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