Download IntroductionImmunology

Introduction to
The Immune Response
Dr. Robert J. Boackle
Room 441 BSB, 792-2552
[email protected]
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?
Lets take a look at the molecular level.
Bacterium
Released Antigens
Surface
Antigens
Bacterial
Surface
Surface
Antigens
Released Proteases
Bacterial
Surface
Bacterial Proteases
play a key role in
Periodontal Disease
unless they are
neutralized by host
antibodies
Antigens
are
foreign
molecules
Bacterium
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
EXTERNAL
ANTIGENIC
DETERMINANTS
Activate B Cells
THERE ARE ALSO
MANY INTERNAL
ANTIGENIC
DETERMINANTS
(not exposed)
Activate T Cells
Antigen Penetration
Antigen Penetration
Antigen Penetration
Toll-like
Receptors
Endotoxin (LPS)
LYMPH NODE
AFFERENT
LYMPHATIC
CAPILLARY
EFFERENT
LYMPHATIC
CAPILLARY
VEIN
ARTERY
Antigens in
the Lymph are
filtered in the
Lymph Node
EFFERENT
LYMPHATIC
CAPILLARY
VEIN
ARTERY
Antigen Stimulated
Lymph Node
AL = AFFERENT LYMPHATIC CAPILLARIES
Lymphocyte Proliferation
Swollen Lymph Nodes !
AL
AL
AL
AL
B CELL
RICH
T CELL
RICH
AL
EFFERENT
..LYMPHATIC
..CAPILLARY
Movement 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
SelectinsIntegrins
Addressins
These Lymphocytes are the
detectives and responders
They traffic to areas of infection and inflammation!
http://people.musc.edu/~boacklrj/integrinLFA-1.pdf
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
Definitions:
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.
B Lymphocyte Clonal Development
Clones of B Cells
are formed within
the Bone Marrow of
humans
No Antigen
Needed!
STEM CELLS in the BONE MARROW are
pre-programmed with information
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
After contacting
antigens
Selected
Clones of
B Lymphocytes
and
T Lymphocytes
Activate and
Proliferate
Clones of
Clone B1
B Lymphocytes
Clone B2
CloneB3
become activated by
exposed antigenic
determinants on
antigens
And Proliferate
Clonal
Selection
Theory
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
Expand
MORE
MORE
X
EXTERNAL
EXTERNAL
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
Antibody
On the B cell surface
Antigenic
Determinant
One antigenic molecule may
have several different Exposed
ANTIGENIC DETERMINANTS
Example of Three
(exposed) Antigenic
Determinants on this
foreign protein.
B cell Clone # 1
B cell Clone # 2
B cell Clone # 3
A Separate Antibody Response results (at the
same time) to each of these exposed antigenic
determinants on this one antigenic molecule
We term these B Cell Host Responses
and the resulting production of
Specific Antibody Responses
as
Humoral (Fluid) Immunity
Humoral Immunity
Exposed
BL
+
Antigenic
Determinant
Specific Clonal
Response
B lymphocytes interact with exposed antigenic
determinants via the antibody receptors they produce
on their surface.
So how large must an antigenic
determinant be to be “seen” by
a B Lymphocyte?
For B cell antibody, Each Antigenic Site (Determinant) is a function of
1)
Non-Identity with any Host Substance
Outside Molecular Exposure outside charges and its
conformation (must fit into the specific binding site of Antibody)
2)
- +
Antibody
On the B cell surface
+
-
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
THYMUS
T Lymphocyte Clonal
Diversification
in the Thymus
A lot of dividing &
living and a lot of dying
STEM CELLS from the
(no foreign antigens
needed in the Thymus)
Mature T Lymphocytes
Produced
(no foreign antigens were
needed)
STEM CELLS from the
T
T
In Pregnant Women
X-rays are forbidden
because there is no time for
DNA repair in rapidly
dividing cells.
STEM CELLS from the
T lymphocytes divide
slowly in the absence
of antigens and may
live for years
TL
TL
TL
TL
T Cell Receptors are the
T Lymphocyte’s Receptors
for antigens
(Not antibodies)
Processed antigenic determinants cause the
Proliferation of this Specific T cell clone
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
T Lymphocytes
“Cell Mediated Immunity”
Clones of
Clone T1
T Lymphocytes
become activated by
different (internal)
antigenic determinants
(fragments)
And Proliferate
Clonal
Selection
Theory
Clone T2
CloneT3
Upon activation, each of the
activated clones expands.
That is, the cells in that clone
divide and multiply.
“PROLIFERATION”
Example of the location of Proliferating B and T Cell Clones
1
2
4
3
http://people.musc.edu/~boacklrj/Tcells
inLymphNodes.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 Addressins
Please see http://people.musc.edu/~boacklrj/integrinLFA-1.pdf
Important Definitions:
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.
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
Processed
TL
+
Antigenic
Determinant
Specific T Cell
Clonal Response
ACTIVATED T CELLS LIBERATE
BIOLOGICALLY ACTIVE MOLECULES
I
N
TL
TL
Presented
antigenic
determinant
TL
C
Y
T
O
K
I
N
E
S
T
E
R
L
E
U
K
I
N
S
Chemotactic
Molecules
(Interleukins)
Circulation of
Lymphocytes
Circulating Policemen
Circulation of Lymphocytes from Blood to Lymph (after binding
to the Peripheral Lymph Node Addressin molecules on the
Postcapillary High Endothelial Venules in the Lymph Nodes),
then from Lymph back to Blood via the Thoracic Duct
Peripheral Lymph Node
Addressin PNAd
is on the
Lymph
Node
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
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
(through the Spleen)
After the host has generated an
Immune Response to Antigens,
then we state that those
Antigens were
Immunogenic