Introduction to

The Immune Response Dr. Robert J. Boackle

Room 441 BSB, 792-2552boacklrj@musc.edu

http://people.musc.edu/~boacklrj/Syllabus_.htm

The Student should understand the following concepts from this lecture:

The Nature of Antigenic Determinants

Location of Antigens on Bacterial Cells

After infection, the Filtration of Antigens

Lymphocyte Clones (B Cells and T Cells)

B and T Lymphocyte Clonal Development

B and T Lymphocyte Clonal Proliferation

Lymphocyte Circulation and Trafficking

Non-self Substances

Antigens

[Ag]

Where are antigens located?Where are antigens located?

Lets take a look at the molecular level.Lets take a look at the molecular level.

Bacterium

Released AntigensSurface Antigens

Bacterial

Surface

Released ProteasesSurface Antigens

Bacterial

Surface

Bacterial Proteases play a key role in

Periodontal Disease

unless they are neutralized by host

antibodies

Bacterium

Antigens are

foreign molecules

Each Antigen (each foreign molecule)

(for example a bacterial surface enzyme)

has several regions that our body detects as foreign.

These areas on the molecule are termed Antigenic Determinants

X

EXTERNAL

THERE ARE ALSO MANY INTERNAL

ANTIGENIC DETERMINANTS

(not exposed) Activate T Cells

EXTERNAL ANTIGENIC

DETERMINANTS Activate B Cells

Antigen Penetration

Antigen Penetration

Antigen Penetration

Toll-like Receptors

Endotoxin (LPS)

VEIN

ARTERY

LYMPH NODE

EFFERENT LYMPHATIC CAPILLARY

AFFERENT LYMPHATIC CAPILLARY

VEIN

ARTERY

EFFERENT LYMPHATIC CAPILLARY

Antigens in the Lymph are filtered in the Lymph Node

AL = AFFERENT LYMPHATIC CAPILLARIES

AL

AL

AL

AL

B CELL RICH

T CELL RICH

AL

EFFERENT ..LYMPHATIC ..CAPILLARY

Antigen Stimulated Lymph Node

Lymphocyte Proliferation

Swollen Lymph Nodes !

Movement of Lymphocytes from “Blood to Lymph” occurs in the Lymph NodesMovement of Lymphocytes from “Blood to Lymph” occurs in the Lymph Nodes

Antigens in the Blood are filtered

in the Spleen

Lymphocytes are the police force of the Immune System

These Lymphocytes are the detectives and responders

They traffic to areas of infection and inflammation! http://people.musc.edu/~boacklrj/integrinLFA-1.pdf

Selectins-Integrins

Addressins

Location of Lymphocytes:

Lymph and Lymph Nodes

Blood and Spleen

Thymus

Bone Marrow

Lymphoid Tissues Associated with the Mucosa (Tonsils, Gut, Respiratory Tract)

Any area after infection

Regulation of the Expression of DNA is the key to the production

of different kinds of Lymphocytes

And to the understanding of

Lymphocyte Clonal Development

The ability of a population of Lymphocytes to SPECIFICALLY

recognize a foreign antigen

1) One Clone of B Lymphocytes is a population of B lymphocytes derived from one original mother B lymphocyte and therefore all members are identical in every way.

2) One Clone of T Lymphocytes is a population of T lymphocytes derived from one original mother T lymphocyte and therefore all members are identical in every way.

Definitions:

3) There are thousands of B cell clones and thousands of T cell clones in our body that exist in low numbers until we have an infection.

4) Stem cells are pre-programmed with the DNA-information to generate thousands of different clones of B and T lymphocytes (to bind to thousands of different antigenic determinants).

5) An Antigenic Determinant adheres to the best fitting Clone of B or T Lymphocytes.

Definitions:

B Lymphocyte Clonal Development

STEM CELLS in the BONE MARROW are pre-programmed with information

Clones of B Cells are formed within

the Bone Marrow of humans

No Antigen Needed!

Mature B lymphocytes divide very slowly in the

absence of antigens BL

BL

BL

What are the Lymphocyte Receptors for antigenic determinants integrated with the membranes of lymphocytes?

For B lymphocytes the Receptors are Antibodies

For T lymphocytes the Receptors are T Cell Receptors

IN THE PRESENCE OF ANTIGENS, Clonal Proliferation (B Cell clonal expansion), followed by Differentiation into Plasma cells that

produce identical fluid phase antibodies (Ab)

What do we mean by the phrase

“Clones of Lymphocytes”

Only those lymphocyte clones that bind in a

specific way to antigens are stimulated.

Clones of

B and T Lymphocytes

(inactive)

Clonal Selection

Theory

Selected

Clones of

B Lymphocytes

and

T Lymphocytes

Activate and Proliferate

After contacting antigens

Clones of

B Lymphocytes

become activated by exposed antigenic determinants on

antigens

Clonal Selection Theory

Clone B1

Clone B2

CloneB3

And Proliferate

Proliferation of ONE B Cell Clone

after contacting antigen.

Clonal Proliferation after binding to one exposed antigenic

determinant on antigens.

Clonal Expansion

(Memory Cells)

Clone

Expand

MORE MORE

Expand

X

EXTERNALEXTERNAL ANTIGENIC

DETERMINANTS bind to Specific B Lymphocyte

Clones

B lymphocytes interact with an exposed antigenic determinant via antibody-receptors on their surface.

All cells in this “clone” of B lymphocytes (BL) produce antibodies on their surface that interact with only one

type of Antigenic Determinant.

Antigen

Antigenic Determinant

AntibodyOn the B cell surface

The Antigen

One antigenic molecule may have several different Exposed

ANTIGENIC DETERMINANTS

Example of Three (exposed) Antigenic Determinants on this

foreign protein.

A Separate Antibody Response results (at the same time) to each of these exposed antigenic determinants on this one antigenic molecule

B cell Clone # 1

B cell Clone # 2

B cell Clone # 3

We term these B Cell Host Responses

and the resulting production of

Specific Antibody Responses

as

Humoral (Fluid) Immunity

Humoral Immunity

BL +Exposed

Antigenic Determinant

Specific Clonal Response

So how large must an antigenic determinant be to be “seen” by

a B Lymphocyte?

B lymphocytes interact with exposed antigenic determinants via the antibody receptors they produce

on their surface.

Exposed Antigenic Determinants are Comprised of at least Five to Six amino acids

For B cell antibody, Each Antigenic Site (Determinant) is a function of

1) Non-Identity with any Host Substance

2) Outside Molecular Exposure outside charges and its conformation (must fit into the specific binding site of Antibody)

AntigenicDeterminant

AntibodyOn the B cell surface

+-

-+

Res

t o

f th

e A

nti

gen

Now the --B Cell may become activated

One clone of B lymphocytes

is activated by

One Antigenic

Determinant

Clone 1

Clone 2

Clone 3

2,000 Antibodies per

second per plasma cell

Live only two or three days

The clones of B Lymphocytes that bind with

the highest affinity to the

antigenic determinant are stimulated the

most

Now we will discuss T lymphocytes

T Lymphocyte Clonal Diversification is in the

Thymus&

And occurs in the Absence of foreign antigens

STEM CELLS from the

THYMUS

T Lymphocyte Clonal Diversification in

the Thymus

A lot of dividing & living and a lot of dying

(no foreign antigens needed in the Thymus)

STEM CELLS from the

Mature T Lymphocytes Produced

(no foreign antigens were needed)

TTT

STEM CELLS from the

In Pregnant Women

X-rays are forbidden because there is no time for

DNA repair in rapidly dividing cells.

T lymphocytes divide slowly in the absence of antigens and may

live for years

TL

TL

TL

T Cell Receptors are the T Lymphocyte’s

Receptors for antigens

(Not antibodies)

TL

Processed antigenic determinants cause the Proliferation of this Specific T cell clone

TL

TL

TL

TL

This T Cell does not

bind to this antigenic

determinant and so is

not activated

TL

Processed antigenic determinants cause the Proliferation of this Specific T cell clone

TL

TL

TL

TL

TL

TL

TL

T Lymphocytes

“Cell Mediated Immunity”

Clones of

T Lymphocytes

become activated by different (internal)

antigenic determinants (fragments)

Clonal Selection Theory

Clone T1

Clone T2

CloneT3

And Proliferate

Upon activation, each of the

activated clones expands.

That is, the cells in that clone

divide and multiply.

“PROLIFERATION”

1

2

3

4

Example of the location of Proliferating B and T Cell Clones

http://people.musc.edu/~boacklrj/TcellsinLymphNodes.pdf

From Your Textbook on page 14

“The Selectins mediate transient interactions between leukocytes and endothelial cells or blood platelets.

There are three members of the selectin family:

L-selectin, which is expressed on leukocytes;

E-selectin, which is expressed on endothelial cells; and

P-selectin, which is expressed on platelets.

The selectins recognize cell surface carbohydrates. One of their critical roles is to initiate the interactions between leukocytes and endothelial cells during the migration of leukocytes from the circulation to sites of tissue inflammation.

The selectins mediate the initial adhesion of leukocytes to endothelial cells. This is followed by the formation of more stable adhesions, in which integrins on the surface of leukocytes bind to intercellular adhesion molecules (ICAMs), which are members of the Ig superfamily expressed on the surface of endothelial cells.

The firmly attached leukocytes are then able to penetrate the walls of capillaries and enter the underlying tissue by migrating between endothelial cells.”

Quoted from Selectins-Integrins AddressinsPlease see http://people.musc.edu/~boacklrj/integrinLFA-1.pdf

1) Any one lymphocyte has only one type of receptor (>10,000 receptors per cell) and each of those receptors on its surface are all identical in every way (including binding to one specific type of antigenic determinant).

2) Each cell in a Clone is identical in every way. Therefore, all the receptors on the cells that comprise a clone have the same affinity for a particular antigenic determinant.

Important Definitions:

The T Cell Receptors are all identical on every cell in a clone of T Cells

The T Cell Receptors do not interact with exposed antigens like antibodies do

on B lymphocytes.

Rather T Cell Receptors detect internal (previously hidden) antigenic

determinants that must be processed (e.g., digested or fabricated) by other

cells and then presented to the T Lymphocytes in the correct way.

Cell Mediated Immunity

TL +Processed

Antigenic Determinant

Specific T Cell Clonal Response

ACTIVATED T CELLS LIBERATE BIOLOGICALLY ACTIVE MOLECULES

TL

TL

TL

CYTOKINES

I

N

T

E

R

L

E

U

K

I

N

S

Presented antigenic

determinant

Chemotactic Molecules

(Interleukins)

Circulation of Lymphocytes

Circulation of Lymphocytes from Blood to Lymph (after binding Circulation of Lymphocytes from Blood to Lymph (after binding to the Peripheral Lymph Node Addressin molecules on the to the Peripheral Lymph Node Addressin molecules on the Postcapillary High Endothelial Venules in the Lymph Nodes), Postcapillary High Endothelial Venules in the Lymph Nodes), then from Lymph back to Blood via the Thoracic Ductthen from Lymph back to Blood via the Thoracic Duct

LymphNode

Circulating Policemen

Peripheral Lymph Node Peripheral Lymph Node

Addressin Addressin PNAd is on the

Berg EL, Robinson MK, Warnock RA, Butcher EC. J Cell Biol. 1991, 114::343-9.

The human peripheral lymph node vascular addressin called PNAd, is a ligand for LECAM-1, the peripheral lymph node homing receptor.The trafficking of lymphocytes from the blood into lymphoid organs is controlled by tissue-selective lymphocyte interactions with specialized endothelial cells lining post capillary venules, in particular the high endothelial venules (HEV) found in lymphoid tissues and sites of chronic inflammation. Lymphocyte interactions with HEV are mediated in part by these lymphocyte homing receptors and tissue-specific HEV determinants, the vascular addressins. PNAd is molecularly distinct from the mucosal vascular addressin termed MAdCAM-1.

Circulation of Lymphocytes from Circulation of Lymphocytes from Blood to Lymph (in the Peyer’s patches)Blood to Lymph (in the Peyer’s patches)

The mucosal vascular addressin termed MAdCAM-1 and

the PNAd are found on venules feeding mucosal lymphoid tissues such as the Payer’s Patches

Briskin MJ, McEvoy LM, Butcher EC. Nature. 1993, 363:461-4.

Tissue-specific homing of lymphocytes to mucosal tissues

The mucosal vascular addressin (MAdCAM-1) is selectively expressed on high endothelial venules (HEV) of mucosal lymphoid organ and on lamina propria venules and helps direct lymphocyte traffic, (such as IgA committed B cells) to these mucosal tissues.

Circulation of Lymphocytes in Blood Circulation of Lymphocytes in Blood (through the Spleen)(through the Spleen)

After the host has generated an

Immune Response to Antigens,

then we state that those Antigens were

Immunogenic