Transcript chapter16

The Adaptive Immune
Response
Chapter 16
Note: In this class, antibody and
immunoglobulin are synonymous
The Adaptive Response is Slow to Start
During childhood, billions of T cells and B cells (lymphocytes) are
generated, but only a few of these can recognize a given species of
pathogen
When these cells recognized the particular pathogen, they begin to
rapidly divide that results in a dramatic increase of pathogen-specific
cells over several days - termed clonal expansion
A single lymphocyte can divide in about 8 hours (3 divisions/day)
In 5 days, 215 divisions occur, resulting in 32,768 cells
During these first few days of infection, the pathogen can cause
substantial pathology to the individual
If the pathology is severe enough, it can cause the death of the
individual
Because of this delay, it is critical that the innate immune response
immediately engage the pathogen and delay its actions long enough
for the adaptive response to join the battle
16.1 Strategy of the Adaptive
Immune Response
All microbial components are potential antigens for
the immune response
Antigens are any molecules that can elicit an immune
response
Primary Immune Response
The first exposure to an infectious agent
Slow to start
Often with pathology
Secondary Immune Response
Any additional exposures to the pathogen
Very quick to respond - usually without symptoms
16.1 Strategy of the Adaptive
Immune Response
The Two Adaptive Immune Responses
Type I immunity (formerly cell-mediated immunity)
Type II immunity (formerly humoral or antibody
immunity)
These responses are often mutually exclusive
Immunity
Innate
Adaptive
Type I
Type II
16.1 Strategy of the Adaptive
Immune Response
Overview of Humoral (Type II) Immunity
B cells are covered with thousands of copies of a membranebound immunoglobulin, termed B cell receptor (BCR) or
surface Ig (sIg)
The immunoglobulin is specific for a particular molecule from a
particular species of pathogen
If the pathogen enters the body, then this cell will bind to it (or
its products) by virtue of its BCR
This results in the activation and maturation of the B cell into
a plasma cell, which then begins to secrete soluble versions of
its immunoglobulin
These antibodies can circulate in blood and lymph for years
If they bind to the antigen, they target it for destruction
16.1 Strategy of the Adaptive
Immune Response
Overview of Cellular (Type I) Immunity
Subsets of T cells
Helper T (Th) cells
Secretes cytokines that mediate local immune responses
Augment activities of the innate response
Are the “generals” of the immune response
Cytotoxic T (Tc) cells
Physically interact with cells harboring a pathogen (such as
a virus) and kills the cell
Are the “special forces” of the immune response
Regulatory T (Treg) cells
Suppress inflammation as the immune response wanes
16.2
Anatomy
of
the
Lymphoid
System
Lymphatic vessels contain
lymph
Secondary lymphoid organs
are where immune cells
gather to coordinate their
activities
Lymph nodes
Spleen
Peyer’s patches (large intestine)
Many others
Primary lymphoid organs are
where immune cells develop
from stem cells
Bone marrow
16.3 The Nature of Antigens
Antigen composition
Protein
Lipids linked to other
macromolecules
Carbohydrates linked to
other macromolecules
A microbe usually has
tens to thousands of
antigenic determinants
(aka, epitopes) that can
be recognized by the
immune system
16.4 The Nature of Antibodies
Antibodies are glycoproteins
(carbohydrates and polypeptides)
Structure and Properties
Two arms that compose the Fab
(fraction antibody) region that bind to
antigenic determinants (the “business
end”)
Antibodies are divalent
One stem (Fc - fraction crystalizable)
that can bind to phagocyte receptors or
complement proteins
16.4 The
Nature of
Each antibody
is composed
of Antibodies
Two identical light (L) polypeptide chains
Two identical heavy (H) polypeptide chains
These polypeptides have intrachain and
interchain disulfide bonds (covalent) that hold
the chains together and maintain the antibody’s
3D shape
There are 5 antibody classes based upon the H
chains
IgG
IgM
IgE
IgA
The class of the antibody
dictates its biological functions
16.4 The Nature of Antibodies
The variable regions of H
and L chains dictate
binding to the antigen
The constant regions of
H and L chains
determine the 3D
structure and the
biological activities of the
antibody
16.4 The Nature of Antibodies
Protective Outcomes of Antigen-Antibody (Ag:Ab)
Binding
Antibodies bind to antigens with noncovalent interactions
Early in the adaptive response, antibody affinity is weak, while
late in the response it is very strong
Effects of antibody binding to antigen
Neutralization - blocks the biologically-relevant portion of an
antigen, rendering it inactive
Immobilization and preventing adherence
Agglutination and precipitation
Opsinization facilitates phagocytosis
Complement system activation
Antibody-dependent cell cytotoxicity (ADCC)
16.4 The Nature of Antibodies
• Immunoglobulin classes
• IgM
•IgG
•
First secreted antibody
•
•High affinity
Exists as a pentamer (valency
of 10)
•Several subclasses
Efficient at complement
•Some are efficient complement
fixation
fixers
Primary antibody against LPS
•Others mediate ADCC
Low affinity, but high avidity
•Some cross the placenta and are in
breast milk (colostrum)
• Avidity is the collective
strength of interaction
•
•
•
•Most common Ab in serum
16.4
The
Nature
of
Antibodies
Immunoglobulin classes
IgA
Most abundant Ab
Exists as monomers
(blood/tissues) and dimers
(secreted)
Breast milk
The J chain holds two IgA
Ab together to form the
dimer and provides
protection from digestive
enzymes
•IgD
•Usually expressed as BCR
•No known functional role
•IgE
•Only small amounts are
produced
•Efficient at inducing
degranulation of granulocytes
•May be protective against
helminths
•Associated with allergies
16.5 Clonal Selection and Expansion
of Lymphocytes
Clonal selection theory states that antigens select T
and B cells for expansion
The presence of antigen stimulates the naive T and
B lymphocytes into mitosis and differentiation that
leads to a large pool of antigen-specific effector
lymphocytes
As the infection is cleared, antigen becomes
limiting and most of the responding lymphocytes
die (99% or more)
The remaining lymphocytes serve as memory cells,
poised to engage the pathogen should it recur
16.6 B Lymphocytes and the Antibody
Response
Antigens recognized by B cells
T-independent (do not require T cell help)
Non-proteinaceous (e.g., LPS)
Cannot class-switch from IgM to others
Do not induce durable immunity
T-dependent (requires T cell help)
Proteins
Class switching to IgG, IgA, IgE
Usually provide long-term immunity
B cell activation to protein antigen
A B cell has thousands of identical BCR molecules protruding
from its surface
These BCR have identical specificity (clonotypic) because they
have the exact same amino acid sequences
If a protein antigen is bound by these BCR, it is internalized
The internalized antigen is fragmented into peptides of 10-15
amino acids
The peptides are assembled on MHC class II proteins, which are
then presented on the B cell surface
A helper T cell that recognizes the peptide engages the B cell to
activate it by:
Releasing cytokines (noncognate signals)
Cognate (physical) interactions with the B cell
The B cell begins secreting antibodies (which are soluble
versions of the BCR)
16.6 B Lymphocytes and the Antibody
Characteristics of the
primary B
Response
cell response
Class-switching to other
isotypes
Affinity maturation by
programmed mutation of
antibody variable genes
Most mutations result lower or no
change in affinity of BCR
Some result in higher affinity BCR
and these out compete B cells with
lower affinity
Generation of memory B cells
These three events require T
16.6 B Lymphocytes and the Antibody
Response
Characteristics of the secondary B cell response
The memory cells, which can number in the tens
of thousands, are capable of rapid response to
recurrent infections
They do not have to undergo class-switching
They do not have to undergo affinity maturation
They undergo clonal expansion again
This occurs so rapidly, symptoms of illness are
rare
16.6 B Lymphocytes and the Antibody
Response
The response to T-independent antigens
Reliant upon repetitive motifs of the antigen on the surface of
the microbe
Results in cross-linking multiple BCR
This causes B cell activation and secretion of soluble antibody
(IgM only)
16.7 T Lymphocytes: Antigen
Recognition and Response
General characteristics of T cells
Possess a clonotypic T cell receptor (TCR)
The TCR is virtually identical to one Fab antibody arm
Recognize antigenic peptide fragments of microbial
proteins
The peptide fragments must be bound to a major
histocompatibility complex (MHC) molecule
MHC class I molecules are for presenting peptide antigens
from intracellular microbes (i.e., infected cell) and target those
cells for destruction by Tc cells
MHC class II molecules are for presenting peptide antigens
from extracellular microbes (i.e., NOT infected cell) and
presenting those peptides to Th cells, which secrete cytokines
that mediate the local immune response
16.7 T Lymphocytes: Antigen
Recognition and Response
The MHC I pathway targets a cell for destruction
Intracellular pathogens use cellular ribosomes to
synthesize their proteins
Some of these proteins are fragmented and
inserted into the lumen of the ER
MHC I proteins bind to the peptides and then are
displayed on the cell’s surface
CD8+ Tc cells recognize these microbial peptides
and kill the cell
Puncturing holes in the membrane with perforin
Inducing a death signal that causes DNA fragmentation
The MHC II pathway is for activating Th cells that
secrete cytokines to mediate immune responses
during infections
Only professional antigen presenting cells (APC), such as
macrophages, dendritic cells, and B cells, participate in this
pathway
They capture extracellular antigens and internalize them
B cells use their BCR
Macrophages use phagocytosis
Dendritic cells use pinocytosis
The antigens are fragmented into peptides phagolysosomes that
possess MHC II proteins, which bind to the peptides
The MHC II:peptide complex is displayed on the cell surface
CD4+ Th cells recognize the peptide and respond by making
cytokines
16.7 T Lymphocytes: Antigen
Recognition and Response
Subsets of CD4+ Th cells
Th1 cells secrete inflammatory cytokines
Th2 cells secrete cytokines that augment B cell
responses
Treg (regulatory) cells secrete antiinflammatory cytokines
The responding subset can determine
susceptibility or resistance to a pathogen