of Complement C1, Alternative & Lectin pathways C3a, C5a, iC5b,6,7 C5b,6,7,8,9 C4b, C3b, iC3b Tag Signal Recognize foreignness

  9. Complement Effectors C1q--opsonic MBL--opsonic C4b--opsonic C3b--opsonic, removal of IC iC3b--opsonic C3d--activation of B cells C3a--mast cell release C5a--chemotaxis, superoxide iC5b67--chemotaxis C5b,6,7,8,9--cytokine and lysis of Neisseria

  10. Spectrum of Disease Caused by Neisseria meningitides Low burden of organisms, moderate disease, but often recurrent ±Ab C’ deficient + Ab C’ intact No disease Colonization No Ab C’ intact Fulminant disease: Intact complement lyses organisms and releases LPS

  11. Innate Immunity Cellular effectors: Neutrophils-- Monocytes-- Macrophages-- Reticulo-endothelium of liver and spleen-- NK cells--lysis phagocytosis + NADPH oxidase

  12. Receptors of Innate Immunity-- Recognize PAMPs: Pathogen Associated Molecular Patterns Scavenger Receptors Integrin (Mac-1) Toll-like Receptors

  13. Toll-like Receptors Predominately on monocytes and macrophages Ten different receptors that associate as homo- or heterodimers

  14. Toll-like Receptors Receptor Dimer 1/1, 2/6 4/4 5/5 Pathogen-derived Ligand zymosan, gm+ cell wall LPS flagellin

  15. Adaptive Immunity Receptors: B cell receptor T cell receptor These receptors mutate during the life time of an individual and are positively selected in response to the particular antigens encountered. B and T cell receptors recognize details, not general patterns.

  16. Ag MHC Recognized Source Complex by T cell Effect CD8+ lysis CD4+ Th1 act.MØ Th2 help B cell Endogenous--Class 1 eg. Virus encoded proteins Exogenous----Class 2 Intravesicular eg.intracellular bacteria Endocytic eg.extracellular bacteria

  17. Overview of Adaptive Immunity Endogenous proteins (made by the cell’s own ribosomes) such as viral proteins, associate with Class 1 MHC and are expressed on the cell surface. If a CD8 T cell recognizes the Ag in the MHC class 1--Ag complex, the cell will be lysed.

  18. MHC-1 MHC-1 Adaptive Immune Responses Cytosolic/Class 1 pathway: Transport vesicle ER Proteosome Viral proteins

  19. Effectors of Adaptive Immunity For Influenza infected epithelial cell: CD8+ Perforin + Granzymes Fas L Fas MHC-1 Lysis Apoptosis

  20. Endogenous Antigens--overlap of Innate and Adaptive Immunity IFN CD8+ NK lysis lysis Early Infection, MHC Uninfected cell, expressing self antigens Later infection, viral Ag-MHC-1

  21. Innate and Adaptive Immunity are linked by cytokines-- an adaptive immune response can only be initiated if innate immunity has recognized an antigen as “foreign”. Activation of APC (upregulation of costimulatory molecules) Complement Mast cells PMN NK cells Selection/ Activation of T cell

  22. DC PPR-signaling IL-12 Naive CD4 IL-4, IL-5 IFN IL-4 Th1 Th2

  23. Extracellular pathogens Intracellular pathogens Neisseria Cryptococcus S. pneumoniae Salmonella H. influenza E. coli Listeria S. pyogenes S. aureusmTB

  24. Adaptive Immune Responses to Antigens Synthesized by Bacteria Intravesicular Ag Acidification of phagosome Addition of MHC class 2 Presentation of Ag in MHC class 2 complex To CD4 T cells (Th1) Activation of infected M Extracellular Ag Endocytosis by APC-- Presentation of Ag in MHC class 2 complex to CD4 T cells (Th2) Activation of B cells = Ig production

  25. Adaptive Immune Responses Intravesicular/Endocytic/Class 2 pathway: M Ag MHC-2 TB Ag MHC-2 tb MHC -2 MHC -2

  26. Effectors of Adaptive Immunity For TB infected macrophage: CD4, Th-1 IL12 IFN TB Ag MHC-2 Activated MØ NADPH oxidase iNO

  27. The Killing of Intracellular Pathogens Strategy of the pathogen: Induce the host to ingest it, and then with the use of specific virulence factors, prevent lysosomes from fusing with its phagosome.

  28. The Story of Nramp 1970’s--genes for susceptibility to salmonella, tb, and leishmania map to same genetic locus in mice 1990’s--gene cloned, found in RE cells of mice and men Natural resistance associated macrophage protein (Nramp).

  29. The Story of Nramp H+ H+ H+ Fe++ Mn++ lysozyme H+ lysozyme Phagolysosome Lysosome Phagosome

  30. Consequences of Nramp deficiency: 1. Pathogen-derived superoxide dismutase can not function without Mn++. 2. Phagosome-lysosome fusion is impaired 3. Acidification of phagolysosome impaired 4. Excess Fe++ around mycobacteria encourages their growth/survival.

  31. DC PPR-signaling IL-12 Naive CD4 IL-4, IL-5 IFN IL-4 Th1 Th2

  32. Th2 Pathway Th2 Ag-specific B cell lymphoblast plasma cell

  33. The interaction between APCs and CD4 T cells is strengthened by adhesion molecules. CD4 CD28 CD40L -- X-linked hyper IgM CD40 B7 APC Activated by innate immunity

  34. Why is the distinction between Innate Immunity and Adaptive Immunity relevant for Clinical Medicine? Vaccines are not effective unless they activate innate immunity first. Inflammation secondary to trauma and sepsis syndromes is due to innate immunity. Autoimmunity?

  35. When should you suspect a defect in host defenses? Age of onset of infections PMN--immediate IgG-- delayed to 4-6 mos Common variable Ig deficiency Site of infections Otitis, sinusitis, pneumonia--Ig, C’, PMN Skin--PMN

  36. When should you suspect a defect in host defenses? Type of organism Encapsulated organisms-- Ig, C’, PMN S. aureus. P.cepacia, S. marcescens, Asprigillus spp.--PMN (CGD) Neisseria spp.--complement deficiencies (properdin, C5, C6 C7, C8, C9)

  37. When should you suspect a defect in host defenses? • Sometimes there is a pattern that makes no • sense in terms of host defense mechanisms: • New syndrome • Psychiatric illness

  38. Resources/References Diagnostic and Therapeutic Resources: www.mgh.harvard.edu/depts/id/hmindex.html The Jeffrey Modell Foundation: National Resource Center for Primary Immune Deficiency www.jmfworld.com/jmfworld.html Immune Biology by Janeway, Travers, Walport, and Shlomchik. 2001. 5th edition Garland Publishing, NY Wed 5 PM Immunology Seminars, Armenise Ampt., HMS

  39. Clinical Observation Experimental Studies Immunologic Knowledge

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