Immunologic Tolerance and Autoimmunity Flashcards
What is ummunological tolerance?
Specific unresponsiveness to an Ag.
What is self-tolerance?
All individuals are tolerant to self-Ags.
What dos central tolerance ensure?
That mature lymphocytes are NOT REACTIVE to self Ags.
What results in autoimmunity?
From Breakdown of self-tolerance.
You know negative selection of self-reactive T lymphocytes in the thymus is not perfect. What is this important?
Low level of physiological auto-reactivity that is crucial to normal immune function.
Is tolerance Ag specific?
Yes
What is central tolerance induced by?
Immature self-reactive lymphocytes in the primary lymphoid organs.
What is peripheral tolerance induced by?
Mature self-reactive lymphocytes in peripheral sites.
In central T cell tolerance, what does TCR signaling in immature T cells trigger?
Mitochondrial pathway of apoptosis - negative selection.
Which 2 things does recognition of self Ags by immature T cells in the thymus lead to?
1) Death of the cells by negative selection.
2) Development of Treg cells that enter peripheral tissues.
In which primary lymphoid organ does central tolerance occur?
thymus
What type of T lymphocytes does a small percentage of T cell that emigrate from the thymus and express FOXP3?
Develop into natural CD4+CD25+CTLA4+ Treg cells.
Which type of T cells are key mediators of peripheral tolerance?
Treg cells
What do Treg cells prevent T cells from providing?
Help to B cells in the production of Abs.
True or False:
In peripheral tolerance, Treg cells may inhibit T cell activation by APCs and inhibit T cell differentiation into CTLs.
True
In addition to the natural Treg cells which differentiate in the thymus, mature T cells outside the thymus can also acquire Treg phenotype and functoin.
True
What are induced Treg cells (iTreg cells)?
Mature T cells OUTSIDE THE THYMUS that acquire Treg phenotype and function.
What signal induces FoxP3 expression in naive CD4+ cells in vitro?
By Ag recognition in the presence of TGF-beta.
if IL-6 is NOT present
Between which two T cells types is there a close developmental relationship?
- iTregs
- Th17
Ag recognition in the presence of TGF-beta induces FoxP3 expression if what?
IL-6 is NOT present.
What happens in Ag recognition in the presence of TGF-beta + IL-6?
Prevents FoxP3 expression, induces expression of the retinoic acid receptor (RAR) related orphan nuclear receptor RORgammat expression and therefore, Th17 cell differentiation.
During Ag recognition in the presence of TGF-beta and not IL-6, will iTregs or Th17 cells result?
iTregs
Central B Cell Tolerance
> Immature B cells that RECOGNIZE SELF AGS in the bone marrow with high avidity die by apoptosis or undergo receptor editing and change the specificity of their BCRs.
What is BCR editing?
Further rearrangement and replacement of the IgL-chain genes that occurs until non-self-recognizing receptors are produced or the cell dies.
What does weak recognition of self Ags in the bone marrow lead to?
Anergy (functional inactivation) of the B cells.
What does BCR signaling promote?
Developmental arrest and continued recombination.
True or False:
Receptor editing of the IgL chain leads to expression of a distinct IgL chain, generating cell-surface immunoglobulin that lacks self-reactivity.
True
What does both RAG1 and RAG2 being turned on?
cell death
In peripheral B cell tolerance, what happens to mature B cells that recognize self Ag in peripheral tissues in the absence of specific Th cells?
Rendered functionally unresponsive or die by apoptosis.
What signaling cascade attenuates BCR signaling?
CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phophatase.
What can defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to?
autoimmunity
What are the three possibilities in central tolerance?
- deleted
- change BCR specificity (B cells only)
- develop into Treg cells
What are the three possibilities in peripheral tolerance?
- inactivated (anergy)
- deleted (apoptosis)
- suppressed by the Treg cells
What does an AIRE deficiency cause?
autoimmune polyendocrine syndrome
incomplete induction of tolerance in the thymus
What does impaired production of regulatory T cells (FoxP3 deficiency) cause?
IPEX syndrome
What does a complement deficiency of C1q and C4 lead to?
Decreased clearance and impaired tolerance induction by apoptotic cells .
What is CTLA-4 polymorphisms?
Altered immune signaling thresholds.
What gene has a mutation leading to the failure of central tolerance?
AIRE
What gene has a mutation leading to the defective clearance of immune complexes; failure of B cell tolerance?
C4
What gene has a mutation leading to the failure of anergy in CD4) T cells?
CTLA-4
What gene has a mutation leading to the defective deletion of anergic self-reactive B cells; reduced deletion of mature CD4 T cells?
Fas/FasL
What gene has a mutation leading to the deficiency of regulatory T cells?
FoxP3
What gene has a mutation leading to the defective development, survival or function of regulatory T cells?
IL-2; IL2R alpha/beta
What gene has a mutation leading to the failure of negative regulation of B cells?
SHP-1
What is the key function of medullary thymic epithelial cells?
Have a key function as APCs.
What do medullary thymic epithelial cells express?
A large number of self-Ags that are presented to developing T cells.
What does mutations in AIRE (autoimmune regulator) cause?
Breakdown of central tolerance.
What is mutation in AIRE associated with, leading to the breakdown of central tolerance?
Decreased expression of self-Ags in the thymus.
When AIRE is functioning normally, Ags are recognized by immature Ag-specific T cells, leading to the deletion of self-reactive T cells. What happens in the absence of functional AIRE?
Self-reactive T cells are not eliminated and they can enter tissues where the Ags continue to be produced and causes injury.
T cell responses are induced when?
1) TCR recognizes an Ag presented by APC (signal 1).
2) CD28 recognize B7 costimulators on the APCs (signal 2).
If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signaling from the TCR complex. Blocking may be the result of?
- Recruitment of phosphatases to the TCR complex.
- Activation of ubiquitin ligases that degrade signaling proteins.
- Engagement of inhibitory receptors CTLA-4.
True or False:
The anergic T cell remains viable but is unable to respond to the self Ag.
True
What is the best established inhibitory receptor?
CTLA-4
True or False:
When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function is the terminate T cell responses.
True
What family of receptors is CTLA-4 a member of?
CD28-family receptor
What kind of receptor is CTLA-4?
An inhibitory receptor - provides signals that terminate immune responses and maintain self-tolerance.
What is seen in CTLA-4 KO mice?
uncontrolled lymphocyte activation with massively enlarged LNs and spleen and fatal multi-organ lymphocytic infiltrates is seen in CTLA-4 KO mice.
What are the two important properties of CTLA-4?
> 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.
What type of cell is CTLA-4 expressed on?
regulatory T cells and mediates the suppressive function of these cells by inhibiting the activation of naive T cells
Name two diseases that are enhanced by blocking CTLA-4 with Abs in mice.
type 1 diabetes and Graves’ disease
What is the cell-extrinsic action of CTLA-4?
CTLA-4 on Treg cells or responding T cells binds to B7 molecules on APCs or makes unavailable to CD28.
What is the cell-intrinsic function of CTLA-4?
Engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of that cell.
True or False:
Treg cells are positively selected in the thymus via strong TCR interactions with self-Ags.
True
after recognition of self-Ags they are NOT ELIMINATED by apoptosis
How do Treg cells protect themselves from negative selection in the thymus?
Produce anti-apoptotic molecules.
True or False:
Treg cells express FoxP3 transcriptional factor and are CD4+CD25+ positive.
True
What does IL-2 do for Treg cells?
Critical for survival and functional competence of Treg cells.
What are Treg cells?
Endogenous long-lived populations of self-Ag-specific T cells.
serve to PREVENT potentially AUTOIMMUNE REACTIONS
What do Treg cells do in peripheral tissues?
Suppress the activation of self-reactive lymphocytes.
Natural Treg cells -> are generated by self Ag recogition in the thymus.
Inducible Treg cells -> are produced by Ag recognition in LNs and GI tract.
True
What is the function of TGF-beta?
> INHIBITS the proliferation and effector functions of T cells.
> INHIBITS development of Th1 and Th2 subsets but PROMOTES Th17 in cooperation with IL-1 and IL-6.
> INHIBITS activation of M1 macrophages
> REGULATES the differentiation of induced FoxP3 Treg cells.
> STIMULATES production of IgA by inducing B cells to switch to the isotype.
> PROMOTES tissue repair after local immune and inflammatory reactions subside stimulating collagen synthesis and matrix-modifying enzyme production by macrophages and fibroblasts.
What percentage of people in the world have an autoimmune disease?
5%
True of False:
There are 60-70 diverse autoimmune diseases which affect various tissues of the human body.
True
True of False:
There is no fundamental difference between the structures of self auto-Ags and non-self Ags because Ags are all proteins composed by the same amino acids.
True
What results in a autoimmue chronic disease?
hypersensitive immune system that causes one’s own immune system to attack the self
What is immunologic ignorance?
T cell that are physically separated from their specific Ag (the BBB) cannot become activated, a process termed immunologic ignorance.
(immunologic ignorance)
What is the process known as deletion?
T cell that express the Fas CD95 can receive their signals from cells that express FasL and undergo apoptosis, a process known as deletion.
(deletion)
What signaling inhibits T cells activation?
CTLA-4 (CD152) that binds CD80 on APC.
(inhibition)
Regulatory T cells can inhibit through the production of which inhibitory cytokines?
> IL-10
TGF-beta
(suppresion)
List the four ways in which autoimmunity is prevented.
> immunologic ignorance
deletion
inhibition
suppression
What features favor immune responses in APCs?
high levels of costimulators
What features favor tolerance in APCs?
low levels of costimulators and cytokines
What features favor immune responses in presence of adjuvants?
Ags with adjuvants: stimulate helper T cells.
What features favor tolerance in presence of adjuvants?
Ags without adjuvants: non-immunogenic or tolerogenic.
What features favor immune responses in portal of entry; location?
subcutaneous, intradermal; absence from generative organs.
What features favor tolerance in portal of entry; location?
intravenous, mucosal; presence in generative organs.
What features favor immune respones in persistence?
short-lived (eliminated by immune response).
What features favor tolerance in persistence?
prolonged
What are the two postulated mechanisms of autoimmunity?
> Various genetic loci may 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 tissue injury.
True or False:
Autoimmune diseases may be either SYSTEMIC or ORGAN SPECIFIC, depending on the distribution of the auto-Ag that are recognized.
True
What is responsible for tissue injury in different autoimmune diseases?
various effector mechanisms
Autoimmune diseases tend to be?
> chronic
progressive
self-perpetuating
The failure of what underlies causes of all autoimmune diseases?
Failure of the mechanisms of self-tolerance in T or B cells.
In the genetics of autoimmunity, most autoimmune diseases are?
complex polygenic traits
In genetics of autoimmunity, what do most affected individuals inherit?
Multiple genetic polymorphisms that contribute to disease susceptibility.
Amoung the genes that are associated with autoimmunity, the strongest associations are with what?
MHC genes
True or False:
Polymorphisms in NON-HLA genes is also associated with autoimmunity.
True
What do susceptibility genes act with to cause autoimmune diseases?
environmental factors
List the three ways in which microbial Ags can initiate autoimmune disorders?
> Molecular mimicry
> Polyclonal (bystander) activation
> Release of previously sequestered Ags.
What is molecular mimicry?
An environment trigger in which microbial Ags can initiate autoimmune disorders.
> Rheumatic fever is triggered by streptococcal infection and mediated by cross-reactivity between streptococcal Ags and cardiac myosin.
Multiple sclerosis - T cells react with myelin basic protein and peptides from Epstein-Barr virus, influenza virus type A, and human papillomavirus.
What is polyclonal (bystander activation?
An environment trigger in which microbial Ags can initiate autoimmune disorders.
> Microbial infection can also cause polyclonal activation of autoreactive lymphocytes (cytokine field).
What is release of preveiously sequestered Ags?
An environment trigger in which microbial Ags can initiate autoimmune disorders.
> Microbes that kill cells can cause inflammation, the release of sequestered Ags, and autoimmunity.
True or False:
Autoimmune diseases are much more common in women than in men.
True
What are autoimmune diseases much more common in women?
Estrogens exacerbate systemic lupus erythematosus (SLE) in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.
Drugs can also alter the immune repertoire. Give examples.
Penicillins and cephalosporins can bind to RBC membrane and generate a neoantigen that elicits an auto-Ag that causes hemolytic anemia.
True or False:
The blockade of TNA-alpha (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and Multiple Sclerosis (MS) in certain persons.
True
*TNF-alpha has inhibitory effects on activated T cells, but it remains unknown how TNF-alpha induces autoimmunity.
