College aantekeningen Immunologie research en kliniek (5052IMRK6Y)

Lecture 1 Immunological interactions and B cells

The first cells to react to infection are
macrophages. They are long lived. Since they wait
around in the tissue until something happens.
When they become activated they take up
bacteria and changes (maturation/differentiation).

The pathogen recognition receptors (toll like receptors) recognize PAMPs.
The macrophages release cytokines which makes the membrane permeable so
fluids that can get into the tissue  other immune cells get into tissue to help
against infection. There is also complement in the fluids which can activate on
the bacteria.
Inflammation: influx plasma, neutrophils and monocytes  increased
inflammatory reaction  increased lymph drainage to lymph nodes and
activation antigen presenting cells (APCs)  induction specific immune response
 influx of antibodies and T cells.

T cells need to be activated in the lymph nodes by dendritic cells that have taken
up the pathogen. Parts of the pathogen itself also goes to lymph nodes where
they activate the B cells.

CD8 or CD4 T cells are inactive T cells, so only after activation they become
effector cells. So CD8 cells become cytotoxic T cells  only now becomes
cytotoxic because now has machinery to kill. CD4 cells become T helper cell.

TLR activation by PAMPs induce innate and
adaptive responses.
TLR activation causes intracellular parts to
come together and induce signaling. Get
gene transcription which helps maturation
of the cells.
Vaccine needs PAMPs (or PAMP like
structure) to activate TLRs. Otherwise DCs
won’t mature and move to lymph nodes.


DC migrates to T cell zone. It produces
antigen on MHC molecules to activate the T cells. All the T
cells in the lymph nodes use their integrins to shortly interact
with the DC. If it recognizes the pathogen, the T cell makes a
immunological synapse so that the DC can give other signals
which are necessary for maturation and proliferation (clonal
expansion). After few days they get signal to migrate out of
lymph node.

, cSMAC = central supramolecular activation
cluster

pSMAC = peripheral supramolecular activation
cluster


TLR activation of APC gives rise to 4 signals for T
cell responses. TLR activation triggers protein
production so make extra MHCII molecules. Also
get cytokine production.
1. TCR/MHC peptide  antigen
2. Co-stimulation
3. Cytokines  what type of cell it needs to
become
4. Induction homing  where it needs to go
Anergy  only get signal 1 so cell inactivates itself. So need co-stimulation. Co-
stimulation only from cells that have triggered TLR so they have pathogen  is
safety mechanism against auto-immune.

It is the PAMP that determines which cytokines are
produced. And it are the cytokines that determine
what T helper cells are produced.
IL12  TH1
TGF-beta, IL1, IL6  TH17
TGF-beta, IL10 (anti-inflammatory) and low co-
stimulation  Treg cells


BCR is an antibody that recognizes intact
antigen. In bone marrow there is selection of
self-reacting B cells. Then goes to lymph nodes
where it can bind antigen. If activated you get
plasma cells, that secrete antibodies, or memory
cells, that go to bone marrow.


BCR consists of mIg and IgA/IgB. mIg (membrane bound
immunoglobulin) recognizes specific antigen, consists of heavy
and light chain. IgA/IgB initiate cell signaling upon crosslinking of
mIg by specific antigen.




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, Have thymus dependent and
independent antigens. First signal of
independent B cells is the binding of
antigen to BCR. Second signal is binding
PAMP to TLR. This causes secretion of
IgM, which causes (partial) elimination
of the pathogen. IgM is
pentamer/hexamer, so have a lot of
constant domains. It binds to bacteria
and then the complement can bind IgM very well. So is multiplier for complement
activation. So is nice to have early in infection.
It is secreted as a multimeric structure because the monomeric parts have low
affinity, so would otherwise only have two arms to bind. So excreted as
multimeric form so that the total binding force is high and can bind pathogen
well. But because of this structure it doesn’t help well with phagocytosis.

T cell dependent B cells differentiate in the
lymphoid organs. Then leave and go into the
blood to sight of infection or to bone marrow
(memory cells). Need T cell stimulation or
otherwise go into apoptosis
First step is binding of antigen to BCR (signal 1),
taking this up and degrading it to put on MHCII
proteins to present to T cells. Also get CD40,
which are co-stimulatory proteins. The CD4 T cell can bind the B cell and help B
cell. This is signal 2 which is anti-apoptotic. Signal 3 is CD4 T cell cytokines. This
leads to class switching to IgG/IgE, somatic hypermutation and affinity
maturation.

Can label T cells with CFSE  can track T cell proliferation. Daughter cells will be
less vibrant than the mother cell because they divide the dye.

The follicular T helper cells (Tfh) are key in
providing B cells help. Are needed for germinal
center (GC)-reaction and therefore needed for long
lived humoral immunity.
At the border of B and T cell zones the B and T cell
interact. Some B cells here become already short
lived plasma cells  produce short lived antibodies.
When T cell can bind the B cell, some T cells can
migrate in the B cell zone (follicle). So get memory B cells and short and long
lived plasma cells.
Activated B cells go to the dark zone (lot of B cells
together where they proliferate). Will also get, next
to class-switching, hypermutation  some have
higher binding affinity than others. Then goes to
light zone where it can bind follicular DCs (FDCs,
can hold antigen in lymph node). The B cells with
high affinity can then take up the pathogen again




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