Tolerance Flashcards
T-cells must be tolerant to _____. How is this accomplished?
self-antigens; through central tolerance or peripheral tolerance
What is central tolerance?
self-reactive T cells are killed
What is peripheral tolerance?
these T cells are “turned off” by inappropriate signaling
What causes tolerance?
very low or very high antigen doses
How do antibodies regulate antibody production?
through negative feedback mechanisms
How does antibody regulation affect newborn animals?
Hinder successful vaccination of newborn animals as a result of maternal immunity
How do Treg cells control immune responses?
secretion of cytokines such as IL-10 and TGF-b
How do Th17 cell regulate inflammation?
by secreting IL-17
Immune system and the CNS system are closely interconnected and influence each other. True or false?
True
What percentage of TCR and BCRs are self reactive?
20-50%
Where does negative selection occur?
in primary lymphoid tissue
Where are self-reactive lymphocytes “turned off”?
secondary lymphoid organs
What is the definition of tolerance?
unresponsive to an antigen
What is the definition of autoimmunity?
reactivity against self
When can tolerance occur?
If immature lymphocytes are exposed to antigen early in life and lymphocytes remain tolerant even when exposed later in life
What characterizes autoimmunity?
a condition characterized by specific antibody or cell-mediatd immune response (activated T cells) against the constituents of the bodys own tissues
Severe autoimmunity results on _____________.
autoimmune disease
What are autoantigens?
the bodys own tissues
What are dizygotic twins?
non-identical twins; different genetic makeup
Do dizygotic twins share a placenta?
yes
Why do CTLs not reject skin grafts from dizygotic twins?
Bone marrow cells colonize each other in chimeric calves. Each chimera is tolerance to its twin cells and will accept its twin despite the genetic difference.
What is the result of a BVDV intrauterine infection in a pregnant cow?
non-cytopathic BVDCV infects fetus and cows become persistently infected (PI) and remains a carrier for life
What are the consequences of PI calves?
they are seronegative and tolerant to BVDV virus and they are a carrier
What are the types of tolerance?
central and peripheral
How does central tolerance work?
developing lymphocytes react to self antigens and induce negative selection
Which cells remain in a tolerant state longer? T or B cells?
T cells
Which cells are more easily made tolerant? T or B cells?
T cells
How does peripheral tolerance work?
mature lymphocytes recognize self antigens in the peripheral lymphoid tissues leading to mechanisms of removal or inactivation
What signals a T cell for destruction in peripheral tolerance?
low doses of antigen OR lack of costimulation
Thymic epithelial cells express ______ that promotes expression of ______.
aire transcription factor; self antigens
What are the exceptions to central tolerance?
brain, eye, testis
Negative selection is regulated by the _____.
air gene
The aire gene is an autoimmune regulator. True or false?
true
T cells with TcRs that bind with ____ affinity to many self antigens are programmed to ____. What is this called?
high; die
negative selection
Gene defects lead to ___________ and _________.
ineffective central tolerance; autoimmunity
What is fas?
CD95: death receptor pathway (apoptosis)
What are the consequences of mutations of the fas gene?
self reactive lymphocytes do not undergo apoptosis
negative selection of T cells can not occur
What are the mechanisms of B-cell tolerance?
negative selection (Apoptosis)
receptor editing of variable region genes
What is receptor editing?
Immunoglobulin genes recombine so that a new light chain is splices with a heavy chain
What is the product of receptor editing?
a B-cell receptor that is no longer specific to self antigen
What three mechanisms can suppress mature self-reactive T-cells that?
anergy or fucntional inactivation
deletion (activation induced apoptosis)
suppression
When does anergy occur?
when cells recognize self-antigens/ TcR binds to antigen without adequate levels of costimulatory signals or inhibition of co-stimulatory pathway
What is happening when deletion occurs?
activation of induced apoptosis
activation of cell self-antigen stimulates T cell clones that kill each other by FasL/Fas pathways
What pathway is used in deletion for T cell clones to kill each other?
FasL/Fas pathways
Suppression by _____, produce ____ or ____.
Tregs; TGF-b; IL-10
What provides inflammory signals?
PRR-PAMP, cytokines
What are the inhibitory receptors for co-stimulation?
CTLA-4; PDI
What is the normal response to antigen recognition?
T-cell proliferation and differentiation. Explained more below.
Antigens recognized in the presence of strong co-stimulation/growth factors (IL-2) stimulate production of anti-apoptotic proteins
What happens to cause cell death in activation-induced apoptosis?
Engagement of death receptors
Recognition of self antigens may trigger apoptosis that results in deletion of the self reactive T-cells though expression of fas/fas ligand
How are regulatory T cells generated?
By combined actions of IL-2 and TGF-b as well as the presence of retinoic acid
How do Tregs suppress mature self reactive lymphocytes?
they produce the suppressive cytokines, TGF-b, IL-10, IL-35
suppresses T cell and macrophage function
Tregs mediate suppression by secreting ____ and ____.
TGF-b; IL-10
How is antibody diversity generated?
VDJ recombination in primary organs
Random somatic mutation in germinal centers of lymph nodes or spleen
What percentage of immature B cells have self-reactive receptors?
55-75%
What are the induction mechanisms of peripheral B-cell tolerance?
clonal exhaustion
immune complexes bind B-cell inhibitory receptors
T-cells induce B-cell apoptosis
idiotypic networks
Clonal exhaustion by repeated antigenic challenge results in what?
results in plasma cells but no memory B-cells
What induces anergy in B-cell peripheral tolerance?
CD32 (FcyRII)
What is rhogam?
antibody to Rh factor prevents the Rh- mother from responding to Rh+ cells
peripheral B-cell tolerance
What are some examples of immune complexes binding to B-cell inhibitory receptors?
myeloma patients, maternal antibody in neonates (rhogam)
T-cells induce B-cell apoptosis via ________.
Fas expression
Idiotypes networks dampen ________.
antibody response
What are idiotypic networks?
antibodies against antibodies
How does presence of maternal antibody in newborn delay the onset of immunoglobulin synthesis?
through negative feedback
What feedback loops lowers the production of IgG by B-cells when there is a surplus?
CD32 (FcyRIIB) has a low affinity for IgGs and down-regulates antibody production in the presence of IgG-Antigen complexes. This shuts off the ability of BCR to become regulated.
PSNS and SNS nerves secrete _____ that regulate cytokines - __/__ balance.
neurotransmitters; Th1; Th2
