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Mar 5, 12, 19, 2007
Host Defense Against InfectionHost Defense Against Infection
Immune Evasion
IMMUNOBIOLOGY 6th ed.
Janeway, Travers, Walport & Shlomchik (2005)
Chapter 2 Innate Immunity
Chapter 10 Adaptive Immunity to Infection
ReferencesReferences
1. The diversity of pathogens
2. The general course of infection
3. The front line of host defense
4. Receptors of the innate immune system
5. Induced innate responses to infection
6. The course of the adaptive response to infection
7. The mucosal immune system
8. Immunological memory
OutlineOutline
1. The Diversity of Pathogens1. The Diversity of Pathogens
A Variety of Microorganisms A Variety of Microorganisms Can Cause DiseaseCan Cause Disease
5 main types of pathogens:
Viruses DNA viruses, RNA viruses
Bacteria Gram+/Gram-, Cocci/Bacilli, Spirochetes,
Mycobacteria, Richettsiae, Chlamydias, Mycoplasmas
Fungi
Protozoa
Worms
(Fig. 10.3)
Pathogens Infect the Body through Pathogens Infect the Body through A Variety of RoutesA Variety of Routes
External epithelia: External surface
Wounds & abrasions
Insect bites
Mucosal surfaces: Airway
Gastrointestinal tract
Reproductive tract (Fig. 2.2)
Pathogens Can Be Found in Various Pathogens Can Be Found in Various Compartments of the BodyCompartments of the Body
Pathogens Can Damage Tissues in Pathogens Can Damage Tissues in A Variety of WaysA Variety of Ways
Direct mechanisms of tissue damage: Exotoxin production Endotoxin Direct cytopathic effect
Indirect mechanisms of tissue damage: Anti-host antibody Immune complexes Cell-mediated immunity
(Fig. 10.5)
2. The General Course of 2. The General Course of InfectionsInfections
Figure 2-1
The Response to An Initial Infection The Response to An Initial Infection
Occurs in 3 PhasesOccurs in 3 Phases
Infection - A Series of StagesInfection - A Series of Stages
1 2 3 4 51 2 3 4 5
The Course of A Typical Acute InfectionThe Course of A Typical Acute Infection
3. The Front Line of Host 3. The Front Line of Host DefenseDefense
Figure 2-4 part 2 of 2Surface Epithelia Provide Surface Epithelia Provide
Barriers to InfectionBarriers to Infection
Lysozymes
Figure 2-5Phagocytes Recognize Phagocytes Recognize Microbial ComponentsMicrobial Components
LPS receptors (CD14)
Toll-like receptor-4 (TLR-4)
Scavenger receptor
Mannose receptor
Glucan receptor
Figure 2-6Phagocytes Produce Bactericidal Phagocytes Produce Bactericidal
Agents on the Ingestion of MicroorganismsAgents on the Ingestion of Microorganisms
The Complement SystemThe Complement System
Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction.
1. Alternative pathway : pathogen surfaces
2. Mannan binding-lectin pathway : lectin binding to pathogen surfaces
3. Classical pathway : Ag:Ab complexes
Functions: phagocytosis inflammation lysis
4. Receptors of the Innate 4. Receptors of the Innate Immune SystemImmune System
1. Soluble Molecules:
Collectin family : e.g., Mannan-binding lectin (MBL), C1q
LPS-binding protein (LBP)
C-reactive protein (CRP) : binds phosphocholine portion of LPS
2. Cell-bound chemotactic receptors:
f-Met-Leu-Phe receptor : binds the N-formylated peptide fMLP
Pattern Recognition MoleculesPattern Recognition Molecules
3. Cell-bound phagocytic receptors:
Mannose receptor : binds certain sugar molecules on microbes
Scavenger receptor : recognizes certain anionic polymers, sialic
acids & acetylated LDL
4. Signaling receptors :
Toll-like receptor 4 (TLR-4) : associated with LPS-LBP-CD14
Toll-like receptor 2 (TLR-2): recognizes proteoglycans of G(+)
Activation of NFB
Production of cytokines & chemokines
Expression of co-stimulatory molecules, e.g., B7.1, B7.2
LPS Signals through the LPS Signals through the Toll-like Receptor 4 Toll-like Receptor 4
(TLR-4)(TLR-4)
Innate Immune Recognition by Innate Immune Recognition by Toll-like ReceptorsToll-like Receptors
LPS Induces the LPS Induces the Migration of Migration of Langerhans’ CellsLangerhans’ Cells
Langerhans’ cells: immature dendritic cells resident in the skin
Structure of a Toll-like Receptor (TLR)
(XLXXLXLXX)
Toll/IL-1R
highly conserved among all members of the TIR family
5. Induced Innate Responses to 5. Induced Innate Responses to InfectionInfection
Macrophages Release lipid mediatorsMacrophages Release lipid mediators of Inflammation of Inflammation
Prostaglandins
Leukotrienes
Platelet-activating facor (PAF)
Macrophages Secret Macrophages Secret Pro-inflammatory Cytokine Pro-inflammatory Cytokine IL-1IL-1
Activates vascular endothelium
Activates lymphocytes
Local tissue destruction
Increases access of effector cells
Fever,
production of IL-6(Fig. 2.39)
Macrophages Secret Macrophages Secret Pro-inflammatory Cytokine Pro-inflammatory Cytokine TNF-TNF-
Activates vascular endothelium
Increases vascular permeability
Increased entry of IgG, complement, and cells to tissues
Increased fluid drainage to lymph nodes
Fever
Mobilization of metabolites
Shock (Fig. 2.39)
Lymphocyte activation
Increased antibody production
Fever
Induces acute-phase protein production
Macrophages Secret Macrophages Secret Pro-inflammatory Cytokine Pro-inflammatory Cytokine IL-6IL-6
(Fig. 2.39)
Macrophages Secret Macrophages Secret Pro-inflammatory Cytokine Pro-inflammatory Cytokine IL-8 (CXCL8)IL-8 (CXCL8)
Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection
(Fig. 2.39)
Macrophages Secret Macrophages Secret Pro-inflammatory Cytokine Pro-inflammatory Cytokine IL-12IL-12
Activates NK cells
Induces the differentiation of CD4 T cells into TH1 cells
(Fig. 2.39)
Liver acute-phase proteins increase of opsonization
Bone marrow endothelium neutrophil mobilization phagocytosis
Dendritic cells TNF-stimulates migration to lymph nodes & maturation initiation of adaptive immune response
IL-1/IL-6/TNF-IL-1/IL-6/TNF- Have a Wide Spectrum of Have a Wide Spectrum of Biological Activities That Help Coordinate the Biological Activities That Help Coordinate the
Body’s Responses to InfectionBody’s Responses to Infection
(Fig 2.46)
Hypothalamus increased body temperature
Fat, muscle protein & energy mobilization to allow increased body temperature decreased viral & bacterial replication & increased antigen processing & specific immune response
(Fig 2.46)
- Small polypeptides- Produced by phagocytes, endothelial cells, keratinocytes, fibroblasts & smooth muscle cells- All chemokines are related in a.a. sequence & functions- Chemoattractants for immune cells- CXC, CC, C & CXXXC (CX3C) chemokines
ChemokinesChemokines
CXC : CXCL8 (IL-8), CXCL7 (PBP, -TG, NAP-2), CXCL1 (GRO), CXCL2 (GRO), CXCL3 (GRO), CXCL10 (IP-10), CXC12 (SDF-1), CXCL13 (BLC)
CC : CCL3 (MIP-1), CCL4 (MIP-1), CCL2 (MCP-1),
CCL5 (RANTES), CCL11 (Eotaxin), CCL18 (DC-CK)
C : XCL1 (Lymphotactin)
CXXXC : CX3CL1 (Fractalkine)(CX3C) (Fig. 2.41)
Adhesion Molecules in Leukocyte InteractionAdhesion Molecules in Leukocyte Interaction
Selectins Bind carbohydrates, P-selectin (CD62P)
Initiate leukocyte- E-selectin (CD62E)
endothelial interaction
Integrins Bind to cell-adhesion molecules LFA-1 (CD11a/CD18)
& extracellular matrix CR3 (CD11b/CD18)
Strong adhesion CR4 (CD11c/CD18)
Ig superfamily Various roles in cell adhesion ICAM-1 (CD54)
Ligand for integrins ICAM-2 (CD102)
VCAM-1 (CD106)
PECAM (CD31)
(Fig. 2.42)
Integrins Mediate AdhesionIntegrins Mediate Adhesion
Neutrophils Cross the Blood Vessel Neutrophils Cross the Blood Vessel Wall to Enter Inflammatory SitesWall to Enter Inflammatory Sites
Acute-phase Response Produces Molecules Acute-phase Response Produces Molecules
That Bind Pathogens But Not Host CellsThat Bind Pathogens But Not Host Cells
Interferons Are Antiviral Proteins ProducedInterferons Are Antiviral Proteins Producedby Cells in Response to Viral Infectionby Cells in Response to Viral Infection
NK Cells Are An Early Component of NK Cells Are An Early Component of the Host Response to Viral Infectionthe Host Response to Viral Infection
NK Cells Distinguish Infected NK Cells Distinguish Infected from Uninfected Cellsfrom Uninfected Cells
NK Cells Distinguish Infected NK Cells Distinguish Infected from Uninfected Cellsfrom Uninfected Cells
6. The Course of the Adaptive 6. The Course of the Adaptive Response to InfectionResponse to Infection
In vertebrates, the immune system can be divided into two branches:
“innate immunity”
and
“adaptive immunity”.
Innate Immunity
- Innate immune system is phylogenetically conserved and is present in almost all multicellular organisms.
- Recently-identified Toll-like receptors recognize specific patterns of microbial components and regulates the activation of innate immunity.
Adaptive Immunity
- Adaptive immunity detects non-self through recognition of peptide antigens using antigen receptors expressed on the surface of B and T cells.
- In order to respond to a wide range of potential antigens, B and T cells rearrange their immunoglobulin (Ig) and T cell receptor (TCR) genes to generate over 1011 different species of antigen receptors.
- Engagement of antigen receptors by the cognate antigen triggers clonal expansion of the T and B lymphocytes.
- Late (after 96 hr) - Inducible - Specific Ab & T cells - Memory
Barrier functions IgA in luminal spaces IgE on mast cells local inflammation
Response to extracellular pathogens IgG, FcR-bearing cells IgG + IgM + classical C pathway
Response to intracellular pathogens T-cell activation of ф by IFN-
Response to virus-infected cells cytotoxic T cells, IFN-
Summary of Adaptive Immune ResponseSummary of Adaptive Immune Response
The Time Course of Infection in Normal The Time Course of Infection in Normal & Immunodeficient Mice & Humans& Immunodeficient Mice & Humans
Characteristics of Recognition Molecules Characteristics of Recognition Molecules of the Innate & Adaptive Immune Systemsof the Innate & Adaptive Immune Systems
7. The Mucosal Immune System7. The Mucosal Immune System
The Mucosal Surfaces of the Body Are The Mucosal Surfaces of the Body Are Particularly Vulnerable to InfectionParticularly Vulnerable to Infection
1. Detect and kill pathogenic organisms gaining entry through the gut.
2. Avoid immune responses to food antigens.
3. Avoid immune responses to commensal bacteria ( > 400 species, ~ 1014 in the colon and ileum).
GALT – gut-associated lymphoid tissues
MALT – mucosa-associated lymphoid tissues
Tonsils
Adenoids
Peyer’s patches (small intestine)
Appendix
Lymphoid follicles (large intestine and rectum)
Peyer’s PatchesPeyer’s Patches
Janeway Fig 1-10
M Cells Take Up Antigens from the Lumen of M Cells Take Up Antigens from the Lumen of the Gut by Endocytosis Immune Responsethe Gut by Endocytosis Immune Response
IgA Is the Major Ab Isotype in the GutIgA Is the Major Ab Isotype in the Gut
Transcytosis of IgA Ab Across Epithelia Is Mediated by Transcytosis of IgA Ab Across Epithelia Is Mediated by the Poly-Ig Receptor, A Specialized Transport proteinthe Poly-Ig Receptor, A Specialized Transport protein
Janeway 9.20
Salmonella Can Penetrate the Gut Salmonella Can Penetrate the Gut Epithelial layer by 3 RoutesEpithelial layer by 3 Routes
Infection by Infection by HelicobactorHelicobactor pyloripylori Causes Causes Peptic Ulcers and Carcinoma of the StomachPeptic Ulcers and Carcinoma of the Stomach
8. Immunological Memory8. Immunological Memory
1. Immunological memory is long-lived after infection or vaccination.
2. Both clonal expansion and clonal differentiation contribute to immunological memory in B cells.
3. Repeated immunizations lead to increasing affinity of antibody owing to somatic hypermutation and selection by antigen in germinal centers
4. Memory T cells are increased in frequency and have distinct activation requirements and cell-surface proteins that distinguish them from armed effector T cells.
5. In immune individuals, secondary and subsequent responses are mediated mainly by memory lymphocytes.
Summary of Immunological MemorySummary of Immunological Memory
Expression of Expression of Cell-surface Cell-surface Molecules on Molecules on
Memory T Memory T CellsCells
Summary of Innate ImmunitySummary of Innate Immunity
- Immediate (0 – 4 hr) - Nonspecific - Innate - No memory - No specific T cells
Barrier functions skin, epithelia
Response to extracellular pathogens phagocytes alternative C pathway MBL C pathway
Response to intracellular pathogens macrophages
Response to virus-infected cells NK cells
Summary of Early Induced ResponseSummary of Early Induced Response
- Early (4 – 96 hr) - Nonspecific + specific - Inducible - No memory - No specific T cells
Barrier functions local inflammation local TNF-Response to extracellular pathogens mannan-binding lectin CRP, C T-independent B-cell AbResponse to intracellular pathogens NK-dep ф activation IL-1, IL-6, TNF-, IL-12Response to virus-infected cells IFN-, IFN- IL-12-activated NK cells