Transcript Slide 1

Immunology
Part II: Adaptive Immunity
Lecture #18
Bio3124 1
Overview of Specific (Adaptive) Immunity
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three major functions
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recognize nonself
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Discriminates btw self and nonself, antigenic determinants
respond to nonself: specific, diverse (>1011 antigens)
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effector response
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eliminates or renders foreign material harmless
anamnestic response
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upon second encounter with same pathogen immune system
mounts a faster and more intense response
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remember non-self: memory cells
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Antigens and Haptens
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Antigens: elicit immune response
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Epitopes: antigenic determinant sites
on antigens to which antibody binds;
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Whole cells, large and complex molecules
Proteins-> linear vs conformational
Valence
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number of epitopes on an antigen
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determines number of antibodies to bind antigen
Haptens
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small organic molecules
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antigenic when bound to larger carrier molecule
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e.g., penicillin binds serum proteins among
allergic patients
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Types of specific immunity (adaptive)
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humoral immunity
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also called antibody-mediated immunity
based on antibody activity and B-cells
cellular immunity
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also called cell-mediated immunity (CMI)
based on action of specific kinds of T
lymphocytes
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Cell Mediated Adaptive
Immune Response
(CMI)
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Recognition of Foreignness
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distinguishing between self and non-self
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allows for selective destruction of invading pathogens without
destruction of host tissues
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MHC molecules:
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APCs present foreign antigens to T cells
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T-cells mediate launching either cell mediated immune
response (CMI) or humoral response (antibody)
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MHC-I: presents antigens of endogenous origin eg. viral
infection; all nucleated cells
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MHC-II: antigens of exogenous origin eg bacteria/toxins
entering APC; include macrophages, dendritic cells, B-cells
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MHC-I and MHC-II
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MHC-I:
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α-chain: 45 kD, α1, α2 and α3
domains
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β2 microglobulin: 12 kD,
associated with α3
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α1 and α2: antigen binding
pocket
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MHC-II
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α-chain and β-chain
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Form large antigen binding
pocket for peptide
presentation by APCs
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Antigen processing and presentation
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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
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Antigen processing and presentation
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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
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T- Cell Biology
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major players in cell-mediated immune
response
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have major role in B-cell activation
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produce regulatory cytokines; Cytotoxic
function
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recognize and bind antigens using specific
TCR
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Specific binding to antigen presented by
antigen-presenting cells (APCs) using
MHC-I or MHC-II
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CD3 complex activation & signaling and
proliferation, cytokine production
T-cell receptor (TCR)
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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
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MHC-I and Cell Mediated Immune Response
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On the scene: virus
infected nucleated cells
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MHC-I: viral antigen
presented on MHC-I
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CTL response:
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activated by
binding to antigen
presented on MHC-I
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Differentiate
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Targets:other infected
cells
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Kill target cells by
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perforin and granzyme
Inducing apoptosis
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MHC-II and Cell Mediated Immune Response
CTL response via MHC-II
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Can also be activated through TH1
helper T-cells and MHC-II
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TH1 activation: two signals required
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1st signal: TH1 binds by CD4 to
antigen presented by MHC-II on
infected APC
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2nd signal: B7 and CD28 interaction
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Triggers IL-2, IFN and TNF
production
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Activate Naïve cytotoxic T cells
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attacks other infected cells
presenting same Ag on MHC-I
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Cytolysis or apoptosis ensues
Helper memory cells
produced
APC is not targeted
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Humoral Adaptive
Immune Response
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B-Cell Biology
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immunologic roles
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proliferate and differentiate into plasma
cells
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Produce antibodies and memory cells
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act as APC
BCR: B-cell receptor (monomeric IgM)
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accompanied by Igα and Igβ
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BCR binds to its specific antigen
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Capping: BCR clustering through Igα and
Igβ
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Signaling to nucleus -> DNA recombination
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differentiate into plasma cells -> secrete
antibodies
Capping
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B-cell Ag specificity & clonal selection theory
Billions of different B cells
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Antibodies attached to
membrane
Each cell binds different
antigens
Clonal Selection
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Cells that bind antigen replicate
Differentiate to plasma cells
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Secrete antibodies
Some differentiate to memory cells
Second antigen exposure
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Memory cells replicate,
differentiate
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B-Cell Activation
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needs antigen binding (triggering)
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leads to proliferation and differentiation into plasma cells
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cytokines produced by helper T cells can act on B
cells and assist in growth and differentiation
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typically antigen-specific
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two mechanisms for antigen-specific activation
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T- dependent
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T- independent
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T dependent B-Cell Activation
Triggered by bacteria, hapten-carrier, proteins
requires two signals
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antigen-BCR interaction
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T cell cytokines
Three cells involved:
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macrophages
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T-helper cells
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B-cells specific for antigen
Mechanism:
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Naïve TH0 cells bind Ag/MHC-II on APC
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Activated to TH2 cells
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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
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T-independent B cell activation
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T-independent antigens
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polymeric antigens with large number of identical epitopes
(e.g., bacterial lipopolysaccharides)
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mediate capping and activation
less effective than T-dependent B cell activation
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antibodies produced have a low affinity for antigen
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no memory B cells formed
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Antibodies
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immunoglobulins (Ig)
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glycoprotein made by activated B cells (plasma
cells)
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serve as antigen receptor (BCR) on B cell surface
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found in blood serum, tissue fluids, and mucosal surfaces of
vertebrate animals
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an antibody can recognize and bind antigen that caused its
production
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Immunoglobulin Structure
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same basic structure
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four polypeptide chains
 two identical heavy chains
 two identical light chains
 heavy and light chains
connected to each other by
disulfide bonds
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both chains contain two
different regions
 Constant (C) regions (CL and
CH)
 Variable (V) regions (VL and
VH)
Isotypes: IgM, IgG, IgA, IgD, IgE
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Immunoglobulin Function
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Fab binds antigen
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marks antigen for
immunological attack
activates nonspecific
defense mechanisms that
can destroy antigen
 e.g., opsonization
Fc mediates binding to:
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host tissue
various cells of immune
system
first component of
complement system
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Effector and anamnestic response
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Effector response: first exposure, IgM or IgD
followed by isotype switch to IgG
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Memory cells stored
Anamnestic response
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Some IgM
Lots of IgG
Rapid
intensive response
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Consequences of Antigen-Antibody Binding
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Classical Complement activation
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Antibodies coat antigenic particles
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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
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Classical Complement activation
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Resistance to Viral Infections
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antibodies neutralize viruses
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antibodies enhance phagocytosis of viruses by
opsonization
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interferons cause death of infected cells
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NK cells stimulated by interferons and antibodies
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Cytotoxic T lymphocytes (CTLs) destroy virusinfected cells
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Resistance to Bacterial Infections
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Opsonization: certain antibodies and complement
proteins act as opsonins
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IgM and IgG agglutinate bacteria
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Classical complement activation: antibodies trigger
formation of membrane attack complex
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certain complement proteins attract phagocytic cells
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antitoxin antibodies neutralize bacterial exotoxins
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cytokines attract and stimulate macrophages
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cytokines stimulate T cells and increase population of
cells involved in cell-mediated response
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Summary Animation: CMI and Humoral responses
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