Transcript Slide 1
Immunology
Part II: Adaptive Immunity
Lecture #18
Bio3124 1
Overview of Specific (Adaptive) Immunity
three major functions
recognize nonself
Discriminates btw self and nonself, antigenic determinants
respond to nonself: specific, diverse (>1011 antigens)
effector response
eliminates or renders foreign material harmless
anamnestic response
upon second encounter with same pathogen immune system
mounts a faster and more intense response
remember non-self: memory cells
2
Antigens and Haptens
Antigens: elicit immune response
Epitopes: antigenic determinant sites
on antigens to which antibody binds;
Whole cells, large and complex molecules
Proteins-> linear vs conformational
Valence
number of epitopes on an antigen
determines number of antibodies to bind antigen
Haptens
small organic molecules
antigenic when bound to larger carrier molecule
e.g., penicillin binds serum proteins among
allergic patients
3
Types of specific immunity (adaptive)
humoral immunity
also called antibody-mediated immunity
based on antibody activity and B-cells
cellular immunity
also called cell-mediated immunity (CMI)
based on action of specific kinds of T
lymphocytes
4
Cell Mediated Adaptive
Immune Response
(CMI)
5
Recognition of Foreignness
distinguishing between self and non-self
allows for selective destruction of invading pathogens without
destruction of host tissues
MHC molecules:
APCs present foreign antigens to T cells
T-cells mediate launching either cell mediated immune
response (CMI) or humoral response (antibody)
MHC-I: presents antigens of endogenous origin eg. viral
infection; all nucleated cells
MHC-II: antigens of exogenous origin eg bacteria/toxins
entering APC; include macrophages, dendritic cells, B-cells
6
MHC-I and MHC-II
MHC-I:
α-chain: 45 kD, α1, α2 and α3
domains
β2 microglobulin: 12 kD,
associated with α3
α1 and α2: antigen binding
pocket
MHC-II
α-chain and β-chain
Form large antigen binding
pocket for peptide
presentation by APCs
7
Antigen processing and presentation
MHC-I: Bind foreign peptides
originating in cytoplasm (endogenous
antigens) eg. viral proteins
Viral proteins breakdown to
peptides
pumped into ER via LMP and TAP
α and β chains synthesis on ER
α and β join together in ER lumen
and pick up viral antigenic peptides
Pass through golgi → cell surface
→ antigen presentation
LMP: low molecular mass polypeptide component of proteosome
TAP: transporter of antigen peptides
8
Antigen processing and presentation
MHC-II: Bind foreign peptides originating
outside cytoplasm (exogenous antigens) eg.
bacteria
Enter APCs via endocytosis
Breakdown in endosomes by proteolytic
degradation
In the ER:
MHC-II α and β chains synthesis
Associated with invariant chain, fits in Ag
binding cleft temporarily, all MHC-II
Pass through Golgi, invariant chain
degraded
Endocytic vesicles fuse with golgi vesicles
Fitting antigenic determinant picked up by
MHC-II
Carried and presented on cell surface
9
T- Cell Biology
major players in cell-mediated immune
response
have major role in B-cell activation
produce regulatory cytokines; Cytotoxic
function
recognize and bind antigens using specific
TCR
Specific binding to antigen presented by
antigen-presenting cells (APCs) using
MHC-I or MHC-II
CD3 complex activation & signaling and
proliferation, cytokine production
T-cell receptor (TCR)
10
Types of T-cells
1. T-helper (TH) cells (CD4+ T Cells)
TH0
undifferentiated precursors of TH1 and TH2 cells
carry CD4+ that is MHC-II co-receptor
activated by antigens presented on MHC-II
TH1 cells
produce specific set of cytokines (IL-2, TNFs, IFN)
involved in cellular immunity
responsible for CTLs and macrophage activation
TH2
produce cytokines (IL4, 5, 6, 10, 13)
involved in humoral immunity (B-cell activation)
defend against helminth parasites
2. Cytotoxic T Lymphocytes (CTLs)
CD8+ T cells that have been activated by antigen presented on MHC-1
molecules of nucleated cells
11
MHC-I and Cell Mediated Immune Response
On the scene: virus
infected nucleated cells
MHC-I: viral antigen
presented on MHC-I
CTL response:
activated by
binding to antigen
presented on MHC-I
Differentiate
Targets:other infected
cells
Kill target cells by
perforin and granzyme
Inducing apoptosis
12
MHC-II and Cell Mediated Immune Response
CTL response via MHC-II
Can also be activated through TH1
helper T-cells and MHC-II
TH1 activation: two signals required
1st signal: TH1 binds by CD4 to
antigen presented by MHC-II on
infected APC
2nd signal: B7 and CD28 interaction
Triggers IL-2, IFN and TNF
production
Activate Naïve cytotoxic T cells
attacks other infected cells
presenting same Ag on MHC-I
Cytolysis or apoptosis ensues
Helper memory cells
produced
APC is not targeted
13
Humoral Adaptive
Immune Response
14
B-Cell Biology
immunologic roles
proliferate and differentiate into plasma
cells
Produce antibodies and memory cells
act as APC
BCR: B-cell receptor (monomeric IgM)
accompanied by Igα and Igβ
BCR binds to its specific antigen
Capping: BCR clustering through Igα and
Igβ
Signaling to nucleus -> DNA recombination
differentiate into plasma cells -> secrete
antibodies
Capping
15
B-cell Ag specificity & clonal selection theory
Billions of different B cells
Antibodies attached to
membrane
Each cell binds different
antigens
Clonal Selection
Cells that bind antigen replicate
Differentiate to plasma cells
Secrete antibodies
Some differentiate to memory cells
Second antigen exposure
Memory cells replicate,
differentiate
16
B-Cell Activation
needs antigen binding (triggering)
leads to proliferation and differentiation into plasma cells
cytokines produced by helper T cells can act on B
cells and assist in growth and differentiation
typically antigen-specific
two mechanisms for antigen-specific activation
T- dependent
T- independent
17
T dependent B-Cell Activation
Triggered by bacteria, hapten-carrier, proteins
requires two signals
antigen-BCR interaction
T cell cytokines
Three cells involved:
macrophages
T-helper cells
B-cells specific for antigen
Mechanism:
Naïve TH0 cells bind Ag/MHC-II on APC
Activated to TH2 cells
TH2 cells bind B-cells
displaying same Ag/MHC-II
Produce cytokines IL4,5,6
B-cells proliferate and differentiate
antibody producing plasma cells
Form memory cells
18
T-independent B cell activation
T-independent antigens
polymeric antigens with large number of identical epitopes
(e.g., bacterial lipopolysaccharides)
mediate capping and activation
less effective than T-dependent B cell activation
antibodies produced have a low affinity for antigen
no memory B cells formed
19
Antibodies
immunoglobulins (Ig)
glycoprotein made by activated B cells (plasma
cells)
serve as antigen receptor (BCR) on B cell surface
found in blood serum, tissue fluids, and mucosal surfaces of
vertebrate animals
an antibody can recognize and bind antigen that caused its
production
20
Immunoglobulin Structure
same basic structure
four polypeptide chains
two identical heavy chains
two identical light chains
heavy and light chains
connected to each other by
disulfide bonds
both chains contain two
different regions
Constant (C) regions (CL and
CH)
Variable (V) regions (VL and
VH)
Isotypes: IgM, IgG, IgA, IgD, IgE
21
Immunoglobulin Function
Fab binds antigen
marks antigen for
immunological attack
activates nonspecific
defense mechanisms that
can destroy antigen
e.g., opsonization
Fc mediates binding to:
host tissue
various cells of immune
system
first component of
complement system
22
Effector and anamnestic response
Effector response: first exposure, IgM or IgD
followed by isotype switch to IgG
Memory cells stored
Anamnestic response
Some IgM
Lots of IgG
Rapid
intensive response
23
Consequences of Antigen-Antibody Binding
24
Classical Complement activation
Antibodies coat antigenic particles
FC portions stick out
Fc bound by C1 complex
C1 cleaves C4, C2
C4b2a is a convertase (C3 convertase)
C3 C3a and C3b
C3bC5 form C5 convertase
Cleaves C5 to C5b and C5a
C5b recruits C6, 7, 8 and C9
Form membrane attack complex
Cytoplasmic leakage-> cell dies
C3 convertase
C5 convertase
25
Classical Complement activation
26
Resistance to Viral Infections
antibodies neutralize viruses
antibodies enhance phagocytosis of viruses by
opsonization
interferons cause death of infected cells
NK cells stimulated by interferons and antibodies
Cytotoxic T lymphocytes (CTLs) destroy virusinfected cells
27
Resistance to Bacterial Infections
Opsonization: certain antibodies and complement
proteins act as opsonins
IgM and IgG agglutinate bacteria
Classical complement activation: antibodies trigger
formation of membrane attack complex
certain complement proteins attract phagocytic cells
antitoxin antibodies neutralize bacterial exotoxins
cytokines attract and stimulate macrophages
cytokines stimulate T cells and increase population of
cells involved in cell-mediated response
28
Summary Animation: CMI and Humoral responses
29