Immune tolerance/ Regulation Flashcards
what is the most imp factor to controlling immune response
ANTIGEN
It induces activation, proliferation + differentiation of lymphocytes
what happens to the lymphocytes once antigen is ridden of
The immune response subsides.
Most lymphocytes specific for it die by apoptosis.
Only a few of the best are kept as memory
cells.
B lymphocytes hv inhibitory Fc receptors for IgG. What does this do
Prevents the B-cell activation.
Its a signal that there are already enough IgG antibodies, + no further production is needed.
where does this feedback regulation (Fc inhibitor stuff) evident
Myeloma: susceptibility to bacterial infection is increased + normal immunoglobin production is impaired.
T cells: T cell lymphoma leads to deficiency for normal T cells + susceptibility to intracellular pathogens
CD4 T helpers up regulate immune response. what down regulates immune response. what do they do
Regulatory T cells/ T suppressors (TREG)
Treg cells form in the thymus. They distinguished by expression of transcription factor FoxP3.
It switches on a set of genes responsible for regulatory activity.
They interact with other T cells on surface of antigen presenting cells and down-regulate T effector activity by contact-dependent signaling / cytokines.
Antibodies can have different antigenic determinants on them. what are the determinants located on the V region called?
Idiotypic
Antibodies against them = Anti idiotypic antibodies
What role does the idiotype - anti idiotype network hv on immune system
regulates immune response but more a secondary role
whats an exception with this idiotype network
B cells reacting against T-independent antigens.
They may stimulate each other by anti-idiotype
antibodies instead of using T-helpers.
How does the idiotype – anti-idiotype network works
- presence of an antigenic determinant (epitope) stimulates production of Ab, which
introduces production of other types Ab2 (Ab2α, Ab2β, Ab2γ).
what does each Ab2α, Ab2β, Ab2γ do
. Ab2α is directed to the idiotope of Ab1
- Ab2β is directed to the paratope of Ab1
- Ab2γ is directed to the near antigen epitope-binding site idiotope of Ab1.
what are Anti-idiotypic antibodies used for
stop autoantibodies from attacking self cells with
minimal side effects and long- lasting immunity.
What are Ir (Immune response) gene
genetic mapping shows they identical to mHC genes
What causes a poor response (MHC and antigen)
when particular MHC variant doesn’t bind to antigen well / in complex where antigen resembles a self antigen + induces tolerance
what shows the diversity of MHC
that no MHC is good for all antigens
Nueroendocrine reg- what substances supress/ upregulate immune response
Supress: Glucocorticoids, testosterone and
progesterone
upregulate: estrogens, thyroid hormones, growth hormone + insulin
whatt are Glucocorticoids also used for
immunosuppressive drugs (after
transplantation).
Secreted during stress response; therefore,
stress makes us susceptible to
infections.
Def immune tolerance
lack of immune response against a substance
that has access to normalfunctioning
immune system + characteristics of
antigen.
**Tolerance to self antigens
where does self vs non self discrimination occur. when does it become inefficient
INNATE IMUNITY: Phagocytes have pattern recognition receptors detecting the characteristic surfaces of bacterial cells.
inefficient: When foreign substances cannot be recognized as foreign by their general appearance.
(pathogen toxin “looks” like any other protein.)
** True immune tolerance, , is acc adaptive by definition. what is it then
Immune tolerance is a function of the entire immune system. It recognizes self antigens based on the
context in which they appear.
What is an example of Blood chimeras
RAY OWEN CALF EXPERIMENT - dizygotic twin calves who had diff blood types apparently exchanged blood cell precursors in utero through placenta
What was observed with early exposure to antigen to tolernace? evidence?
exposure to an antigen early in
life INDUCES TOLERANCE to that antigen (normally used to distinguish between self and non-self.
- Peter Medawar.
He exchanged skin grafts between dizygotic cattle twins and found that those that carried erythrocytes
from the twin (bone marrow chimeras) accepted also the skin graft.
If antigen removed, tolerance lost. WHY and evidece
Reliable immune tolerance requires continuous
exposure to antigen, especially during development.
- Frog experiment - when organ is removed (eye lens) during devpmt phase then transplanted back, it may be rejected. (1 removed, graft accepted. both removed, tolerance lost and graft rejected
** how to achieve chimerism based tolerance
mixed chimerism - organ and bone marrow from same donor are transplanted at same time
What is clonal deletion
elimination of cells that strongly bind antigen in
the peripheral tissues and then undergo
apoptosis.
lymphocytes differentiating in the central lymphoid
organs are checked for autoreactivity. what happens to those that bind strongly to self antigens
They dont leave organ and die
What is CENTRAL TOLERANCE
Immature B cells reacting to self antigens are forced
to edit their receptors. If editing fails to remove self-
reactivity, the cell is induced to die by apoptosis
(negative selection).
(Autoreactive B cells not that bad cos most of not
activated without T-helpers.)
Autoreactive T cells dangerous. What does central tolerance do to these
thymocytes do negative
selection in thymic medulla.
Stromal cells present self-antigens to them and
induce apoptosis in those that react too strongly.
Limitation to central tolerance
If an antigen is introduced after the foetal / neonatal period, there will already be mature T cells specific for it.
cant eliminate by central tolerance then
PERIPHERAL TOLERANCE ( when central doesnt work)
Elimination of foreign antigens sometimes
requires antibodies cross-reacting with self-antigens.
autoantibodies formed after tissue injury can help to clear the released self-antigens.
what is anergy
if antigen is presented to a naïve T cell without co-stimulatory signal B7, the T cell
becomes inactive
AIRE is tanscriptio factor what does it do
activates genes for many proteins specific for other organs, e.g. insulin. So these
proteins are produced in small quantities and presented to thymocytes in order to establish
central tolerance to them.
what does mutations in AIRE cause
rare autoimmune disorder APS-1 (due to central tolerance failure)
**Medullary thymic epithelial cells with active gene
for AIRE, located in corticomedullary junction of
thymus. what does it do
These cells produce tissue-specific antigens (TSAs) and can give these antigens to thymic dendritic cells.
Dentritic cells present TSAs to immature T cells.
Post-Aire cells also express TSAs but at a lower level and are found near Hassall’s corpuscles.
Expression of TSAs in the medulla affect Treg cells
+ negative selection of T cells, which are critical
for maintaining central tolerance.
what is the role of TREGS for immune tolerance
controlls if immune responses to self-antigens+ foreign antigens if the response is too strong or prolonged
how do TREGS control
works by forcing the too-active lymphocyte into inactive state (suppression).
( will work if antigen-presenting cell supplies В7)
What is proof that TREGS needed to down regulate immune response
evident in boys having no functional Treg cells cos of mutations in marker FoxP3.
Straight after birth,
they develop IPEX syndrome
They get watery diarrhea, eczematous dermatitis, and endocrinopathy
Unless treated by bone marrow transplantation, patients die within 1-2 years.
