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Macrophage Activation & Cytokine Release
Dendritic Cells & Antigen Presentation
Neutrophils – Polymorphonuclear cells (PMNs) are
recruited to the site of infection where they phagocytose invading organisms and kill them
intracellularly. In addition, PMNs contribute to collateral tissue
damage that occurs during inflammation.
Neutrophils & Innate Defense
Antigen Presenting Cells (APCs)
Vascular Permeability
The production of increased vascular permeability during inflammation. The
presence of prostaglandins, leukotrienes, and histamine causes cells lining venules to pull apart, allowing phagocytes to leave the bloodstream and more easily reach
a site of infection. The leakage of fluid and cells causes the edema and pain associated with inflammation.
© 2008 Pearson Education, Inc., publishing as Benjamin Cummings
An Overview of Inflammation
© 2008 Pearson Education, Inc., publishing as Benjamin Cummings
Production of fever in response to infection
© 2008 Pearson Education, Inc., publishing as Benjamin Cummings
Innate Immune Response
! "Antigen-presenting cells (APCs) are
activated through pathogen-associated
molecular pattern (or PAMPs) by
receptors such as TLRs.
! "This activation leads to the production of
inflammatory cytokines and the
expression of co-stimulatory molecules on
the cell surface.
Pattern recognition receptors - PRRs
Mammalian TLR family members & their respective ligands
Interplay of Innate & Adaptive Immune Systems
http://content.nejm.org/cgi/content/full/343/5/338/F3
1
Lecture 3: B Cells and AntibodiesLecture 3: B Cells and Antibodies
*FIRST - Finish up on Innate Immunity:
Complement System
Michele Klingbeil
*FIRST - Finish up on Innate Immunity:
Complement System
Michele Klingbeil
2
Lecture Objectives - Complement
• Understand different pathways of C activation
• Know complement proteins (nomenclature)
• Know the enzymatic and non-enzymatic
mechanisms of complement activation
3
Complement Functions
Historically, complement referred to a heat-labile
serum component that could lyse bacteria
• Host benefit:
– opsonization to enhance phagocytosis
– phagocyte attraction and activation
– lysis of bacteria and infected cells
– regulation of antibody responses
– clearance of immune complexes
– clearance of apoptotic cells
• Host detriment:
– Inflammation, anaphylaxis
2
4
Complement Pathways
5
The Complement System
• More than 20 serum
proteins involved
• Some components
bind to antibody
• Some components
bind to membranes
• Zymogen cleavage
cascade - activation
• C3 most important -
most abundant!
6
Classical Complement Pathway
3
7
Classical Complement Pathway
See animations
at website
8
Mannose Binding Lectin Pathway
Mannose containing Polysaccharides
Similar to Classical Pathway
9
The Membrane Attack Complex
4
10
Terminal Pathway (Lytic Attack)
11
Regulatory Proteins of Complement Pathways
12
Natural Killer Cells
• Lymphocyte lineage
• Normal cells are not killed
because inhibitory signals
from MHC class I molecules
override activating signals
• In tumor cells or virus-infected
cells, reduced expression or
alteration of MHC molecules
interrupts the inhibitory
signals, allowing activation of
NK cells and lysis of target
cells.
Bone marrow
5
13
Natural Killer Cells
14
Innate Immunity to Viral Infections
15
Timing of innate immunity after infection
Barriers - Seconds
Epithelial activation - Minutes
Cytokines/chemokines -
Minutes to days
Neutrophils -
Hours
Monocytes/macrophages - Hours to days
NK cells - Hours to days
Short-lived Long-lived & connect with
adaptive immune system
Complement - Minutes
6
16
Summary of Immune Response
Immune
System
Innate(Nonspecific)
1o line of defense
Adaptive(Specific)
2o line of defense
Protects/re-exposure
Cellular
Components
Humoral
Components
Cellular
Components
Humoral
Components
Anatomical
Barriers
Adaptive(Specific)
2o line of defense
Protects/re-exposure
Humoral
Components
17
Lecture Objectives: B Cells & Antibodies
• Discuss the general properties of all immunoglobulins
• Describe the basic structure of immunoglobulins
• Relate immunoglobulin structure with function
• Define immunoglobulin hypervariable and framework
regions
• Define immunoglobulin classes and subclasses
18
Adaptive Immunity
Immunity established to adapt to infection
• Learnt by experience
• Confers pathogen-specific immunity
• Enhanced by second exposure
• Has memory
• Uses cellular and humoral components
• Is poorly effective without innate immunity
Antibodies reflect infections to which an individual has been exposed:
diagnostic for infection
7
19
B Cell Maturation & VDJ Rearrangement
20
Immunoglobulin Diversity
When a stem cell changes to become a B cell, DNA
segments for both heavy (VDJ) and light (VJ)
Immunoglobulin chains are randomly combined.
Each B cell ends up with functional genes for making
one light and one heavy chain coding for an antibody as
a membrane-bound receptor
Antibody specificity depends on the gene fragments
used.
Antibodies are produced that can react with almost any
chemical structure in nature, including our own proteins
Imprecise recombination and mutation increase the
variability into billions of possible combinations
21
Immunoglobulin (Antibody) Structure
The basic IgG Ab molecule has aMW of ~150kDa
These Abs have a basic structure of4 peptide chains
There are 2 identical light (L) chains~25kDa
There are also 2 identical heavy (H)chains, polypeptides of ~50kDa
Each L chain is bound to a H chainby a –S-S- and non-covalentinteractions (salt linkages, hydrogenbonds and hydrophobic bondsforming a heterodimer
Similar –S-S- and non-covalentinteractions link the identical H-Lcombinations together to form acomplete molecule, a dimer ofdimers
8
22
Immunoglobulin Fragments
Ag
Binding
Complement Binding Site
Placental
Transfer
Binding to Fc
Receptors
23
Immunoglobulin regions
Heavy & Light ChainsDisulfide bondsInter-chain
Intra-chain
Variable & ConstantRegions
–VL & CL
–VH & CH
Hinge Region
CH1
VL
CL
VH
CH2 CH3
Hinge Region
Carbohydrate
Disulfide bond
24
Antibodies and Epitopes
9
25
B Cell Response to Antigen
26
B Cell Receptor
2 major parts• External Immunoglobulin
• Specificty for antigen
• Short cytoplasmic tail - no
direct signaling
• Internal Ig!/Ig" dimer -
cytoplasmic tail for intracellular
signaling
• Responder to what mIg “sees”.
• Other important components
(not essential for exam)
27
B Cell Receptor - Additional Complexity
CD21
(C3d receptor)
CD19
CD81
(TAPA-1)
Ig!Ig"
CD45
The B cell co-receptor
10
28
B Cell Receptor Complex Signaling
Concept of complex signaling pathways involved:
Do not try to memorize all these pathways!
29
Antibody Isotypes
30
Ig Isotype Functions
11
31
Ig Isotype Distribution
32
Cytokine Regulation of Ig Isotypes
33
Humoral Immune Response
12
34
Amazing Immunoglobin Diversity