Lecture 24: Tolerance and Autoimmunity Flashcards
state of specific unresponsiveness to an antigen induced by prior exposure to that antigen
immune tolerance
tolerance is an active process
How does the immune system address inevitable reactivity to self
Elimination of self-reactive T cells in the thymus: Central tolerance
Failure to provide the signals to induce a T cell response: Peripheral tolerance
what is AIRE (autoimmune regulator)
transcription factor that facilitates expression of non-thymic proteins in the thymus to test reactivity
_____ anergy is initiated when T-cells are exposed to antigen in the absence of costimulation
Clonal
what is the mechanism of clonal anergy
suppression of NFKB and decreased production of cytokines (IL-2)
lasts for several weeks
what is immune paralysis
high doses of antigen that bypass APCs, bind TCR directly, lack costimulation and induce paralysis
antigen dose affects ____ of tolerance
induction
Very low doses of antigen fail to send a sufficient signal, inadequate co-stimulation occurs
very high doses can overstimulate the cells and initiate peripheral tolerance
where and when does central tolerance of B-cells occur
occurs in bone marrow once B-cell can express IgM (immature B cell)
random somatic mutations of B-cells occur in __________ organs, and must be controlled peripherally
secondary lymphoid
what things cause mature B cells to undergo peripheral tolerance
chronic antigen recognition
absence of costimulation
excessive suppressor cell activity
excessive T-independent antigen
once an antigen is eliminated, tolerance….
subsides
bone marrow activity (production of new cells) ______tolerance
reduces
immunosuppressive drugs _______ tolerance
prolong
______drive the immune response, _______turn it off
antigens, antibodies
antibodies have a feedback loop on _____cells to ______further production of antibodies
Bcells, inhibit
______antibodies inhibit antibody production in the newborn
maternal
Adaptive immune responses are _______Driven
antigen
adaptive immune response is initiated only when…? when does it cease?
initiated only on exposure to antigen
ceases when antigen eliminated
what happens when self or other antigens don’t reach lymphoid tissue
fail to induce immunity to tolerance
self antigens form immune privledged sites
the effect of antigen can be modulated by…?
adjuvants
antibodies suppress _____cell responses
B
IgM suppresses only..?
IgM
IgG suppresses production of _____ and _____
IgM and IgG
Antibody mechanism of B-cell suppression?
inhibitory B-cell receptor CD32b
abnormally high Ab concentrations (myeloma) inhibit….
normal Ab synthesis
increased susceptibility to infection
what is the action of FcRn (neonatal immunoglobulin receptor)
regulates serum half life of IgG and albumin
endothelium, muscle, hepatic sinusoids
________receptors inactivate or eliminate pathways that are no longer needed, suppress the activity of the lymphocytes when their mission is completed
inhibitory
what does CD32b do
negative feedback that suppresses B-cell activation
crosslinking of BCR and Ab bound to CD32 w/ antigen
what is the function of Treg cells
homeostasis of peripheral immunity + tolerance
induce apoptosis in effector cells
what immunosuppressive cytokines do Treg cells produce
- IL-10
- IL-35
- TGF-B
suppression of Tcell and macrophage function
Treg deficiency results in…?
multisystemic autoimmunity and massive inflammation
what are the Treg cells in cattle
WC1.1, WC1.2, γ/δ and Tcells
where do Treg cells originate from, where are they induced
Originate in thymus
induced in secondary lymphoid tissues (most important in intestine)
what induces cell cycle arrest in effector Tcells
Galectin
what does CTLA-4 do
induces apoptosis of effector T cells
what are the 3 ways Treg cells suppress immune responses
direct contact
suppressive molecules
interference w/ antigen presentation
what ILs activate M2
IL-4, IL-13
effect of Indoleamine 2,3 dioxygenase
tryptophan depletion and cell cycle arrest
stress is highly …..
immunosuppressive
disease resulting from an attack by an individual’s immune system against its own tissues
autoimmune disease
Up to what percentage of new B and T cell receptors can bind self antigens?
50%
what is cental tolerance
elimination of self-reactive T cells in the thymus
what is peripheral tolerance
Failure to provide the signals to induce a T cell response
what does it mean for tissues to be immune privileged
Areas of the body where inflammatory immune response does not occur following exposure to an antigen, ex) the eyes
Which type of cell does not remain tolerant as readily as the other, and will reactivate if tolerance is not maintained?
B-cell
what is functional deletion
The cell is still in the body, but the cell is no longer functioning
can self antigens can induce immunity or tolerance.
no
what is FoxP3
Transcriptional repressor protein of regulatory T cells
What 3 things must be present for an immature Th cell to become a Treg cell?
IL-2, TGF-B, Retinoic Acid
Can suppress macrophages, Th1 cells, Th2 cells, dendritic cells, natural killer cells, and Th17 production
IL-10
Regulates T-cell activation, macrophages, and B-cell function
TGF-B
What is the classically activated regulatory macrophage known as?
M1
What regulatory macrophage s activated by IL-4+IL-13 and induces tolerance, suppresses inflammation, and is responsible for tissue repair?
M2
IL-22 is produced by..?…and involved in..?….
Produced by Th17, involved in tissue healing
IL-17 is produced by_______,stimulates____________ and mobilizes________
Produced by Th17 cells, stimulates growth factors, Th cells, epithelial cells, macrophages. Also mobilizes neutrophils to promote inflammation.
