Immunological Bioinformatics Or Finding the needle in the haystack Morten Nielsen [email protected].
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Transcript of CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of...
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Department of Systems Biology
Technical University of Denmark
Immunological Bioinformatics
Introduction tothe immune system
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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
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Department of Systems Biology
Technical University of Denmark
Figure 1-20
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Department of Systems Biology
Technical University of Denmark
Effectiveness of vaccines
1958 start of small pox eradication program
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Department of Systems Biology
Technical University of Denmark
The Immune System
The innate immune system
The adaptive immune system
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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)
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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
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Department of Systems Biology
Technical University of Denmark
Adaptive immune response
Signal induced– Pathogens
• Antigens– Epitopes
B Cell
T Cell
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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
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Department of Systems Biology
Technical University of DenmarkCartoon by Eric Reits
Humoral immunity
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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
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Department of Systems Biology
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The macrophage
engulfs the antigen
by phagocytosis.
Lysosome containing enzymes
Antigen engulfed in vesicle
http://www.pfizerlearninglab.co.uk/
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Department of Systems Biology
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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/
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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 andproteins combining
Class IIMHC proteins
http://www.pfizerlearninglab.co.uk/
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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/
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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 (TH)
macrophage (antigen-presenting cell)
receptors which bind to specificantigen/MHC protein complex
http://www.pfizerlearninglab.co.uk/
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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/
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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/
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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/
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Department of Systems Biology
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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/
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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
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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/
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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/
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Department of Systems Biology
Technical University of Denmark
Fragments of the
digested antigen
remain after
processing within
the vesicle.
Processed antigen
Class IIMHCprotein
http://www.pfizerlearninglab.co.uk/
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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/
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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/
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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/
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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/
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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/
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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.
Memorycell
Plasma cells
http://www.pfizerlearninglab.co.uk/
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Department of Systems Biology
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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/
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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/
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Department of Systems Biology
Technical University of Denmark
Cellular Immunity
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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 108 different T & B cell clones
Receptors made by recombination & N-additions
Somatic mutation during immune response
Repertoires are (partly) random– Randomness requires self tolerance
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Department of Systems Biology
Technical University of Denmark
MHC-I molecules present peptides on the surface of most cells
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Department of Systems Biology
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CTL response
Healthy cell
Virus-infectedcell
MHC-I