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Immunology Immunology Part II: Part II: Adaptive Immunity Adaptive Immunity Lecture #18 Lecture #18 Bio3124 Bio3124 1

Immunology Part II: Adaptive Immunity

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Immunology Part II: Adaptive Immunity. Lecture #18 Bio3124. Overview of Specific (Adaptive) Immunity. three major functions recognize nonself Discriminates btw self and nonself , antigenic determinants respond to nonself : specific, diverse ( >10 11 antigens ) effector response - PowerPoint PPT Presentation

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ImmunologyImmunologyPart II:Part II: Adaptive ImmunityAdaptive Immunity

Lecture #18Lecture #18Bio3124Bio3124 11

Overview of Specific (Adaptive) Immunity

three major functionsthree 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 cells2

Antigens and Haptens Antigens: elicit immune response

Whole cells, large and complex molecules

Epitopes: antigenic determinant sites on antigens to which antibody binds; 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

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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

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Cell Mediated Adaptive Cell Mediated Adaptive

Immune ResponseImmune Response

(CMI)(CMI)

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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

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MHC-I and MHC-II

MHC-I: 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-IIMHC-II α-chain and β-chain

Form large antigen binding

pocket for peptide

presentation by APCs7

Antigen processing and presentation

MHC-I: 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 proteosomeTAP: transporter of antigen peptides

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Antigen processing and presentation

MHC-II: MHC-II: Bind foreign peptides originating

outside cytoplasm (exogenous antigens) eg.

bacteria Enter APCs via endocytosis Breakdown in endosomes by proteolytic

degradationIn 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 productionT-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 11

MHC-I and Cell Mediated Immune Response On the scene: On the scene: virus

infected nucleated cells

MHC-I: MHC-I: viral antigen

presented on MHC-I

CTL response: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

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MHC-II and Cell Mediated Immune Response

CTL response via MHC-IICTL 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 cellsproducedAPC is not targeted

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Humoral Adaptive Humoral Adaptive

Immune ResponseImmune Response

1414

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

B-Cell Biology

Capping

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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,

differentiate16

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

B-Cell Activation

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T dependent B-Cell Activation Triggered by bacteria, hapten-carrier, proteinsrequires two signalsrequires two signals

antigen-BCR interaction T cell cytokines

Three cells involved:Three cells involved: macrophages T-helper cells B-cells specific for antigen

Mechanism: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

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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

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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

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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

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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

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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

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Consequences of Antigen-Antibody Binding

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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

C5 convertase

C3 convertase

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Classical Complement activation

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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 virus-

infected 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

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Summary Animation: CMI and Humoral responses

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