Tolernace Flashcards
antigens that elicit the functional Activtion of lypho bearing specific receptors for those antiG
Immunogenic antigens
Activation via immunogenic antiG require what 3 things
- co-stim of T cells by activated APCs
- foreign antiG not present during B/T cell devo
- acute antiG exposure
elicit functional INACTIVATION of killing of lymphocytes bearing specific receptors for those antiG
Tolerogenic antigens
Killing of lymphocytes that bear specific receptors can have what 3 thigs
- present antiG w/out co-stimulation or T cells help
- delete antiG that recognize self antiG
- chronic antiG exposure
antigens that are IGNORED by lypphocytes bearing specific recetpors for those antignes
Ignorance or Non-immunogenic
the specific UNRESPONSIVENESS of normal adaptive immune sytem to SELF antibengs
Immunologic tolerance
T cell tolerance is long/short lived
long lived
B cell tolerance is long/short lived
short lived and less complete than in T cells and
What three things can induce tolerance
- immunologic maturity : neonates/elderly are immuno immature and respond poorly to antiG
- AntiG structure and dose: respond to a simple molecule at really high or really low dose
- Immunosuppresive therapy enhances tolerance
Immunosuppresive therapy enhances
tolerance
AntiG structure and dose:
respond to a simple molecule at really high or really low dose
abnormal immune responses to self antigens and non-pathogenic antigens lead to
autoimmune
loss of tolerance to self antig
autoimmunity
immune response to envirom antig
allergy
immune respone in transplant
transplant rejection of GVHD
immature lymphocytes exposed to self antigen have 4 options
- apoptosis
- change in receptor (B cells edit)
- Devo of regulatory T lymphocytes
- ESCAPE
If lyphocytes escpase Central tolerance and recognizes self antigens in periphery… three options occur
- Anergy
- Apoptosis
- Suppressed by Treg
Tolerance obtained by immature cells in generative lymphoid organs (bone marrow for B cells or thymus for T cells) as they encounter self antiG
Central tolerance
tolerance obtained by mature cells in peripheral lymp tissue
peripheral tolerance
The T cell maturation goes through regular checkpoints:
1st checkpoint is: does the T cell express the proper _____ recomibation on this chain______
VDJ recombination on the TCR betta chain
Second checkpoint for T cell: Does immature T cell express this combination ______ on this chain ____
VJ comibination on the TCR alpha chain
3rd checkpoint for T cell devo: Does the antiG receptor recgonize self antig?
weak results in
strong results in
weak means you get positive selection
strong recognistion of self is negative selection
When pro T cells leave the bone marrow, they head to the Thymus andn are said to be
double negative: don’t express CD4 or CD8
Immature T cells called _______ beging to express both TCR betta and TCR alpha and are now _______ for CD4 and CD8
thymocytes
double positive for CD4 and CD8
Double positive T cells will undergo this process as our 3rd checkpoing
positive and negative selection
First step of maturation of T cells occurs in ______
thymic cortex
When T cells are in thymic cortex, they recognize either MHC I (CD8 + ) or MHC II (CD4+) in a process called
positive selection
after recognized MHC I or II in cortex, T cells move to ______ to be presented with Self antiG in process called:
medulla
negative selection
Defects in negative selection often result in
mature T cells that recognize self antiG = autoimmunity
Weak recognition of MHC + self peptide by TCR and co receptor (either CD8 or CD4) results in
positive selection
No recognition of MHC + self peptide by TCR and co-receptor results in
death by neglect
Strong recognition of MHC + self pep by TCR and co receltpr results in
negative selection
Surviving cells of positive selection are not
CD8 + or CD4+ naive T cells and exit thymus to enter periphery
T cells under go + selection in the
corticoepithelium as cortical epithelial cells present self-peptide to double positive thymocytes
T cells undergo - selection in
medullary epithelial cells that express the Aire transcription factor gene
This gene drives expression of numerous tissue specific self-peptides to T cells in medullarly epi of thymus
Aire gene
Before undergoing negative selection, T cell thymocyte populations consist of :
Self and foriegn antiG specific Single positive T cells
Positive selection results int
self and foreign antiG recognizing thymocytes that are either CD4 or CD8 positive
Loss of Aire results in
lack of negative selection of self-reactive T cells in thymus
these make autoantiBs to immune proteins important in controle of fungal infections
Aire helps with IL-17
pt devos wide range of auto-antiBs to organ-specific antiG of endocrine organs and liver and skin
loss of Aire
clinical syndrome associated with autoimmune adrenal and parthyroid disease
APCED
see autoimmune hypothryoidism, hypogonadism, vitiligo and pernicious anemia with this diesease
Autoimmune polyendocrinopathy candidiasis ectoderlal dystrophy = APECED
APECD is caused by
defect in AIRE thus failure of negative selection thus lots of self reactive T cells
These guys are key to stepping in when Central tolerance isn’t complete
T reg cells (self-reactive CD4 + cells)
What do T reg cells express
foxP3
T reg cells are positive for what CD’s?
CD24, CD25 and Foxp3
Activation by MHC+ self peptide stimulates T cell apoptosis by these three methods:
Anergy, suppresion, deletion
this is induced when mature T cells recognize self peptide in peripheral tissues or in mucosa
Periperal T cell tolerance
Develeop in thymus once they recognize selfantigen by immature double positive thymocytes
T regs
T regs are activated in periphery by:
self antigen and IL-2
APC’s lack co-stim molecules (like B7) thus results in
anergy
T cells express _______ moleclue to send inhibition signal to T cells upong bindint to the APC B7
CTLA-4
T cellls express CD28 that bind to _____
and with high levels of B7 the T cells are:
ITAM (acitvation)
activated d/t that CD28 + B7 levels
T cells express CTLA-4 that bind to _______
and will low levels of B7, the T cells become
ITIM( inactivation)
anergic via that CTLA-4 signal
What is this?
T regs bind directly to mature T cells to introduce inhibitory signal CTLA-4 (surface bound TGFbetta) and kills the T cell that is regonizing self antigen via performin/granZ
Contact Dependent T regulation: Suppresion
T regs cells secrete high levels of TGFbetta and IL-10 that inhibit T cell activation (of T cells recognizing self antiG) so it can’t interact with the APC
contatct INdependent T regulation: suppresion
You can uses CTLA-4 immunotherapy on
inhibits second signal by stopping of the binding of CD28
Rheumatoid arthritis
psoriasis
IBD
Type I diabetes
Mutation in Foxp3 and we see hyper-inflammatory mucosa
(bowel, skin, pancrease, ) think IBD!!! Think Boys!
Immune dysregulation polyednocrionpathy X linked syndrome
IPEX in boys
IPEX tx is
BMT to reboot immune system
Repeated exposure to self-antiG leads to:
cell death d/t deficiency of survival signals
cell death by engagement of death receptors
Ultimately… T cell deletion
Death receptor ligand is
Fas and FasL
tolorogenic self antiG located in:
generatie organs and will induce negative selection and other mech. of central tolerance
Tolerogenic self antiG and acompnying costimulation:
lack of co-stimulators can lead to anergy or apoptosis or devo of T regs
Tolerogenic self antiG duration of antiG exposure:
long lived persistance, so prolongued TCR engagement may induce apop to get T cell deletion in periphery
3 factors that contribute to tolerance or breakdown in tolderance
location
abundance
persistance
1st checkpoint for B cell : does immature B lymp express _____ recombined antiG receptor in the _______chain
VDJ
IgHeavy chain
2nd checkpoint for B cell: does immature B cells express ____ in this receptor chain
VJ
IgLight
3rd checkpoint: does antiG receptor recognize ______
self
strongly—must die
weakly— can live
Where does B cell complete maturatoion
w/in bone marrow
Central B cell tolerance is based wholly on strength of nascent surface immunoglobin (_____ or ______) to reconize soluble _______
IgD or IgM
self-antiGens
If a B cell recognizes self antiG with High avididty, what happens?
- receptor editing of the IgL chain
2. Deletion via apotosis (upregulates pro-apoptosis genes)
If B cell recognizes self antiG will low avidity what happens (so NO avidity)
Anergy-
Where does receptor editing happen in the B cell if there is high avidity to self-antiG
in the IgLight
How do B cells receptor edit?
internalize the BCR, generate new IgL with some new VJ recomination events and try again
Where does peripheral B cell tolernace occur
germinal centers during immune response
How is peripheral B cell tolerance different from naive B cells?
short lifespan
defects in BCR
defects in gerinal centerl
immune response against self antiG, failure of tolerance
autoimmunity
What are prinicple factors of autoimmune disease
- inherit genes which contribute to FAILURE of SELF-TOLERANCE
- Envi triggers that activate self reactive lymphocytes
What is our perfect storm for developing autoimmunity
envirornment + genetically susupecitlbe indivdual
Multpile genes will predispose indi to autoimmune disease: for twins this means
one devos disease, other very likey if gets same enviroment exposures
Many autoimmune disease have been linked to this gene
MHC or particular HLA allele
Are mutations in HLA genes the cause of autoimmune diesase
NO…. some can inherit it and not develope it but it can contribute
How does mutation in MHC contribute to autoimmune disease
- defects in central tolerance bc of ineffecient display of self antigens so we don’t get rid of immunogenic T cells
- Defect in peripheral tolerance–> mutant MHC may not trigger Treg cells
How do microbes upregulate autoimmunity?
assuem you have APC that is presenting a self antiG that then gets infected with a microbe… it will upregulate it’s co-stimulatory signals so it’s like…. hey T cell, help, i’m infected, but T cell that is reactive to self antiG will react to that self antiG it’s displaying and not the microbe that infected the APC
A microbe is ingested and displayed by APC… T cell that is kinda retarded regonizes this microbe, but it really is specific for self antigen so it startes to repliate and attack self tissue… this is example of
microbe mimicry
immune system developed this to suppress autoreactive lymphocytes
immune tolerance
This occurs when adaptive immune response is directed against self antigens to elicit tissue damage
autoimmune disease
autoimmune disease are multifactorial and may result from: 3 things
immunological abnormalities
susceptibility genes
infections
this induces death of immatre lypmp that encounters self antigen in bone marrow or thymus
central tolerance
this results from recogniztion of self-antiG by mature lymphocytes in periphery
peripheral tolerance
This is the positive and negative selection 3rd checkpoint in T cell devo
Central T cell tolerance
Mech of peripheral T cell tolerance include:
anergy
suppresion
deletion
this is induced when immature cells recognize self antiG in bone marrow
Central B lymphocyte tolerance
tolerance through anergy when mature B cells recognize self antiG w/out T cel help
Peripheral B tolerance
Strongest gene that contributes to devo of autoimmunity is
HLA for mostly T cell releated autoimmune disesase
Infections can predispose to autoimmunity through
induce abherrant co-stim moleucle or
molecular mimicry
