Alien Invasion II
Univ.-Prof. Dr. Albert Duschl
The mantra
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RISK = HAZARD x EXPOSURE
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This is the basic formula for all risk assessment.
(Actually it would be even more correct to say that
risk is a function of hazard and exposure).
No hazard (commensal bacteria), high exposure
= No risk
High hazard, no exposure (dangerous stuff not in
contact with the body) = No risk
Low hazard + Low exposure = Low risk
Etc.
For „low risk“ scenarios it needs to be considered
whether there are risk persons.
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Immunity makes professional risk assessment
(and has understood Paracelsus, in contrast to
some people I know).
CTL/TH
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T-cell are either
CD4+ T-Helper cells or
CD8+ cytotoxic T-cells
(CTL).
CD4 binds to MHC II,
CD8 to MHC I.
The CD8/MHC I
contact mediates
killing, so the T-cell is
here the effector cell.
Helpers work mostly
via the secretion of
immunoregulatory
cytokines.
+
CD8 ,
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+
CD4
T-cells are activated in
situations where
inflammation already
exists. The innate
immune response
provides the signals to
stimulate DC migration to
the lymph node.
Note: Inflammation and
innate immunity are
sometimes considered to
be synonyms.
If you want to avoid
confusion, say we are
following here a type 1
adaptive immune
response.
In view of a kill
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Perforin: Pore protein,
disrupts membranes
and allows granzymes
to enter
Granzymes:
Proteases, cleave
caspases and induce
apoptosis
Serglycin:
Glycoprotein, supports
granula formation.
FasLigand: Binds Fas,
a death receptor that
induces apoptosis.
Which T-helpers?
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T-cells can differentiate into different subsets. It is
crucial to make the right decision since reversing it
is very difficult. What do we want for a bacterial
pathogen?
Correct: TH1. At least to begin with. The main
product is IFN-g, a strong activator of
macrophages which supports inflammation.
TH2 is ineffective against bacteria. It could cause
an allergic reaction.
TH17 organizes a sustained, chronic inflammation.
May be necessary if you cannot eradicate the
bacteria quickly.
Treg (regulatory T-cells) induce tolerance. Not
actually a good idea if you face pathogens, but
great for wound healing later on.
© Martin/Resch: Immunologie
Innate lymphoid cells: New kids in town
Signals from injured or infected tissues expand and activate NK cells, ILC1s, ILC2s, and ILC3s.
Gérard Eberl et al. Science 2015;348:aaa6566
Published by AAAS
To B or not to B
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B-cells are within lymph nodes
concentrated in B-cell follicles.
Different antigen-presenting
cells (APC) travel there via
different routes, giving the BCR
a chance to sample intact
antigens.
Now we need to get the T-cells
to the same site and create a
T/B/APC interplay.
Note that the follicular dendritic
cells are important for
organizing the follicles but are
not APC. They are specialized
myofibroblasts and belong to
the lymph node fibroblastic
reticular cells.
Stimulating B-cells
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B-cells can recognize the intact antigen via BCR and they interact with activated
T-cells, which together results in specific B-cell activation, development of plasma
cells and isotype switching. These events are spatially and temporally separated.
OK, so the
follicular helper
cell (FH) is
another type of
T helper. Let‘s
leave it at that.
Class switching
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B-cells get 3 signals from
T-cells:
TCR/antigen/MHC:
Recognize this antigen!
CD40/CD40L: Perform class
switching!
Cytokines. Switch to the
following isotype.
How it works
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The genes for IgM and IgD
are close together, so there
can be read-through.
For all other isotypes a
section of DNA is looped out.
It is possible to switch
repeatedly, but never
backwards, since the DNA in
the looped-out circle is
degraded and lost.
Class switching does not
affect the N-terminal VDJ
sequence, so antibodies of
all isotypes can be produced
against the same antigen.
Affinity maturation
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Already in the lymph node, affinity
maturation takes place.
Hypermutation occurs in the VDJ
region, so the B-cell clones that are
now produced cover a spectrum of
options.
High affinity binding IgM (or IgD)
provides strong signals for getting
T-cell help.
Signal strength also regulates
proliferation activity. The B-cells
with the highest binding affinity
produce the largest clones and
develop later into memory B-cells.
That is why vaccination works.
Alternative splicing
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IgM can be produced as
membrane protein or in soluble
form by alternative splicing. IgD
remains normally always a
membrane protein.
All other Isotypes (IgG, IgA and
IgE) are produced only as
soluble forms.
IgG is the most frequent one –
an excellent activator for
complement and incidentally,
also the only on to cross the
blood-placenta barrier.
Antibody variability
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VDJ recombination takes place
during B-cell development in the
bone marrow.
For T-cells, similar mechanisms
occur in the thymus.
At that point, the light and heavy
chain genes are not altered. Only
the V, D and J segments are
affected. For each of them, all
copies except one are eliminated by
looping out.
The final VDJ will constitute the Nterminal domain of the light or heavy
chain. Both light and heavy chain
contribute to antigen binding and
undergo VDJ rearrangement.
So your biology teacher was not quite right:
Not all somatic cell have the same genome.
Even more antibody variability
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VDJ recombination is not
performed as accurately as it
would be possible.
In addition, specific enzymes
can add a few nucleotides that
were not present in the original
genome (!).
These N and P nucleotides
contribute to variability and make
the number of possible
antibodies even higher than VDJ
alone would allow. We really go
to a lot of trouble to ensure a
wide spectrum of antigen
recognition.
Mediocrity
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This is one of the few
processes where it is
best to be mediocre.
No binding to MHC:
Cells go into apoptosis.
Strong binding to MHC:
Cells go into apoptosis.
Moderate binding to
MHC: Survival signals,
maturation, release
from bone marrow or
thymus.
The lymphocytes are
now naïve B- or T-cells.
Antibody classes
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Different antibody classes are
specialized for different functions, to
which we will come in future lectures.
There is nothing obligatory about
having five Ig classes. If you would be a
lungfish you would think three is
normal.
© Janet Stavnezer, Chris T. Amemiya. Evolution of isotype switching
Seminars in Immunology, Volume 16, Issue 4, 2004, 257–275
http://dx.doi.org/10.1016/j.smim.2004.08.005
Joint venture
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A lot of effort (and bile) has been spent in
the early decades of immunology to
determine whether immunity is cellular of
humoral (i.e. cell based or serum based).
This was not really a productive
discussion, since clearly both are
necessary and act together.
Still, cellular and humoral immunity are
maintained as historically developed
concept, so next time we will discuss
humoral immunity.
The two university scepters may not be
the best of illustrations, but otherwise you
have to wait until your sponsio to see
them.
Imperial (left) and papal (right) scepter of the
University of Salzburg (1656)