Transcript Document

Host Defense Against Infection
Immune Evasion
Mar 5, 12, 19, 2007
References
IMMUNOBIOLOGY 6th ed.
Janeway, Travers, Walport & Shlomchik (2005)
Chapter 2 Innate Immunity
Chapter 10 Adaptive Immunity to Infection
Outline
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
1. The Diversity of Pathogens
A Variety of Microorganisms
Can 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
A 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
Compartments of the Body
Pathogens Can Damage Tissues in
A 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
Infections
The Response to An Initial Infection
Occurs in 3 Phases
Figure 2-1
Infection - A Series of Stages
1
2
3
4
5
The Course of A Typical Acute Infection
3. The Front Line of Host
Defense
Surface Epithelia Provide
Barriers
to
Infection
Figure 2-4 part 2 of 2
Lysozymes
Figure
Phagocytes Recognize
Microbial Components
LPS receptors (CD14)
Toll-like receptor-4 (TLR-4)
Scavenger receptor
Mannose receptor
Glucan receptor
2-5
Phagocytes Produce Bactericidal
Agents on the Ingestion
of
Microorganisms
Figure 2-6
The 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
Immune System
Pattern Recognition Molecules
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
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 NFkB
 Production of cytokines & chemokines
 Expression of co-stimulatory molecules, e.g., B7.1, B7.2
LPS Signals through the
Toll-like Receptor 4
(TLR-4)
Innate Immune Recognition by
Toll-like Receptors
LPS Induces the
Migration of
Langerhans’ Cells
Langerhans’ cells:
immature dendritic cells
resident in the skin
Structure of a Toll-like Receptor (TLR)
(XLXXLXLXX)
highly conserved
among all
members of the
TIR family
Toll/IL-1R
5. Induced Innate Responses to
Infection
Macrophages Release lipid mediators
of Inflammation
Prostaglandins
Leukotrienes
Platelet-activating facor (PAF)
Macrophages Secret
Pro-inflammatory Cytokine IL-1

Activates vascular endothelium
Activates lymphocytes
Local tissue destruction
Increases access of effector cells

Fever,
production of IL-6
(Fig. 2.39)
Macrophages Secret
Pro-inflammatory Cytokine 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)
Macrophages Secret
Pro-inflammatory Cytokine IL-6

Lymphocyte activation
Increased antibody production

Fever
Induces acute-phase protein production
(Fig. 2.39)
Macrophages Secret
Pro-inflammatory Cytokine IL-8 (CXCL8)

Chemotactic factor recruits neutrophils, basophils, and T cells
to site of infection
(Fig. 2.39)
Macrophages Secret
Pro-inflammatory Cytokine IL-12

Activates NK cells
Induces the differentiation of CD4 T cells into TH1 cells
(Fig. 2.39)
IL-1/IL-6/TNF- Have a Wide Spectrum of
Biological Activities That Help Coordinate the
Body’s Responses to Infection
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
(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)
Chemokines
- 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
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 Interaction
Selectins
Bind carbohydrates,
P-selectin (CD62P)
Initiate leukocyte-
E-selectin (CD62E)
endothelial interaction
Integrins
Bind to cell-adhesion molecules
& extracellular matrix
Strong adhesion
Ig superfamily Various roles in cell adhesion
Ligand for integrins
LFA-1 (CD11a/CD18)
CR3 (CD11b/CD18)
CR4 (CD11c/CD18)
ICAM-1 (CD54)
ICAM-2 (CD102)
VCAM-1 (CD106)
PECAM (CD31)
(Fig. 2.42)
Integrins Mediate Adhesion
Neutrophils Cross the Blood Vessel
Wall to Enter Inflammatory Sites
Acute-phase Response Produces Molecules
That Bind Pathogens But Not Host Cells
Interferons Are Antiviral Proteins Produced
by Cells in Response to Viral Infection
NK Cells Are An Early Component of
the Host Response to Viral Infection
NK Cells Distinguish Infected
from Uninfected Cells
NK Cells Distinguish Infected
from Uninfected Cells
6. The Course of the Adaptive
Response 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.
Summary of Adaptive Immune Response
- 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-
The Time Course of Infection in Normal
& Immunodeficient Mice & Humans
Characteristics of Recognition Molecules
of the Innate & Adaptive Immune Systems
7. The Mucosal Immune System
The Mucosal Surfaces of the Body Are
Particularly 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 Patches
Janeway Fig 1-10
M Cells Take Up Antigens from the Lumen of
the Gut by Endocytosis Immune Response
IgA Is the Major Ab Isotype in the Gut
Transcytosis of IgA Ab Across Epithelia Is Mediated by
the Poly-Ig Receptor, A Specialized Transport protein
Janeway 9.20
Salmonella Can Penetrate the Gut
Epithelial layer by 3 Routes
Infection by Helicobactor pylori Causes
Peptic Ulcers and Carcinoma of the Stomach
8. Immunological Memory
Summary of 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.
Expression of
Cell-surface
Molecules on
Memory T
Cells
Summary 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 Response
- Early (4 – 96 hr)
- Nonspecific + specific
- Inducible
- No memory
- No specific T cells
Barrier functions
Response to extracellular pathogens
Response to intracellular pathogens
Response to virus-infected cells
local inflammation
local TNF-
mannan-binding lectin
CRP, C
T-independent B-cell Ab
NK-dep ф activation
IL-1, IL-6, TNF-, IL-12
IFN-, IFN-
IL-12-activated NK cells