Immunological Bioinformatics - Center for Biological Sequence ...

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2 Οκτ 2013 (πριν από 4 χρόνια και 1 μήνα)

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CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Immunological Bioinformatics

Introduction to

the immune system

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Vaccination



Vaccination




Administration

of

a

substance

to

a

person

with

the

purpose

of

preventing

a

disease



Traditionally

composed

of

a

killed

or

weakened

micro

organism



Vaccination

works

by

creating

a

type

of

immune

response

that

enables

the

memory

cells

to

later

respond

to

a

similar

organism

before

it

can

cause

disease

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Figure 1
-
20

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Effectiveness of vaccines

1958 start of small pox
eradication program

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


The Immune System


The innate immune system



The adaptive immune system

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


The innate immune system



Unspecific


Antigen independent


Immediate response


No training/selection hence no memory


Pathogen independent (but response might
be pathogen type dependent)


CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


The adaptive immune system

Pathogen specific



Humoral



Cellular

http://www.uni
-
heidelberg.de/zentral/ztl/grafiken_bilder/bilder/e
-
coli.jpg

Bacteria

http://en.wikipedia.org/wiki/Image:Aids_virus.jpg

Virus

http://tpeeaupotable.ifrance.com/ma%20photo/bilharzoze.jpg

Parasite

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Adaptive immune response



Signal induced


Pathogens


Antigens


Epitopes


B Cell

T Cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Antibody
-

Antigen interaction

Fab

Antigen

Epitope

Paratope

Antibody

The antibody recognizes
structural properties of the
surface of the antigen

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Cartoon by Eric Reits

Humoral immunity

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The immune response
starts with an antigen
approaching a cell of
the immune system,
here a
macrophage
.

antigen

macrophage

http://www.pfizerlearninglab.co.uk/

The Humoral Response
-

Activation
Phase

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark




The macrophage
engulfs the antigen
by phagocytosis.

Lysosome
containing
enzymes

Antigen engulfed in vesicle

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The vesicle containing an antigen
fuses with a lysosome. The
enzymes in the lysozome break
down the antigen into fragments.
This is
antigen processing
.



antigen processing

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



Inside the macrophage, the processed
antigens combine with special



class II MHC proteins
. These proteins can
move to the cell surface membrane.

enzymes and

proteins combining

Class II

MHC proteins

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The antigen/MHC protein complex is displayed on
the immune cell surface membrane. The
macrophage is now known as an
antigen
presenting cell
.

Processed antigen/

MHC protein complex

Antigen
-
presenting cell

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The next stage involves a
helper T cell
(also know as a T
-
helper cell) as
well as the macrophage

T helper cell (T
H
)

macrophage (antigen
-
presenting cell)

receptors which bind to specific

antigen/MHC protein complex

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The receptors on the
helper T cell

enable it to bind to the specific
antigen
-
MHC complex

of the
antigen presenting cell
.

macrophage (antigen
-
presenting cell)

helper T cell

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The binding of the helper T cell with the antigen
-

MHC protein complex triggers the
macrophage to release proteins (
cytokines
) that
activate

the helper T cell.

Cytokines from
macrophage

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The activated helper T cell now releases its
own

cytokines

Cytokines
from helper
T cell

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The released cytokines stimulate the helper T cell to reproduce and form a
clone of cells. Each new cell has the same receptors as the original helper T
cell, so they are specific for the original antigen.

Clone of helper T cells

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



Another phase of the immune
response begins with a
B cell
. The
B cell has
membrane bound
globular receptor proteins

(called
IgM
). Some of these are specific for
the same antigen presented earlier
by the antigen presenting cell.

antigen

B cell

IgM receptor

http://www.pfizerlearninglab.co.uk/

The Humoral Response
-

Effector Phase

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The B cell’s receptor
protein (an IgM) binds to
the antigen, and the cell
engulfs the antigen by
endocytosis
.

IgM bound to

antigen engulfed

by cell

lysosome

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The vesicle formed
inside the B cell fuses
with a lysosome. This
contains digestive
enzymes which break
down the antigen.

Fused vesicles containing
antigen and enzymes from
lysosome

B cell

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



Fragments of the
digested antigen
remain after
processing within the
vesicle.


Processed antigen

Class II

MHC

protein

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The processed antigen
is attached to Class II
MHC receptors within
the B cell, and is
transported to the
membrane.

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The MHC proteins form a
complex with the antigen
which is displayed on the
surface of the B cell. It has
become another type of
antigen presenting cell

Antigen/MHC protein complex

B cell (antigen presenting cell)

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



A helper T cell from the clone of cells produced earlier specifically
recognises the antigen presented by the B cell.

Antigen
-
presenting B cell

Helper T cell clone

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The helper T cell cell binds to the antigen/MHC protein
complex displayed by the B cell.


This triggers the release of cytokines from the T cell. Once
the cytokines are released the helper T cell no longer binds
to the B cell.


Cytokines released by


helper T cell


helper T cell binds to

antigen complex on B cell

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The cytokines released by the helper T
cell stimulate the
B cell

to divide and form
a clone of identical cells

B cell clones

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



The B cells continue to divide and form two
groups of clones. Some are long


lived
MEMORY

cells. Most are antibody
-
secreting
PLASMA cells.

Plasma cells have extensive
endoplasmic reticulum and many ribosomes.

Memory

cell

Plasma cells

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



Plasma cells are essentially antibody factories.
They produce and secrete antibodies identical to
those of the surface receptors of the original
parent B cell

antibodies

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark



Like the IgM surface receptors on the parent B cell, the
antibodies can
bind to

and
inactivate

the antigens, forming
an
antibody
-
antigen complex
. This complex makes it
easier for other white blood cells to engulf the antigen
(phagocytosis).

Antibody
-
antigen complex

http://www.pfizerlearninglab.co.uk/

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Cellular Immunity

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Diversity is a hallmark of the
(adaptive) immune system

Diversity of lymphocytes


Huge diversity within a host


At least 10
8

different T & B cell clones

Receptors made by recombination & N
-
additions

Somatic mutation during immune response

Repertoires are (partly) random


Randomness requires self tolerance

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


MHC
-
I molecules present peptides on
the surface of most cells

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


CTL response

Healthy
cell

Virus
-

infected

cell

MHC
-
I

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS

Department of Systems Biology


Technical University of Denmark


Anchor positions

MHC class I with peptide