Lymphoid Organ

1.

1. Wh

What

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are t

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func

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tion

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s for

or pr

prim

imar

ary

y

lymphoid organs?

lymphoid organs?

2

2.. W

Wh

haat a

t arre t

e th

he f

e fu

un

nccttiio

on

ns f

s fo

orr

secondary lymphoid organs?

secondary lymphoid organs?

Part

Part

I

I

Introduction

Introduction

Chapter 1. Overview of the Immune System

Chapter 1. Overview of the Immune System

Chapter 2. Cells and Organs of the Immune System

Chapter 2. Cells and Organs of the Immune System

Part

Part

II

II

Generation

Generation

of

of

B-cell

B-cell

and

and

T-cell

T-cell

Responses

Responses

Chapter 3. Antigens

本章大綱

_:

1. Immunogenicity Versus Antigenicity

2. Factors That Influence Immunogenicity

3. Epitopes

4. Haptens and the Study of Antigenicity

5. Pattern-Recognition Receptors

拉丁文

_-

immunis: exempt

英文

_-

immunity:

the state of protection

from infectious disease

Immunogenicity:

Immunogen

the ability to induce a humoral and/or

cell-mediated immune response

Antigenicity:

Antigen

the ability to combine specifically with

Ab and/or cell-surface Ig/TCR

Antigens

Distinctive Membrane Molecules

On Lymphocytes

B lymphocyte T lymphocyte

- Although all molecules that have the property of immunogenicity also have the property of  antigenicity, the reverse is not true.

-

Haptens

by themselves, of inducing a specific immune response.

Contribution of the immunogen to

immunogenicity:

- Foreighness - Molecular size

- Chemical composition and heterogenicity

- Susceptibility to antigen processing and presentation

Contribution of the biological system to

immunogenicity:

- Genotype of the recipient animal

- Immunogen dosage and route of administration - Adjuvants

Foreignness

-The greater the phylogenetic distance between two species, the greater the structural (and

therefore the antigenic) disparity between them.

- Some macromolecules (e.g., collagen and cytochrome c) were highly conserved

throughout evolution and therefore display very little immunogenicity across diverse species lines.

- Some self-components (e.g., corneal tissue and sperm) are effectively sequestered from the

immune system, so that if these tissues are injected even into the animal from which they originated, they will function as immunogens.

Molecular size

- There is a correlation between the size

of a macromolecule and its mmunogenicity. - The best immunogens tend to have a

molecular mass approaching 100,000 Da. - Generally, substances with a molecular

mass less than 5,000 – 10,000 Da are poor immunogens.

Chemical composition and complexity

- Synthetic homopolymers tend to lack  immunogenicity regardless of their size.

- All 4 levels of protein organization – primary, secondary, tertiary and quaternary – contribute

to the structural complexity of a protein and hence affect its immunogenicity.

• Lipid

Susceptibility to antigen

processing and presentation

- Ability to be processed and presented with an MHC molecules on the surface of an antigen-presenting cell or altered self-cell

•• DoDoes es smsmalall pl pepeptitide de is is a ga gooood ad antntigigenen?? •• HoHow tw to mo makake ae antntibibodody ay agagaininst st smsmalalll

peptide? peptide?

Hapten:

Hapten:

Small organic molecules that are

Small organic molecules that are antigenicantigenic but

but not immunogenicnot immunogenic..

Carrier:

Carrier:

Large molecules that are chemically coupled Large molecules that are chemically coupled to

to hahaptptenenss yiyieleldd immunogeniimmunogenic c hapten-carrierhapten-carrier conjugates

Contribution of the biological system

to immunogenicity:

- Genotype of the recipient animal

- Immunogen dosage and route of administration

Immunogen dosage and route of 

Administration

Doses: too low → no response

too high → tolerance

Routes: orally (從口入的)

parenterally (非從口入的)

- intravenous (iv) : into a vein - intradermal (id) : into the skin

- subcutaneous (sc) : beneath the skin - intramuscular (im) : into a muscle

Adjuvants

- Latin adjuvare, to help

- Substances that, when mixed with an antigen

and injected with it, enhance the immunogenicity of that antigen.

Effects of adjuvants

1. Prolong antigen persistence

- slower release of antigen at the injection site

2. Enhance co-stimulatory signals

- increased expression of MHC & B7 molecules - secretion of cytokines

→ increased antigen-presenting ability → maximal activation of T

Hcells

3. Induce granuloma formation

- formation of a dense, macrophage-rich mass of cells

Contribution of the immunogen to

immunogenicity:

- Foreighness - Molecular size

- Chemical composition and heterogenicity

- Susceptibility to antigen processing and presentation

Contribution of the biological system to

immunogenicity:

- Genotype of the recipient animal

- Immunogen dosage and route of administration - Adjuvants

- Immune cells do not interact with, or recognize, an entire immunogen molecules; instead,

lymphocytes recognize discrete sites on the

macromolecule called

epitopes, or

antigenic

determinants.

- The recognition of antigens by T cells and B cells is fundamentally different.

T-cell and B-cell epitopes

- Because B cells bind antigen that is free in

solution, the epitopes they recognize tend to be highly accessible sites on the exposed surface

of the immunogen.

- Because most T cells recognize antigen only when it is combined with an MHC molecule, T cell epitope, as a rule, cannot be considered apart from their associated MHC molecules.

Conformation of the epitope

recognized by B cells

1. The ability to function as a B-cell epitope is determined by the nature of the antigen-binding site on the antibody molecules

3-D structure of an octapeptide hormone (angiotensin II) complexed

with a monoclonal Ab Fab Fragment.

Red: angiotensin II Blue: the heavy chain Purple: the light chain

Model of interaction between hen egg-white lysozyme (HEL) and Fab fragment of anti-HEL antibody

light chain (yellow) a glutamine residue (red) heavy chain (blue)

HEL (green)

- The interactions of Ab with Ag are through non-covalent bonds.

- 4 types of non-covalent bonds:

a. Ionic (or electrostatic) bond

Ionic bonds form between surfaces of  opposite charge.

b. Hydrogen bond

Hydrogen bonds form between hydrogen atoms and two other electronegative atoms such as oxygen and nitrogen.

c. Van der Waals’ force

Van der Waals’ forces occur at very close ranges between two atoms. Fluctuations in the electrical charge within electron clouds can lead to attractive or repulsive forces

between atoms, dependent on the distance between them.

d. Hydrophobic bond

Hydrophobic bond is created by the behavior

of hydrophobic subunits in aqueous environments. These tend to be pushed together to minimize the instability they cause in the network of hydrogen-bonded water molecules.

2. The B-cell epitope on native proteins generally are composed of hydrophilic amino acids on the protein surface that are topographically accessible to

Ab elicited by immunization with the (T,G)-A-L copolymer react largely with the exposed tyrosine and glutamic acid residues. Anti-(T,G)-A-L Abs do not

3. B-cell epitopes can contain sequential or nonsequential amino acids.

Sperm whale myoglobulin contains 5 sequential B-cell epitopes

Hen egg-white lysozyme composes one nonsequential (conformational) epitope

Inhibition of reaction between HEL loop and anti-loop antiserum by natural loop or closed synthetic loop only

4. B-cell epitopes tend to be located in flexible regions of an immunogen and display site mobility.

5. Complex proteins contain multiple

overlapping B-cell epitopes, some of which are immunodominant.

1. Antigenic peptides recognized by T cells form trimolecular

TCR and MHC-peptide

←TCR

← peptide

2. - The antigen-binding cleft on an MHC

molecule interacts with various oligomeric peptides (nonamer for class I & 12 –25

residues for class II) that function as T-cell epitopes.

- A given MHC molecule can bind a variety of different peptides (broad but selective interaction).

3. Antigen processing is required to generate peptides that interact specifically with MHC molecules.

Processing and presentation of 

4. T-cell epitopes tend to be on the “inside” of the protein molecule

5. Immunodominant T-cell epitopes are determined in part by the set of MHC molecules expressed by an individual.

Correlation of MHC-binding ability and T-cell-activating ability of synthetic peptides

Landsteiner (1920s & 1930s):

- the specificity of the immune response - the enormous diversity of epitopes that

the immune system is capable of recognizing - many biologically important substances,

e.g., drugs, peptide hormones, can function as haptens.

Drug allergies

When medicines become

immunogens, …………..

Pattern recognition receptors

–Receptors of the innate immune

system that recognize molecular

patterns or motifs present on or

within pathogens but absent in

the host.

TABLE 3-5 REACTIVITY OF ANTISERA WITH VARIOUS HAPTENS (2)