The Humoral Immune Response

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Chapter 9 The Humoral Immune Response
This chapter deals with (i) activation of B
cells, (ii) distribution of antibodies and (iii)
destruction of antigen as a result of being
targeted by antibodies
Antibodies protect extracellular spaces, blood
and certain surfaces from microorganisms
Most antibody (B cell) responses need help
Help comes from T cells (signal 2) Most help
comes from TH2 but TH1 can also provide
help There are also antibody responses that do
not require T help (Thymus-independent or
T-independent antibody responses) T help controls
or partly controls B cell proliferation, class
switching, initiation of somatic mutations and
memory
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Activation by antigen binding and helper T cell
interactions
Activation is proliferation and differentiation
Examples of the mechanisms used by antibodies to
get rid of antigens (mechanisms can be Ig
isotype-specific)
Also induces inflammation
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Some responses require T help whereas other do not
B cell activation
T-independent antibody response generally have1.
no memory2. no isotype switching3. no
somatic mutations
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For B cells, help is Signal 2
For us, signal 2 is provided to B cells by CD40L
and and IL-4 (other cytokines involved,
too) Recall, T cell activation up-regulates T
cell expression of CD40L (and next slide)
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Slide 12 chapter 8
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T help for B cells is via the same antigen that
is recognized by the B cell However, not
necessarily by the same epitope
Linked recognition
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(Specific for peptide 52-67)
Antigen processing
B cell antibody is specific for peptide 68-74
Antigen presentation
TH can recognize any of these peptides and
provide help
Linked recognition
(Specific for peptide 34-48)
MHC class II
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B cell and T helper cells recognize epitopes of
the same molecular complex but not necessarily
the same epitopes.
Linked recognition
Figure 9.4
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If T cells recognize only peptides, how do you
make antibodies to polysaccharides or other
non-protein macromolecules?
Linked recognition
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IL-4 is secreted in the direction of the B cell
so there is little bystander effect on
neighboring B cells
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Those B cells and T cells that bind antigen are
trapped in the T cell zone of the peripheral
lymphoid organ where they can both get activated
and interact
Recall T cell circulation from Chapter 8
Some B cells in the primary focus differentiate
into plasmablasts and plasma cells, leave the
area and make antibody. Others go to the B cell
zone
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Plasmablasts have surface Ig and secrete Ig they
interact with TH cell and they divide. Plasma
cells are generally no longer responsive to
antigen and do not need T cell help.Most plasma
cells are terminally differentiated they do not
divide and most, but not all, die in days or
weeks)
Signal 1 Signal 2
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See slide 11 for B-T interaction in T cell zone
Primary focus Germinal center. Lots of cell
proliferation (centroblasts)
B cell zone
T cell zone
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Germinal centers (GC) contain B cells, follicular
dendritic cells (FDC) and T cells
(antigen-specific B and T cells in the GC)
Centrocyte is B cellcentroblast is a dividing B
cell
In the germinal centers, B cells undergo
Germinal centers are mostly proliferating B cells
but also many (10) T cells

• somatic hypermutations
• affinity maturation
• isotype switching

Figure 9.10 7th ed
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Follicular dendritic cells present native antigen
1. bound by antibody and Fc receptors and 2.
bound by complement and complement receptors
Some of the early antibody is from plasmablasts
Follicular dendritic cell presenting native (not
processed) antigens
Figure 9.14
B cells competing to bind the antigens presented
by follicular dendritic is probably where the
competition that drive affinity maturation occurs
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Somatic hypermutations (point mutations) to fine
tunes the responseAffinity maturation by
competition for activation
silent
neutral
deleterious
positive
Clone 1
Clone 2
Clone 3
Clone 4
Clone 5
Clone 6
Clone 7
Clone 8
Only clones 2 and 7 survive
neutral, deleterious and positive with respect
to binding affinity
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Competition for binding to antigen and
cross-linking, both at the surface of a
follicular dendritic cell which is presenting
antigen (see previous slide)
The fate of most clones from the previous
slide First, clones 3,4,5 die later clones 1,6,8
die (and 50-100 other, too)
The fate of a few clones from the previous
slide Clones 2 and 7 survive and constitute the
final GC
Although 50-100 different antigen-specific B
cells originally comprise a GC, by the end of the
response all the B cells are from a few clones
(several GC per response)
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Activated B cells eventually differentiate into
plasma cells, for the secretion of antibody, and
memory B cells. Most plasma cells survive for a
few day to a few weeks. Some are long-lived
(account for much of the circulating
antibodies). Memory B cell live a long time
(years). Memory B cells keep the changes that
they acquired in the germinal centers (e.g.,
class switched, somatic mutations).
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Early events in primary foci provide immediate
antibody Germinal centers provide more effective
antibody.? more (proliferation and
differentiation into plasma cells)? high
affinity (somatic mutation, affinity
maturation)? switched
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Signal 2 (CD40L) from TH cells is required for
class switching and TH cells make cytokines that
influence which class results
This is mouse data
Class switching occurs in the germinal center
(and other places) see next slide panel 3
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Summary of B cell activation and selection by
thymus-dependent antigens
Activated by TH cells (not shown here)
Primary focus Germinal center. Lots of cell
proliferation (centroblasts)
B cell zone
T cell zone
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There are two classes of thymus independent (TI)
antigens TI-1 and TI-2
How B cell respond to TI-1 antigens depends on
the antigen concentration
TI-1
Bacterial lipopolysaccharides (LPS) is the
prototypical TI-1 antigen.
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TI-2 antigens contain highly repetitive
structures (epitopes). Highly repetitive epitopes
cross-link the BCRs and that activates the B cells
Bacterial capsule polysaccharides are prototypic
TI-2 antigens
It is not known for sure which cells produce the
cytokines and how they interact with the B cells.
Too low a density of repeating epitopes and they
do not activate. Too high a density of repeating
epitopes and they anergize.
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Thymus dependent (TD) Thymus independent (TI)
Summary of different classes of antigens
Contradictory?
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T-independent antibody response generally
have 1. no memory 2. no isotype switching 3.
no somatic mutations
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Now, we know how antibody is made. So, how does
it work and where does it work?
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Transcytosis of IgA across epithelia
Lumen
Polymeric Ig receptor (receptor for polymeric
Igs, i.e., IgA and IgM)
Note figure 11.13
There are many IgA producing plasma cells in the
tissues adjacent to epithelial surfaces and ducts
so most of the secreted Ig is IgA
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Summary of distribution of Ig isotypes
In utero the fetus gets lots of maternal
IgG. After birth, the infant gets lots of IgA in
colostrum and milk (this Ig protects the oral
cavity and the gut)
Passive immunity is the transfer of antibodies
from one individual to another. Active immunity
is when a individual generates their own immune
response
Note that IgD is not shown anywhere on this
figure and has no known role in destruction of
antigens (only known function is as a BCR)
Monomeric IgA
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Antibody Effector Mechanisms How Antibodies
Help Get Rid of Antigens
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Various Bacterial Toxins
Neutralization of a toxin by antibody
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Viruses infect cells by binding to surface
receptors
Viral neutralization by antibody
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Most bacteria need to attach to a surface to
initiate an infection
Antibodies can prevent attachment of bacteria to
cell surfaces (neutralization)
Prevention of adhesion on mucus membranes is
particularly important this is a major role for
secretory IgA
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• IgM
• First
• Few mutation
• High avidity (because of the 10 antigen-binding
  sites and despite low affinity at each binding
  site)
• Good activator of complement

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IgM is highly efficient at fixing (activating)
complement. IgGs can fix complement but are less
efficient.
IgM
A single molecule of IgM bound to a surface can
initiate a complement cascade
Two molecules of IgG can initiate a complement
cascade but getting two bound molecules of IgG
close together can take lots of IgG
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Red blood cells (RBC) help clear immune complexes
(antigen-antibody complexes) from the blood via
complement receptors on the RBCs.
If there are excessive immune complexes that are
cannot be removed from the blood in the liver or
spleen, they tend to get deposited in the
kidneys. This can cause glomerulonephritis
(inflammation of the glomeruli) and kidney
failure.
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Transmembrane Ig (BCR)
Fc receptors (FcR)
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Free Ig does not bind efficiently to Fc receptors
whereas antigen-antibody complexes do bind
efficiently (IgE-FcRe is an exception)
IgM does not have free Fc regions and there are
few Fc receptors for IgM. But IgM is efficient
at complement activation and uses C3b for an
opsonin. (i.e., IgM is not an opsonin but it is
very efficient at inducing production of C3b, a
good opsonin).
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Fc receptors and complement receptors synergize
to make phagocytosis of bacteria and other
organisms very efficient
Recall, antibodies can activate complement and
complement can be activated without antibody
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Schistosome larva (worm) surrounded by eosinophils
This organism is too large to be phagocytized so
eosinophils with surface IgE bound to Fce
receptors(FceR) release toxic compounds around
the parasite
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eosinophils
neutrophil
neutrophil
lymphocyte
basophil
RBC
monocyte
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Antibody dependent cell-mediated cytotoxicity
(ADCC)
Note that the target cell is a host cell, not a
pathognen. Why?
So, NK has two ways to recognize targets (1)
lack of MHC class I on the target (innate
immunity) (chapter 2) or (2) antibody on the
target (adaptive immunity)
Although NK and CTLs recognize targets in quite
different ways, the NK and CTL cytolytic (cell
killing) mechanisms are essentially the same.
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IgE plus antigen causes degranulation of mast
cells (granules contain histamine and other
compounds that cause inflammation)
Note the mast cell has antibody bound to FceR in
the absence of antigen (unlike other FcRs).
Figure 9.30 shows the binding affinity of FceR
for IgE (1010M-1)to be 100 to 50,000 time greater
than the affinity of most other FcRs for antibody.
Mast cell degranulation
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Summary of some of the way that antibodies
function to protect against infections

• Neutralization of toxins, bacteria and viruses by
  inhibition of adherance (or for toxin, sometimes
  blocking active sites)
• Opsonization
• Complement activation
• Immune complex clearance by RBC
• ADCC
• Mast cell degranulation
• Eosinophil degranulation

When are cells involved? Which cells? Which use
FcR (Fc receptors)? Which use CR (complement
rceptors)?
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Summary of the life of a lymphocyte
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Hematopoiesis Summary
Dendritic cells
Natural killer cells
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T cell development
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B cell development Thymus dependent (TD)