MCM 2-16 Immune Regulation Flashcards
describe immunological tolerance
simple definition: unresponsiveness to a SPECIFIC antigen.
Immunological tolerance is unresponsiveness to a specific antigen. It is essential that it is kept at an appropriate level. Lymphocytes have unlimited proliferation potential; if proliferation went unchecked, lymphocytes would commit entirely and unendingly in response to one challenge and fail to respond to future challenges, while using up biological resources. What’s more, if an organism’s immune system recognizes its own cells as a threat, autoimmunity may result. Lastly, it affects vaccination; the target antigen and the host both influence the effectiveness of a vaccination and resultant immunization.
tolerance mechanisms are one of three types
elimination - cell populations that are responsive to a particular antigen are killed by selection
neutralization - responsive cell populations are rendered inactive by anergy.
generation - cell populations capable of inducing antigen-specific tolerance are generated
mechanisms of T-cell tolerance
negative selection
regulatory T-cells
Clonal Anergy
activation inhibition
what does positive selection select for?
selects for t-cells that can see MHC. if they can’t are eliminated in thymus.
If they can see MHC, they emerge with the potential for autoimmunity. Must do negative selection next.
What does negative selection select for?
selects for TCR that recognizes/moderately binds MHCII without becoming activated
what is AIRE? what does it do?
Autoimmune regulator protein.
it allows for expression of peripheral antigens in the thymus. T-cells that react to the peripheral antigen are deleted before exiting the thymus.
Aire inters the nucleus and allowing the transcription of specific genes that otherwise wouldnt be expressed in thymus. including insulin.
AIRE dysfunction leads to
mutations in AIRE are what type of mutation?
autoimmunity. Autoreactive CD8+ T-cells escape to periphery, and cause APECED (autoimmune polyendocrinopathy candadiasis ectodermal dystrophy)
loss of function
what are the receptors on regulatory T cells?
CD25 - high affinity IL-2 Receptor
CD4
TCR
CTLA4-binds to b7 costimulatory molecules on APC’s
what is the definitive marker of Treg
the transcription factor FoxP3 found in nucleus. FoxP3 is master switch that changes the phenotype of a CD4+ helper T- cell into a Treg that prevents auto immunity
What results from FOXP3 dysfunction?
IPEX syndrome
- no Tregs
- allergy
- severe autoimmunity
- female carriers
- males affected
how do Treg promote tolerance?
- Treg locates APC displaying Self-antigen
- Treg is activated but does not proliferate
- Treg remains with APC to carry out suppression via
- secreting suppressive cytokines (interleuken 10, TGFb)
- remove IL2 from area by soaking up with its CD25 receptor (deprives dendrite of proliferative cytokines)
- removal of b7
- killing of APC
how are Tregs generated?
Thymic Tregs arise during positive selection in thymus
induced Tregs differentiate in periphery
Describe establishment of Anergy in t-cell tolerance
if APC not in danger, doesnt detect anything and will not present b7.
But T-cell still sees cognate peptide. T-cell not activated, it enters Anergy - unresponsiveness. T-cell will no longer respond to stimuli at all.
Describe inhibition of T-cell activation as means of tolerance
Signals from the TCR and cd28 co-stimulatory receptor = t cell starts expressing ctla4 on surface. displaces the b7 molecule on the APC from the cd28
the CTLA now binds to the B7, the cd28 is empty, the T cell is inhibited
describe belatacept
CTLA4 fused with modified Fc so it does not activate NK or macrophages
binds to B7 of APC from donor of graft, prevents signaling.
Decreases t cell activation
the CTLA is modified for higher affinity binding
ipilimuma
an anti-ctla-4 antibody that binds CTLA-4 on the T-cell, prvents B7 binding which would inhibit
increases T-cell activation
Overview of Negative selection (3)
deletes autoreactive T-cells based on tightness of binding to self peptide MHC
AIRE causes expression of peripheral antigens in thymus, therefore allowing deletion of reactive T cells
AIRE dysfunction leads to autoimmune disease (APECED)
Overview of regulatory T cells
suppress activation of potentially autoreactive T cells
are CD4+, CD25+, and FoxP3+
FoxP3 dysfunction leads to autoimmune disease (IPEX)
Can be generated in thymus or periphery
clonal anergy
if a T-cell doesnt receive a co-stim signal from APC, cell becomes unresponsible to activation
b cell tolerance (4)
clonal deletion
b cell anergy
functional deletion
suppression of activation
clonal deletion
BCR binds self antigen in bone marrow, does not leave. some die, but not all. some do receptor editing
b cell anergy
b cell anergy prevents immunity against soluble antigens. Will express IgD but not IgM
functional deletion is.
simply the loss of CD4 T-cell help.
destruction of T-cells that would be autoreactive also prevents them from activating autoreactive b-cells
loss of T-cell help means b cell responses are generally limited to IgM and short duration
pre-existing antibodies
can suppress activation of naiive b-cells.
b cells have Fc gamma RIIB, an inactivating Fc receptor. When the naiive b cell sees it’s antigen already decorated with IgG, Fc receptor causes it to not be activated
hemolytic disease of newborn
mother has Rh-. first child is Rb+
mom naive Rb B cells activated at first child, IgM produced, no complications
later child with Rb+, mom’s Anti-Rh memory b cells activated. IgG crosses placenta, big problem.
treatment/prevention of hemolytic disease of newborn?
add immunoglobulin late and during birth in mothers who are Rh-. Lots of Anti-Rh immunoglobulin.
It interacts with the B-cells inhibitory Fc receptor
Anargy b-cell overview
mechanism for removing B-cells tha respond to soluble, non crosslinking antigen
surface IgM expression is very low and anergic B-cell lifespan is very short
overview of antibody suppression
naiive b cell activation is suppressed by circulating pre-existing antibody to same antigen
occurs during rapid uptake of opsonized antigen and inhibitory acivity of Fc-yR2B
used clinically to prevent hemolytic disease of newborn
in general, what makes the best immunogens/antigens?
proteins
- they get bound to BCR
- antigen internalized and processed
- peptide fragment loaded onto MHCII
- t-cell recognizes specific peptide in MHCII
- t cell help initiates an effective antibody response
only proteins can be presented on MHC to T cells
larger antigen =
more b cell epitopes on antigen, more t-cell peptides, greater immune response
what do adjuvants do?
enhance immunogenicity.
not required by vaccines that contain attenuated or killed pathogens - patheogen itself provides the inflammatory stimulus needed.
clinically, ALUM is in vaccine preps that dont have whole cellular components
even among protein antigens, factors including __________________ determine degree of immunogenecity
size (bigger, more immunogenic), route of exposure (subdermal more immugenic) and foriegnness (more different from self = more immunogenic)
adjuvants are important for..
immune stimulation and vaccine effectiveness
uncontrolled expansion of activated T-cells is prevented by the interaction of..
CLTA-4 on activated T-cell and b7 molecules on the APC
