A summary made with the information from all the lectures on Advanced molecular immunology and cell biology. Includes images from the slides used in the lectures.
ADVANCED IMMUNOLOGY AND CELL BIOLOGY
LYMPHNODE DEVELOPMENT
We need lymph nodes for an adaptive immune response and a memory response. The antigen is presented to
the lymphocytes.
Within the lymph nodes there is control of self-reactive lymphocytes.
Formation of lymphoid structures
Stromal & immune cells form clusters (9-12 weeks prenatal) grows out to organized lymphnodes (13-15 weeks
prenatal) with B-cell and T-cell areas.
Lymphotoxinα1β2 and LTβR are essential for lymphoid organ formation. They belong to the TNF receptor
family.
Lymphoid tissue inducers (Lti cells) are the cells that form lymphoid organs together with the stromal
organizers. The Lti cells express LTαβ on the cell surface, the stromal cells have LTβR receptor and when they
bind the stromal cells make chemokines and adhesion molecules. Chemokines attract other cells, adhesion
molecules helps cells stay at their place.
Lymphotoxin-a defiency causes chemokine deficiency so no cells are attracted to the lymph nodes.
There are different fases in lymphnode
development, first is depended on CXCL13
cytokines and CXCR5 receptors, CXCL13
regulates attraction of inducer cells to the
forming lymphnodes.
Retinol (vitamin A) is broken down bij RALDH
into retinoic acid and binds receptors in
nucleus and will turn into transcription factor.
Important in cell differentiation and
proliferation.
Retinoic acid induces CXCL13 production.
RALDH is expressed in nerve fibers. So nerve
fibers produce retinoic acid.
Stromal organizer cells are crucial for lymph node formation. Stromal cells mediate organization.
Bcell area has FDC and Tcell area has FRC. Those are stromal subsets derived from the stromal organizer cells.
,BECs, LECs and FRC can express self-antigens and are involved in control of autoreactivity.
The control of self-reactive lymphocytes
In the tymus central tolerance is regulated by negative selection by T-cells (high TCR affinity for self-antigen
results in apoptosis). This is also regulated by Treg induction that trigger TCR which express CD25 and you get
an IL2 reaction dependent FoxP3 (lower TCR affinity for self-antigen).
this is all due to the expression of self-antigens by mTECs (medullary thymic epithelial cells). Antigen
presentation is by mTECs and DCs.
In the lymphnode there is peripheral tolerance. With low
expression of self-antigen in MHC class I CD8 Tcells will be
deleted. In MHC class II results in CD4 T cells anergy, apoptosis or
Treg maintenance specific for the self-antigens.
The source of self-antigens here are the lymph node stromal cells
and antigen presentation is by stromal cells and DCs.
The function of MHCII on stromal cells: lymph nodes stromal cells
maintain Treg cells with MHCII. And self-antigen presentation in
MHCII by LN stromal cells converts Tn cells into Treg cells.
LN has a dual function, preventing autoreactivity and promoting
immune reactivity.
DENDRITIC CELLS AND MIGRATION, HOST INNATE IMMUNE RECEPTORS
During the innate immune response everything is dependent on
signals (MAMPs/PAMPs/DAMPs).
There is communication between local and distal sites.
The first reaction on microbes is by the complement system. The
most important are C3a and C3b.
Phagocytosis is activated by binding of receptors.
C-type lectins (CLR) recognise ligand structures and
internalize.
FC-receptors (FcR) recognise antibodies on microbes
and internalize.
Complement receptor (CR) recognize complement
fixed microbes.
Toll-like receptors (TLR) do not internalize but are
important in activation and signalling.
FcY receptors
bind immune complexed consisting of IgG and antigens and induce internalization of the immune complexes.
Can have activating or inhibitory effects. Leads to a signalling cascade.
, C-type lectins
Have lectin domains which recognise carbohydrates, which can be
pathogenic or self. Can have activating or inhibitory effect. Are good
for recognition and phagocytosis but also antigen presentation.
Toll like receptors
Recognize PAMPs. Are on the plasma membrane where they bind
dsRNA and on the endosome bind ssRNA (viruses).
The DC integrate pathogen-derived signals (CLR/TLR/FcR) shape the
immune response. >>
The dendritic cells also link the innate with the adaptive immune
system.
Danger signals (DAMPs) cause DC maturation, which increases MHC expression, co-stimulatory molecules,
migration, production of inflammatory cytokines and makes antigen processing/presentation possible.
The innate recognition and uptake
of antigen by DCs instructs antigen
specific CD4 and CD8 T cells.
There are two kinds of pathogen receptors:
-Indirect recognition of pathogen which leads to opsonized microbes: complement receptor and Fc-receptor.
-Direct recognition and binding of pathogesn: scavenger receptors and pattern recognition receptors.
PAMPs are molecular signatures of invading
pathogens, which can be cell wall components
or DNA/RNA. They are recognized by PRRs.
NOD-like receptors and RIG-I-like receptors are
intercellular (in the cytoplasma).
All receptors stimulate NF-kB and it always
comes to stimulating pro-inflammatory
cytokines in the end.
There will always be multiple different receptors
that will be activated at the same time.
MyD88 and TRIF are important in the Toll-like
receptor signalling pathway.
There are 13 different TLRs and several ligands
can bind the same TLRs.
TLRs are importantly found on DCs and
macrophages, but can also be found on other
cells.
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