Lecture 24: Tolerance and Autoimmunity I Flashcards
Immune tolerance
State of specific unresponsiveness to an antigen induced by prior exposure to that antigen
Why is tolerance important
Immune cells don’t attack self cells
How does immune system address reactivity to self
2 ways:
1. Central tolerance-elimination of self reactive T cells in thymus
2. Peripheral tolerance- failure to provide signals to induce T cell response
What is central tolerance
Elimination of self reactive T cells in the thymus
What is peripheral tolerance
Failure to provide signals to induce a T cell response
Anergy
Programmed nonresponsiveness
Negative selection
Elimination of T cells that bind strongly with self in thymus
Positive selection
Elimination of T cells that don’t bind or weakly bind to self-MHC
What is AIRE- autoimmune regulator
A transcription factor that facilitates expression of non-thymus proteins in thymus to test reactivity
What is clonal anergy
Initiated when T cells are exposed to antigen in absence of co-stimulation
What is the mechanism of suppression in peripheral tolerance
Suppress NFKB, decreased production of IL-2, decreased T cell production
What is immune paralysis
High dose of antigen that bypass APC’s bind TCR’s directly, lack of co-stimulation, induce paralysis
How does antigen dose affect induction of tolerance
Very low doses of antigen fail to send sufficient signal, inadequate co-stimulation (tolerance)
Moderate doses=immune response (antibody production)
High doses can overstimulate the cells and initiate peripheral tolerance (immune paralysis)
Where does B cell central tolerance occur
Bone marrow once B cells express IgM
Where does B cell peripheral tolerance occur
Secondary lymphoid organs
What is central tolerance of B cells
Immature B cell exposed to low doses of antigen will cause clonal abortion
What is peripheral tolerance in B cells
Mature B cell undergoes one of the following: exhaustive antigen challenge, absence of co-stimulation, excessive suppressor cell, excessive T-independent
Results in functional deletion and receptor blockade
If an antigen is eliminated tolerance ___
Subsides
If an antigen persists, tolerance ___
Persists
Bone marrow activity (production of new cells) ___ tolerance
Reduces
Immunosuppressive drugs ___ tolerance
Prolong
In general, ___ drive immune response and ___ turn it off
Antigens, antibodies
Antibodies have a feedback loop on B cells to inhibit
Further production of antibodies
____ antibodies inhibit antibody production in newborn
Maternal antibodies (clinical relevant for timing vaccines)
What are some mechanisms of immune control
Antigen, antibody, inhibitory receptors, regulatory cells
What is the result of inadequate immune response
Immunodeficiency, susceptibility to infections
What is the result of an excessive immune response
Allergy, autoimmunity
Adaptive immune responses are ___ driven
Antigen
The effect of an antigen can be modulated by ___
Adjuvants
What Ig does IgM suppress
IgM
What Ig does IgG suppress
IgG and IgM
What is the mechanism of suppression for antibodies
Inhibitory B cell receptor CD32B
How does abnormally high antibody concentrations impact normal antibody synthesis
Inhibits normal Ab synthesis which leads to increased susceptibility to infection
What receptor regulates the half life of IgG and albumin
FcRN
What is the role of inhibitory receptors
Inactive or eliminate pathways that are no longer needed, suppress activity of lymphocytes when mission is accomplished
What is the specific mechanism of action of CD32b
Negative feedback that suppresses B cell activation by cross linking BCR and Ab bound to CD32 with antigen
What cell is responsible for maintaining homeostasis of peripheral immunity and tolerance
Tregs
What immunosuppressive cytokines do Tregs produce
IL-10, Il-35 and TGF-B
Treg deficiency results in
Multisystemic autoimmunity and massive inflammation
What factors make up Treg
CD4+ CD25+FoxP3+ T lymphocytes
What is FoxP3
Specialized transcription factor in generation of Treg cells
What are the Tregs in cattle made of
WC1.1 + WC1.2 + gamma/delta T cells
What are tTregs
Tregs that naturally originate in the thymus
What are pTregs
Tregs that are induced in secondary lymphoid tissue
What 3 signaling molecules are needed to induce pTregs
IL-2, RA, and TGF-B
What cells do Tregs suppress
T cells and macrophages
What are the three ways in which Tregs can suppress the immune system
- Direct contact
- Suppressive molecules
- Interference with antigen presentation
Direct contact Treg suppression causes release of what molecules
TFG-B, perforins and granzymes, Galectin 1, CTLA-4, and TRAIL
What does Galectin do
Induces cell cycle arrest in effector T cells
What does CTLA-4 do
Induces apoptosis in effector cells
What suppressive molecules are released from Tregs
IL-10, TGF-B, IL-35 and PGE2
What molecules are secreted during interference with antigen presentation
Neuropilin 1
IDO
What are the functions of IL-10
Suppress macrophages, suppress Th1 cells, supress Th2 cells, enhance Tregs, suppress Th17 production, supress NK cells, supress DC’s
What is the function of TGF-B
Regulate T cell activiation, regulate macrophages, regulate B cell function
What are the 2 regulatory macrophages
M1 and M2
How are M1 and M2 activated
M1- classically activated
M2- activated by IL-4 and IL-13
What does activation of M2 result in
Induction of tolerance, suppression of inflammation, tissue repair and angiogenesis, produce IL-4, IL-13, IL-10 and TGF-B
What does indoleamine 2,3 dioxygenase do
Tryptophan depletion and cell cycle arrest
What IL is involved in tissue healing
IL-22
What are the functions of IL-17
Induce growth factors, stimulates Th cells, mobilizes neutrophils, stimulate epithelial cells, stimulates macrophages
What happens if the mechanisms that regulate tolerance fail?
Autoimmune disease
Autoimmune disease
Disease resulting from an attack by an individuals immune system against that individuals own tissues
