Download - Immunology Chapter 9
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Chapter 9
Immunity Mediated by
B Cells and Antibodies
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Focus of Chapter 9 How Antibodies Clear Infection
Antibodies recruit “destructive, nonspecific” immune system components to the infecting pathogen How?
Antibodies bind and link the pathogen to effector molecules or cells that will destroy the pathogen
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RECALL
Pathogens
extracellular
B cell PM cell
Antibodiessecreted in
2ND LT & Bone
Marrow
B cell function
extracellular spaces
virus~~~~~~ ~~~ Next cell
bacteria
YYY
intracellular
virusOther Pathogens
fluids
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Ab toxic destructive to pathogens
How do Ab reduce infection?
What happens?
Molecular adaptor(opsonize)
PHAGOCYTOSIS
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pathogen
YY
YY
Y phagocyte
?
?
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Role of AB =
Y
reduces infectionYYY
Neutralize = pathogen surface coveredGrowth/replication
1
YY
Y YYpathogen
Y
Y YY
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COMPLEMENT activation
Recall: Chapter 1, Figure 1.5 Opsonization is enhanced by the actions of complement Complement Ag-binding function of Ab
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Complement = set of proteins that do not discriminate between Ags
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Antibody production by B lymphocytes
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The Development Of B Cells Can Be Divided Into six Broad Phases
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Stem cell in bone marrow to the mature naïve B cell
Location of B cells at the different stages
State of the Ig H- and L- chain genes Form of Ig expressed
Peripheral circulation
Bone Marrow
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B cells need activated T cell help to mature into Ab-secreting Plasma Cells
“Generally” need T cell help This delays onset of Ab production until a week after infection begins
In addition, B cells take time to switch isotype and undergo and affinity maturation…
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Last Two Main Phases of B-cell Development
Plasma cells can differentiate directly from: activated B cells isotype switched, somatically hypermutated centrocytes memory B cells
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T cell help, Isotype Switching & Affinity Maturation
Why? Production of high-affinity antibodies that are MOST effective at
dealing with pathogens During the course of an infection the effectiveness of the Abs
steadily increases Experience retained in the form of memory B cells and high affinity
Abs to provide long-term immunity to reinfection
What’s the alternative to waiting?
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B cell Activation without T-cell Help
Faster primary response to activate B cells without the need for T-cell help Provides early defense Abs IgM isotype and of low affinity Keeps infection at relatively low level until better antibody response
can develop
How do B cells become activated?
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7-1 B-cell activation requires cross-linking of surface immunoglobulin
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Protein or carbohydrate
epitopes
Bacterial cell
Naïve Mature B cell
IgM’s X-linked by repetitive Ag epitopes
Ig
Ig
IgM Ig Ig
Note that BCR signal transduction resembles that of TCR
Signal transductionextracellular intracellular
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How does BCR signal transduction resemble TCR signal transduction
BCR Associated with cytoplasmic
protein tyrosine kinases PTK’s activated by receptor
clustering
Ig & Ig associate with IgM to form functional BCR Cytoplasmic tails with 2 ITAMs Activates intracellular signaling
pathways
TCR Associated with cytoplasmic
protein tyrosine kinases PTK’s activated by receptor
clustering
CD3 associate with TCR to form functional TCR Cytoplasmic tails with 2 ITAMs Activates intracellular signaling
pathways
Similar intracellular signaling pathways!
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B cell Signal Cascade
1. Receptor clustering
2. Receptor-associated tyrosine kinases phosphorylate the ITAMs on the Ig & Ig cytoplasmic tails
3. Syk binds to the phosphorylated ITAMs of the Ig cytoplasmic tail
Tyrosine kinases
Ig cytoplasmic tail(mature naïve B cell)
ITAMs
phosphate
Lyn
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mature naïve
Ig
Lyn
What does Syk bind to? Phosphorylated ITAMS of
chain!!! Recall: clustering of BCRs
minimum of two receptor complexes Syk are close together
What is the result or function of this “closeness”?
Transphosphorylation
Transphosphorylation
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What is the function of the previous intracellular pathway?
Extracellular Intracellular signals! What is the purpose/function of the B cell signal cascade?
Pathway that relays signals produced to the B-cell nucleus
What are the results of the B-cell nucleus receiving signals? Gene expression modulation Why does the IS want to modulate the gene expression in a B-cell
“B-cell Activation”
Is X-linking of the BCR by Ag sufficient to activate a mature naïve B cell?
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NO! Additional signals are required to “activate” a mature naïve B cell
Requirement for the association of BCR with its co-receptor B-cell co-receptor 3 proteins
CR2 = complement receptor 2 CD19 CD81 = TAPA-1
Functions of co-receptor proteins CR2 = binds to complement deposited on pathogen CD19 = receptor signaling chain CD81 = unknown B-cell co-receptor function?????
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How are signals delivered? Binding of CR1 (on the B-cell) to C3b (on the pathogen)
makes it susceptible to cleavage to C3d CR2 (part of the B-cell co-receptor) can then bind to the C3d
Signal is sent through CD19
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Synergetic cooperation between B-cell receptor & B-
cell co-receptor
1. CR2 C3d X-links BCR to its co-receptor
2. Results in clustering together
3. CD19 phosphorylation by BCR-associated tyrosine kinases
4. Phosphorylated CD19 binds intracellular signaling molecules
5. BCR + BCR co-receptor signals, synergize to signals by 1,000- 10,000-fold
Is this “combined effect” of the BCR signal with its co-receptor signal (signal 1) and CD19 BCR intracellular signaling molecules (Lyn, etc) (signal 2) sufficient to activate a mature naïve B cell?
Signal 2
Signal 1
Ig
Ig: Lyn
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Additional signals from helper T cells are required
“Generally” helper CD4 T cell signal requirement Which CD4 T cells help?
The “effector CD4 T cells” produced when naïve CD4 T cells encounter antigen and became activated
Which “effector CD4 T cells”? TH1 or TH2 ?????
Wait a minute…do all mature naïve B cells even require help?
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9-3: The antibody response to antigens does not (always) require T-cell help
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The Ab response to certain Ags DOES NOT require T cell Help
Chemical and antigenical “distinctions” in mammalian versus bacteria polysaccharides, lipopolysaccharides and peptidoglycans
One has repetitive epitopes … Is it bacteria or mammalian?
Repetitive epitopes are a major target of Ab response to extracellular pathogens
Some repetitive epitope Ags can activate mature naïve B cells without CD4 T cell help!
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Whether a B cell needs T-cell help or not depends on the nature of the Ag
Two classifications of Ags Thymus-dependent Ags (TD Ag) Thymus-independent Ags (TI Ag)
Immunodeficient pts without thymus can make Ab against TI Ags
For TI Ags the need for CD4 T cell help can be overcome in 2 different ways
TI-1 Ag Bind to BCR and other receptors on B cells – Ex. (LPS TLR’s)
Combination = B cell induction to proliferate & differentiate
TI-2 Ag Bind to repetitive Ag’s and cause extensive crosslinking of the
BCR’s that no additional signal is needed to activate the B-cell.
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What is LPS?
Lipopolysaccharide (surface of pathogens) Ex: LPS=Gram-negative bacteria
What is LBP? Soluble LPS binding protein
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LPS of gram-negative bacteria can activate B cells to become Ab-producing plasma cells
1. BCR is specific for LPS epitope
2. LPS forms complex with soluble LPS binding protein (LBP)
3. Signals - CD14/TLR-4 + BCR + B-cell co-receptor sufficient to activate B cell plasma cells
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LPS of gram-negative bacteria
can activate B cells to become Ab-
producing plasma cells
1. LPS binding to CD14/TLR-4 = a co-activating signal
2. Co-activating signal for another Ag on the bacterium to bind to its specific BCR
3. This B cell goes on to produce Ab specific for the bacterial antigen, not LPS
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There is a second type of TI Ag: TI-2
Repetitive carbohydrates or protein epitopes at a high density on a pathogen’s surface Stimulate B cells specific for the Ag Extensive X-linking of BCR to B-cell co-receptor
What’s the result of this “Extensive X-linking” May over-ride need for additional signals
How long does this take? 48 hrs after Ag encounter Ex: bacterial cell wall polysaccharides with B-1 cell as the IS
responder
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Ab responses induced by TI-2 Ags
Induce early Ab response to contain an infection – typically B-1 cells Limitations
Little isotype switching >> IgM (some IgG)
No hypermutation What is the result of no
hypermutation?
no affinity for Ag No long-term
immunological memory no long lasting immunity for 2nd encounter
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9-4: Activation of naïve B cells by most antigens requires help from CD4 T
cells
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B cells needing T-cell help and Thymus-dependent Ags (TD Ags)
Bulk of pathogen-specific Ab are produced by TD Ags What does TD antigen do?
TD Ags activate B cells in 2nd LT Does this make sense?
Well…..the 2nd LT is where B cells, specific Ag and helper CD4 T cells are brought together
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B-cell Meets it’s Antigen
If a B-cell meets it’s antigen signals (BCR + co-receptor) are sent to the nucleus and induce changes in
the expression of adhesion molecules and chemokine receptors at the surface
These changes trap the B-cell in the T-cell area close to the B-cell zone. This allows for effector T-cells to test their TCR’s against the Ag-MHC II on
the B-cell cognate interactions and conjugate pairs
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Ag delivery dendritic cells
Who delivers the Ag from the afferent lymphatic vessel?
P-APC, MHCII: dendritic cell
Mature naïve B cells need T-cell help with Thymus-dependent Ags (TD Ags)
1. B cell migrate in blood or afferent lymph to LN
2. B cells leave blood HEV LN cortex meets Ag
3. B-cells are drawn to T-cell areas by CCL21 and CCL 19 just like T-cells
4. B-cell doesn’t meet it’s antigen drawn to follicle by CCL13
5. Ags are trapped in the T-cell areas of LN
6. “Ag specific CD4 T cell helpers” activated in presence of IL-4 Th2 help activate the B-cells
Infected tissue
CCL19 and 21
CCL13
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Recirculating naïve B cells enter the LN T-cell zone from the blood HEV
B cells encounter helper TH2 cells specific for the same Ag
B cells interact with TH2 to form a “1° focus” of proliferating activated B cells and TH2 cells in the medullary cords
Mostly IgM Under influence of IL-
5 & 6
Mature naïve B cells become trapped in the T-cell zone of 2nd LT if they encounter their
“cognate” helper T cell
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Does the BCR have a role in B cell activation?
Does the BCR have a role in B cell activation? Two distinct BCR roles in B cell activation:
Binding antigen sends a signal to the B cells’ nucleus to change gene expression
Internalizing Ag by receptor mediated endocytosis processing and presenting it to helper T-cells
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Two signals B cell proliferation & differentiation into plasma cell
B-cell activation in response to TD-Agrequires T cell help
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What happens when TH2 cell’s TCR binds peptide Ag:MHC class II molecules on the B cell surface?
B cell CD40 :CD40 T cell ligand Why ?
a signal for the B cell to activate the transcription factor, NFB which then up regulates intercellular adhesion molecule 1 (ICAM-1) expression which can bind to LFA-1 on T-cell What’s the functional result of the up-regulation of ICAM-1on the
B cell’s surface? Strengthen the cognate interactions between the B and T-cell Reorganization of cytoskeleton and golgi allow focused secretion of
cytokines onto the B-cell IL-4 being one of the most significant cytokines to drive B-cell
proliferation and differentiation
Signal sent to T-cell nucleus to make of IL-4? Essential for B cell proliferation and development to plasma cells Characteristic of Th2 cells
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What happens to these dividing B cells?
Recall: B cells activated by interaction with cognate helper T cells in the LN T-cell areas form a 1° focus of dividing B and T cells in the medullary cords of the LN
Result is dividing B lymphoblasts and some will secrete IgM How long does a 1° focus of dividing B cells last?
A few days
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How long does it take for a GC to appear?
What is the physiological symptom of GC formation?
Division rate 1/6hr Large metabolically active cells
Centroblast Morphology of follicle changes
secondary follicle Domination by the germinal center (lots of
new B cells)
B cells Medullary cords PM cells
IL5 & IL6
TH2
YY
Y
IgM
1° focus 1° follicles
Still attached to TH2
1
2Can isotype switching happen in a primary follicle?
Several days
1 week Lymph node swelling
some
Primary Focus
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Germinal Center
Specialized B-cell microenvironment where: proliferation Somatic hypermutation Selection of antigen binding
What are dark zones? Close packed centroblasts
What are light zones? Non-dividing centrocytes that
will interact with FDC’s
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9-7 Activated B cells undergo somatic hypermutation and isotype switching in the specialized microenvironment of the
B-cell zone
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Activation proliferation selection
B cell maturation in germinal center
Activation proliferation selection
Common theme of lymphocyte development
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Proliferation in the GC, OkayWhat about hypermutation and affinity
maturation in the GC?
centroblasts dividing
in germinal center
somatic hypermutation
& isotype switching
T-cellcytokines
Nondividing centrocytes
Mutated surface Ig
Post hypermutationSurface Ig of centrocyte
Affinity for a specific antigen
higher
lowerequa
l
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What’s the upshot of this hypermutation & affinity maturation
GC centrocytes express Igs with a range of affinities for the specific Ag The B-cells have to compete again for access to antigen on the
FDC’s and then for access to antigen specific T-cells.
What happens to centrocytes that fail to bind Ag:T-cell CD40 ligand? Centrocytes that fail to bind Ag/CD40 ligand on helper T cell
interaction Apoptosis
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Mutated centrocytes compete!
Mutatedcentrocyte
To engage a helper T cellCentrocyte bind Ag process antigen surface = MHCII + Ag
Mutated centrocytes now compete!
Access of Ag on FDC’s Ag-specific helper T cells
MHCII
1 2
Follicular dendritic cells provide a source of intact Ag
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B cells recognize Ag as FDC surface “immune complexes”
Localized in GC’s FDC’s bind Ag in
form of immune complexes (Ag:complement or Ag:Ab:complement)
1. Bind to FDC Fc receptors
2. Fc and complement receptors on FDCs
Immune complexes are not internalized
Persist on FDC’s for long periods (years)
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Iccosomes are immune-complex coated bodies
Bundles of membrane coated with immune complexes also bud off from the surface of FDCs iccosomes FDCs have a prominent cell
body and dendritic processes Immune complexes are bound
on the FDC surface become clustered prominent beads are formed along the dendrites
Beads shed from the cells iccosomes Iccosomes taken
up by Ag specific B cells in the GC bound B cells process & present Ag
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Newly formed centrocytes move from the dark zone of the gc
to contact FDCs in the light zone
Newly formed centrocytes move from GC dark zone captures Ag from FDC or iccosomes moves to GC light zone outer regions to helper T cells
Engagement of peptide:MHCII by TCR complex & CD40 ligand induces the centrocyte to express Bcl-xL proteins Bcl-xL functions to prevent death by apoptosis
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Hypermutated B cells interact with FDCs displaying surface immune complexes
B cells do not bind Ag or poor Ag binding receptors due to mutated beyond recognition, therefore they cannot compete for access to the FDCs apoptosis
B cells receptors that bind Ag well receive signals from the T cell are induced to express Bcl-xL Results in preventing apoptosis Therefore, these B cells survive
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After somatic hypermutation…B cells with high-affinity receptors for Ag are rescued from apoptosis
I.e. highest-affinity Ag receptors are selected for survival differentiation into Ab-producing plasma cells and into long lived memory cells
Affinity of Abs for specific Ag increase during immune response is called Affinity maturation
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Survivors interact with Ag-specific T cells…Why?
Mutual engagement of ligands and receptors on surviving centrocyte with T helper cell leads to further proliferation of both B and T cells, serves to: increases population of selected high-affinity, isotype-switch B cell Some B cells are directed down the path of plasma or memory cells
Height of adaptive immune response = need large # of Abs to fight infection selected centrocytes leave GC differentiate into Ab-producing plasma cells
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What happens to centrocytes that fail to obtain, internalize & present Ag?
What happens when centrocyte fails does not obtain, internalize and present Ag Apoptosis Macrophage engulfment in the gc
Tingible body macrophages are macrophages that have recently engulfed the apoptotic centrocytes are a characteristic feature of gc, because of their contents they are called “tingible body
macrophages”
What happens when somatic hypermutation produces centrocytes bearing Ig reactive to self-Ag? Contact with helper T cells in the GC render these centrocytes
anergic
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Chapter 9 – Lecture Notes
Immunity Mediated by
B Cells and Antibodies
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Chapter 9
continued
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9-9: Interactions with T cells are required for isotype switching in B cells
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Interactions with T cells are required for isotype switching in B cells, Why?
Cytokine effects on the switching of Ig synthesis to a particular isotype
Induce augment inhibit
1st Igs = IgM and IgD B cells in GC activated by Ag switch H-chain isotype IgG, IgA or
IgE
The isotype to which an individual B cells switches is determined by?
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…Cognate interactions with helper T cell
What does “cognate” mean? Cognate interactions are cell-cell interactions between B
and T lymphocytes specific for the same antigen How does the helper T cell control the particular isotype to
which a switch is made? controlled by the cytokines secreted by the helper T cell
Roles of specific cytokines in switching is area of hot research in immunology
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Interactions with T cells are required for isotype switching in B cells
“Based on mouse B cell experiments” Differences in humans (from mouse) are not worked out
Example, switching to IgA in humans involve TGF- and IL-10, not IL-5
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Which cytokines are most involved?
Prominent players include cytokines secreted by TH2 cells
IL-4, IL-5 and TGF
What do these cytokines do? Activate naïve B cells to differentiate into plasma cells
Secreting IgM Induce the production of other antibody isotypes
IgG2, IgG4 (weak opsonizing Abs) IgA, IgE
IFN- is a characteristic TH1 cytokine Switches B cells to make IgG1 Strong opsonizing Ab in humans
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How do T-cell cytokines induce isotype switching?
Stimulate transcription from the switch regions that lie 5’ to each H-chain C gene
Example, activated B cells exposed to IL-4 Transcription from a site upstream of the switch regions of C1 and
C is detected prior to switching
What’s the molecular mechanism for isotype switching? Transcript opens up the chromatin Makes the switch regions accessible to somatic recombination
machinery Somatic recombination machinery places a new C gene in
juxtaposition to the V-region
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What else does isotype switching by cognate helper T cells require?
B cell surface CD40 binding to T-cell CD40 ligand This is very important…
How do we know this is important? Example, pts who lack CD40 ligand (Hyper-IgM
syndrome) Immunodeficient Abnormally high levels of IgM in blood serum Almost no IgG and IgA B cells are unable to switch isotype Cannot make Ab responses to TD Ags
Males gene for CD40 ligand is on the X-Chr X-linked
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Hyper-IgM syndrome
No GC in Lymph Nodes GC in Lymph nodes
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Isotype switched, affinity matured B-cells can differentiate into plasma cells or memory cells
When the infection is bad, and secreted Ab’s are needed then the centrocytes will be told to become plasma cells – IL-10
As the infection begins to subside, the centrocytes will be told to become memory B-cells – IL-4
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Antibody effector functions
What does isotype switching do? Isotype switching diversifies Ab Fc region functional
properties Two distinct functions of Fc regions
Deliver Ab to anatomical sites otherwise inaccessible Link bound Ag to molecules or cells that will effect it’s destruction
These cells carry Fc receptors (Examples: macrophages and neutrophils).
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9-11 IgM, IgG and IgA Abs protect the blood and extracellular fluids
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IgM, IgG and IgA Ab functions
Protect the blood and extracellular fluids IgM = 1st Ab, pentamer, enters the blood carried to site of
infection Pentameric nature = strong binding to microorganisms or
particulate Ags Large size limits penetration to infected tissue
Reduced ability to passively leave the blood to penetrate infected tissue
No IgM Fc receptors on phagocytic cells or leukocytes IgM cannot directly recruit these cells IgM Fc regions does, however, bind complement and can
activate the complement system
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Which blood-borne Ab is dominant later in an immune response?
IgG Smaller Together IgM and IgG function to prevent blood-borne infection
septicemia
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What about IgA?
Synthesized by plasma cells in 2nd LT Two forms
Monomeric Dimeric
Monomeric IgA Secreted from plasma cells derived from B cells that switched their
Ab isotype in the LN or spleen Enters extracellular spaces and helps IgG protect against bacteria
and virus particles
Dimeric IgA Made in 2nd LT underlying mucosal surfaces
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IgA & IgG are transported across epithelial barriers by specific receptor proteins
Recall: IgM, IgG and monomeric IgA provide Ag-binding within fluids and tissues of the body
Dimeric IgA protects epithelia surfaces that communicate with the external environment (mucosal membranes susceptible to infection) Linings of the GI tract, eyes, nose, throat, mammary glands,
respiratory, urinary and genital tracts Dimeric IgA made in the lamina propria
Connective tissue underlying basement membrane of mucosal epithelium
IgA-secreting plasma cells are on one side and the target pathogens are on the other side
The dimeric IgA molecules are transported across the epithelium by receptors on the basolateral surface of the epithelial cells
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How are IgA & IgG transported across epithelial barriers?
Dimeric IgA bound by a J chain diffuses across the basement membrane
Dimeric IgA bound by the poly-Ig receptor on the basolateral surface of epithelial cell
Transcytosis – receptor mediated transport from one side of a cell to the other of a macromolecule
Complex transcytosis vesicles released apical surface Poly-Ig receptor cleaved releases IgA from epithelial cell
membrane IgA still bound to a fragment of the receptor called the “secretory
component” (holds IgA to mucus) Residual membrane-bound fragment of the poly-Ig receptor is
nonfunctional degraded
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How are IgA & IgG transported across epithelial barriers?
Apical surface
Basolateral surface Receptor
mediated endocytosis
Transcytosis
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Brambell receptor (FcRB)
IgG actively transported from blood into extracellular spaces by an Fc receptor present on endothelial cells Receptor called FcRB Similar structure to MHC class I (1 & 2 domains to bind the Fc
regions of the Ab) Ab:receptor complex
2 molecules of FcRB bind to the Fc region of one IgG IgG delivery to extracellular spaces in connective tissue
protects IgG from degradation pathways of serum proteins IgG relatively long lived half-life
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Brambell receptor (FcRB)
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Passive transfer of immunity
Fetus physically protected by the mother from extracellular microorganisms
What about after birth? Lack actively acquired immunity Vulnerable to infections (microbial colonization of epithelia) Receives IgA from its mother - secreted into breast milk
Transferred to baby’s gut Bind to microorganism preventing attachment to the gut epithelium
Pass in the feces
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What about IgG during pregnancy?
IgG from maternal circulation transported across placenta Directly into the babies bloodstream Therefore babies have a level of IgG protection in their
plasma equal to the mother’s level of IgG protection Transport of the IgG antibodies across the placenta is
also mediated by the FcRB.
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Antibody production is deficient in very young infants
1st year = vulnerable to infection, deficient in Abs During pregnancy maternal IgG Ab transported across the
placenta What happens to this IgG Ab?
Maternally derived IgG is catabolized Gradually decreases until infant’s immune system produces its own
Ab (6 months) Therefore, IgG levels are lowest in infants aged 3-12 months (time
the infant is most vulnerable to infection) Premature babies are even more vulnerable Take longer to attain immunocompetence after birth than full
term babies
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High-Affinity IgG and IgA are used to neutralize microbial toxins and animal venoms
Some bacteria secrete toxins that disrupt the normal function of cells. Diphtheria and tetanus toxins have a binding part and a toxic part. Ab’s that bind to the binding part of the toxic molecule will block the toxins
ability to enter the cell thus blocking its toxic effects. For venoms, passive immunization is used. (antibodies created using a
large animal inoculated with the venom) These antibodies are gathered from the animal and given to a snake bite
victim to neutralize the toxins (no long term immunity)
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High-affinity neutralizing Ab’s prevent viruses and bacteria from infecting cells
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Ab’s link effector cells to the antigen
Abs = only effector molecules produced by B cells Abs = 1 function = “adaptor molecules”
neutralize the pathogen (doesn’t destroy pathogen) bring “pathogens” and “effector” cells together
Why? So effector cells clear/destroy the pathogen
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Fc receptors
Abs bind through their Fc regions Bind to what?
Fc receptors on effector cells Fc receptors are specific for Ig isotype Fc receptors have 2 main purposes
Deliver Abs to sites where they would not be carried by blood and lymph circulation
Attach Ag:Ab complexes to effector cells allowing effector cells to destroy the pathogens
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Fc of Ab and Fc receptor of effector cell
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IgE binds to high-affinity Fc receptors on mast cells, basophils and activated eosinophils.
FcRI has high affinity for IgE. Crosslinking of receptors by antigen causes release of
histamine from mast cells inflammation recruits cells and proteins needed for host defense.
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High points of 9.11 - 9.16 & 9.21 - 9.25
High-affinity IgG and IgA Abs are used to neutralize microbial toxins and animal venoms
High-affinity neutralizing Abs prevent viruses and bacteria from infecting cells
Fc receptors of hematopoietic cells are signaling receptors that bind the Fc regions of Abs
Phagocyte Fc receptors facilitate Ab-coated pathogen recognition uptake destruction
IgE binds to high-affinity Fc receptors on mast cells basophils activated eosinophils
Fc receptors activate NK cells to destroy Ab-coated human cells Antibody-dependent cell-mediated cytotoxicity (ADCC) (look up)
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Immune complexes and the complement system
Immune complexes of Ag:Ab are often ingested by phagocytic cells and destroyed intracellularly fate of most foreign materials that have Abs produced
against them But the fate of immune complexes also depends heavily
upon their ability to activate the complement system
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Immune Complex Clearance
C3b can coat particulate antigen (immune complexes) that can then be bound by erythrocytes and cleared in the liver or spleen.
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Classical Complement Cascade
Need one IgM or at least two IgG. C1 binds to the Fc regions and needs at least two binding
sites to become stable on the pathogens surface. The rest of the cascade proceeds the same way as you
learned previously. Don’t forget that the alternative pathway can amplify the
cascade that was started by the Ab’s (classical).
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The complement system – A review of what you have already learned.
Slides 91 – 119 are to help you in remembering complement
~ 30 serum proteins Interact in a complex reaction sequences
“complement cascade”
Results in the manifestation of inflammation phagocytosis lysis of foreign cells
Why call it COMPLEMENT? The action of these proteins
“complements” antibody-mediated reactions
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Complement components circulate in blood and body tissues
What is the complement system & how does it function? Enzymes that work in a cascade one becomes active
cleaves another to activate it etc. Center stage = C3 cleaved (C3b and C3a) becomes
activated by Abs aggregated in immune complexes bacterial compounds that 1st bind and activate other complement
proteins
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Complement components C3b and C3a
C3b and C3a degradation products have direct opsonizing effects chemotactic effects inflammatory effects
One of the functions is to activate the lytic pathway involving C5-C9
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Several complement pathways Classical pathway Alternative pathway Lectin pathway
Proteins of the complement system (CS) 5% of serum proteins in vertebrates
Classical pathway proteins are designated by number following C for complement
Range C1 C9
Proteins of the alternative pathway C3, C5 C9 proteins factor B factor D
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Cascade
Complement system proteins act in a sequence (cascade) Each protein activates the next one in the series
cleaves the next protein Resulting components have new functions
What jump starts the classical pathway? Ag:Ab
Is it the same for the alternative pathway? No…initiated by bacteria and fungi cell-wall polysaccharides
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C3
C3 has major role in initiation of mechanisms that lead to microbial destruction In fact, both classical and alternative pathways lead to the cleavage
of C3 into fragments C3a C3b
C3a and C3b initiate cytolysis inflammation opsonization
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The complement component C1
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Cleavage of C4 exposes a reactive thioester bond that covalently attaches the C4b fragment to the pathogen surface
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Activated C1s cleaves C4 and C2 to produce C4b and C2a, which associate to
form the classical C3 Convertase
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Formation of the alternative C3 convertase
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The two types of C3 convertase have similar structures and functions
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C3 activation by the alternative C3 convertase is a process analogous to C3 activation by the classical C3 convertase
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View from above of complement deposition
Keep in mind that classical activation is also amplified by the alternative pathway C3 convertase.
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Cytolysis
Most important function of the complement cascade is… destroy foreign cells (microbial/pathogens)
How does the IS do this? damages the cell membrane to the point that the cellular contents
leak out cytolysis
C5 - C9 = membrane attack complex MAC
produces transmembrane channels through the cell membrane
leads to cell lysis or cytolysis
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Inflammation
C3a and C5a contribute to acute inflammation What exactly do they do?
bind mast cells, basophils and blood platelets release of histamine
Histamine increases blood vessel permeability
C5a acts as a powerful chemotactic factor What’s this mean?
C5a is able to attract phagocytes to areas where complement has been fixed
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The Classical Pathway-Step 1: C1 component
C1 component is comprised of three parts C1q (hexamer) C1r (dimer) C1s (dimer)
Held together by calcium ions
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The Classical Pathway-Step 1: Activation of C1
Initiated by the binding of C1q to C1q-specific receptors on the Fc portions of adjacent Abs (minimum 2 IgG Abs or one IgM) Humans, all Abs have these receptors
exceptions of IgG4, IgA and IgE
Abs possessing these receptors bind or “fix” complement Abs without these receptors, cannot fix complement
Once C1q has bound the C1q specific receptors of two adjacent antibodies, it activates C1r, which in turn activates C1s
Activated C1s subcomponent then activates C4
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The Classical Pathway-Step 2: Activation of C4
C4 is the 2nd complement component of the cascade but was the 4th complement component identified, “C4”
Activated C1s activates C4 by cleaving it into two fragments C4a C4b
C4b binds to the surface of the cell membrane near the site of the Ag:Ab complex
Once bound to the surface, C4b then binds the C2a complement component
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The Classical Pathway-Step 3: Activation of C2
C2 component is cleaved by the combined activities of C4b and C1s C2a C2b
C2a portion remains attached to the C4b component on the cell membrane
C4b-C2a complex is referred to C3 convertase C3 convertase activates the C3 component of complement
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The Classical Pathway-Step 4: Cleaving C3 and amplification
C3 is activated by the activity of C3 convertase This cleaves C3
C3a C3b
A single molecule of C3 convertase is capable of activating hundreds of molecules of C3 amplifying the cascade by providing large amounts of C3a and
particularly C3b
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The Classical Pathway-Step 4: Activation of C3
Both C3a and C3b have biological activity C3a functions as an anaphylatoxin C3b attaches to the cell membrane near the site of activation
where it is capable of acting as an opsonin
Some C3b combines with the C3 convertase to form active classical C5 convertase (C4b2a3b)
Active classical C5 convertase activates complement component C5
Alternative C5 convertase (C3b2Bb)
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Wait a minute…What about MAC?
What about it’s formation? Who is MAC?
The membrane attack complex (MAC) formed as the result of the assembly and activation of
complement components C5 through C9 involved in cytolysis of the target cell
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The Classical Pathway-Step 5: Activation of C5, C6 and C7
C5 is cleaved by C5 convertase C5a C5b
Both of which have biological activity C5a functions as an anaphylatoxin and a chemotaxin C5b binds C6 and C7
forming a complex that attaches to the surface of the target cell membrane
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The Classical Pathway-Step 6: Activation of C8 and C9
C8 component of complement then binds the C5b-C6-C7 complex on the cell membrane
This complex is capable of forming small pores in the membrane of the target cell = compromising its integrity
This is enhanced by the polymerization of the C9 complement component
The polymerization of C9 leads to the formation of transmembrane channels target cell lysis
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MAC
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Complement System = Major defense mechanism against microbial infection
Especially extracellular bacteria Complement components are plasma proteins of several functional
groups Become activated by infections in 3 different ways
classical pathways alternative pathways lectin pathways
The activation of phagocytes and inflammatory reactions by complement provides protection before the antibody response develops after the antibody response develops
The defense mechanism of complement-mediated phagocytosis of pathogens evolved long before the existence of Ab
Molecular Hx = Ab that actually provided the “complementary function” rather than the complement