Lecture 19 Flashcards
What is Immunological Tolerance?
specific unresponsiveness to an Ag
All individuals are tolerant to what type of Ags?
Self-Ags (self-tolerance)
The breakdown of self-tolerance results in what?
autoimmunity
What type of selection of self-reactive T lymphocytes in the thymus is not perfect?
negative selection
What level of physiological auto-reactivity is crucial to normal immune function?
low level
Central tolerance is induced in what?
in immature self-reactive lymphocytes in the generative lymphoid organs
Peripheral tolerance is induced in what?
in mature self-reactive lymphocytes in peripheral sites
What does central tolerance ensure?
ensures that mature lymphocytes are NOT reactive to self Ags
What is peripheral tolerance needed for?
to prevent activation of potentially dangerous lymphocytes
T cells responding to ubiquitous Ags presented by thymic epithelial cells and hematopoietic cells are efficiently deleted when?
During intra-thymic development
In the thymus, medullary epithelial cells (mTecs) ectopically express a broad range of organ-specific genes and present or, via thymic DCs, cross-present gene products for what?
negative selection
Tolerizing the T cell repertoire to (peripheral tissue Ag) PTA depends on negative selection in the thymus, but autoreactive T cells can also be eliminated where?
in the peripehry
Induction of both central and peripheral tolerance to PTA involves DCs that carry Ags acquired in nonlymphoid tissues and nonhematopoietic cells that do what?
‘promiscuously’ express PTA
PTA peripheral tissue Ag
In the periphery, lymph node stromal cells show ‘promiscuous’ expression and directly provide ligands that facilitate the deletion of what?
mature autoreactive T cells
TCR signaling in immature T cells triggers _______ pathway of apoptosis - negative selection
mitochondrial
The thymus also has a special mechanism for expressing many protein Ags that are present only in what certain tissues?
peripheral
Recognition of self Ags by immature T cells in the thymus leads to what 2 things?
- the death of the cells by negative selection or
2. the development of Treg cells that enter peripheral tissues
Immature T cells in the thymus encounter what Ags?
Self Ag presented by thymic epithelial cells
Cells with T-cell receptors with no affinity for the complex of self peptide and a self MHC molecule do not receive what signal?
They DO NOT receive a surviving signal and undergo spontaneous apoptosis dying int he thymus
Cells whose T-cell receptors have a high affinity for such complexes receive what signals?
The death signal and are eliminated by means of apoptosis
The remaining T cells that have intermediate affinity for self peptide and self MHC molecule go on to do what?
mature in the thymus and migrate to the periphery, where they can become activated
Immature lymphocytes specific for self Ags may encoutner these Ags in the generative (central) lymphoid organs and are either:
deleted
change their specificity (b cells only)
develop into Treg cells
Mature self-reactive lymphocytes in peripheral tissues may be:
inactivated or deleted
suppressed by the T reg cells
Mutations in what causes Incomplete induction of tolerance in the thymus, failure of central tolerance
AIRE deficiency: autoimmune polyendocrine syndrome
Impaired production of reg T cells
FoxP3 deficiency causes IPEX syndrome
Decreased clearance and impaired tolerance induction by apoptotic cells
Complement deficiency of C1q and C4
Altered immune signaling thresholds
CTLA-4 polymorphisms
AIRE stands for:
AutoImmune REgulator
What process in the thymus is necessary for the maintenance of self tolerance?
Negative selection of T cells
Medullary thymic epithelial cells have a key function as what?
APCs
What do medullay thymic epithelial express a large number of?
Self-Ags that are presented to developing T cells
Mutation in AIRE is associated with decreased expression of what Ags in the thymus?
self-Ags
The AIRE regulates the expression of what type of Ags?
tissue-restricted Ags (TRAs)
Peptides derived from TRAs are displayed on what APCs?
Medullary Thymic Epithelial Cells
Ags displayed on medullary thymic epithelial cells are recognized by immature Ag-specific T cells and cause what to occur
Deletion of self-reactive T cells
In the absence of functional AIRE in medullary thymic epithelial cells, self-reactive T cells are not eliminated and causes what to occur?
The T cells enter tissues where the Ags continue to be produced and cause injury
T cell responses are induced by what 2 signals?
- TCR recognizes and Ag presented by APC
2. CD28 recognize B7 costimulators on the APCs
If the T cell recognizes a self Ag without costimulation, what happens to the T cell?
Becomes unresponsive to the Ag because of a block in signaling from the TCR complex
Blocking in T cell anergy may be the result of what?
- recruitment of phosphatases to the TCR complex
- Activation of upiquitin ligases
- engagement of inhibitory receptors CTLA-4
The anergic T cell remains viable but is unable to respond to what?
Self Ag
When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function is to do what?
Terminate T cell responses
What are the best established inhibitory receptors?
CTLA-4
Individual populations of T cells undergo ______ and ______ upon Ag encounter.
Expansion and contraction
T cell activation is regulated by members of the __-___ family of costimulatory molecules
B7-CD28
What type of receptor is CTLA4?
A CD28-family receptor
Inhibitory
What signals do CTLA4 provide?
Signals that terminate immune responses and maintain self-tolerance
What do CTLA-4 KO mice develop?
Uncontrolled lymphocyte activation with massively enlarged lymp nodes and spleen and fatal multi organ lymphocyte infiltrates suggestive of systemic autoimmunity
Blocking of CTLA-4 with Abs also enhances what?
autoimmune diseases in animal models
Polymorphisms in the CTLA4 are associated with several autoimmune diseases in humans, name two
Type 1 diabetes
Graves’ disease
CTLA-4 has what two important actions?
- CTLA-4 expression is low on resting T cells until the cells are activated by Ag
- Once expressed CTLA-4, terminates continuing activation of these responding T cells
CTLA-4 is expressed on what type of cells? It mediates the suppressive function of these cells by inhibiting the activation of naive T cells.
T reg cells
CTLA-4 mediated inhibition by Treg cells is what type of mechanism?
cell-extrinsic action
The cytokines for common gamma chain, also known as IL-2 receptor subunit gamma are what?
IL-2, 4, 7, 9, 15
Where do Treg cells develop?
In the thymus
Treg cells are positively selected in the thymus via what strong interactions?
TCR interactions with self-Ags
After recognition of self-Ags, Treg cells are (eliminated/not eliminated) by apoptosis
Not eliminated
Treg cells are able to produce anti-apoptotic molecules which protect them from what?
negative selection in the thymus
The generation of some Treg cells requires what cytokine?
TGF-β
Treg cells express ____ transcriptional factor and are CD4+CD25+ positive
FOXP3
Treg cells typically express high levels of what receptor?
CTLA-4
The survival and functional competence of Treg cells are dependent in what cytokine?
IL-2
Treg cells are what type of populations?
Endogenous long-lived populations of self-Ag-specific T cells
Treg cells serve to prevent what types of reactions?
potentially autoimmune reactions
Inducible Treg cells are produced by Ag recognition where?
In LNs
Natural Treg cells are generated by self Ag recognition where?
in the thymus
TGF-β inhibits the proliferation and effector functions of what cells?
T cells
TGF-β inhibits the development of what T cell subsets?
What T cell subset does it promote the development of?
Inhibit development of Th1 and Th2
Promotes Th17 in cooperation with IL-1 and IL-6
TGF-β inhibits the activation of what APCs?
macrophages
TGF-β regulates the differentiation of peripheral ______ T reg cells
FOXP3+
TGF-β stimulates production of what Ab by inducing B cells to switch to this isotype?
IgA
TGF-β promotes tissue repair after local immune and inflammatory reactions subside stimulating what actions?
collagen synthesis and matrix-modifying enzyme production by macrophages and fibroblasts
How many people in the US suffer from autoimmune diseases?
5% or 12-15 million
How many diverse autoimmune diseases affect various tissues of the human body?
60-70
Most autoimmune diseases are treated how?
symptomatically
The autoimmune diseases bring the paradox proposition that “__________________-“
The body both is and is not itself
There is no fundamental difference between the structure of self auto-Ags and non-self Ags because of what reason?
Ags are all proteins
Pathologic immune response against self Ags often clinically manifested as what?
immune-mediated inflammatory diseases
What causes chronic autoimmunity ?
Activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause
What is a result of a hypersensitive immune system?
That one’s own immune system attacks the self
What is immunologic ignorance?
Process in which T cells that are physically separated from their specific Ag (the BBB) cannot become activated
T cells that express the Fas (CD95) can receive their signals from cells that express FasL. What does this interaction cause?
apoptosis/deletion
What binds to CD80 on APC that inhibits T cells activation?
CTLA4 (CD152)
Regulatory T cells can inhibit through the production of inhibitory cytokines such as IL-___ and ____.
10
TGF-B
Weak recognition of self Ags in the bone marrow may lead to what process in B cells?
Anergy (functional inactivation)
Mature B cells that recognize self Ag in the peripheral tissues in the absence of specific Th cells may be rendered what?
functionally unresponsive or die by apoptosis
CD22 inhibitory receptor is phosphorylated by what?
Lyn
What does the active CD22 recruit?
SHP-1tyrosine phosphatase and then attenuates B cell receptor signaling
Defects in lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 inhibitory receptor leads to what?
autoimmunity
How may various genetic loci confer susceptibility to autoimmunity?
In part by influencing the maintenance of self-tolerance
Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells resulting in what?
Tissue injury
Autoimmune diseases may be either systemic or organ specific depending on what?
the distribution of the auto-Ag that are recognized
Various ______ mechanisms are responsible for tissue injury in different autoimmune diseases
effector
Autoimmune diseases tend to be chronic, progressive and _______.
self-perpetuating
Failure of the mechanisms of self-tolerance in T or B cells underlies cause of all _________.
autoimmune disease
What is the initial innate immune response?
inflammation
Most autoimmune diseases are complex _____ traits
polygenic
Affected individual inherit multiple genetic _______ that contribute to disease susceptibility
Polymorphisms
Susceptibility genes act with _________ to cause the diseases
environmental factors
Among the genes that are associated with autoimmunity, the strongest associations are with _____ genes
MHC
Polymorphisms in non-____ genes are also associated with autoimmunity
HLA
Microbial Ags can initiate autoimmune disorder through:
Molecular mimicry
Polyclonal (bystander) activation
Release of previously sequestered Ags
Rheumatic fever is triggered by streptococcal infection and mediated by cross-reactivity between streptococcal Ags and _________.
Cardiac myosin
Molecular mimicry
Multiple-sclerosis - T cells react with ________ and peptides from epstein-barr virus, infleunze virus type A,and human papillomavirus.
Myelin basic protein
Molecular mimicry
Microbial infection can also cause polyclonal activation of autoreactive _______.
lymphocytes (cytokine field).
Polyclonal activation
Microbes that kill cells can cause inflammation, the release of sequestered Ags, and _______.
autoimmunity
Release of perviously sequestered Ags
Autoimmune diseases are much more common in what sex?
women
Estrogens exacerbate ___________ in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.
Systemic lupus erythematosus (SLE)
Drugs can also alter the immune repertoire: penicillins and cephalosporins can bind to _____ membrane and generate a neoantigen that elicits an auto-Ag that causes hemolytic anemia
RBC
The blockade of TNF-a (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and ________ in certain persons.
multiple sclerosis
TFN-a has inhibitory effects on activated ___ cells, but it remains unknown how TFN-a induces autoimmunity
T
