MCM 2-16 Immune Regulation

Question 1

describe immunological tolerance

Answer 1

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.

Question 2

tolerance mechanisms are one of three types

Answer 2

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

Question 3

mechanisms of T-cell tolerance

Answer 3

negative selection
regulatory T-cells
Clonal Anergy
activation inhibition

Question 4

what does positive selection select for?

Answer 4

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.

Question 5

What does negative selection select for?

Answer 5

selects for TCR that recognizes/moderately binds MHCII without becoming activated

Question 6

what is AIRE? what does it do?

Answer 6

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.

Question 7

AIRE dysfunction leads to

mutations in AIRE are what type of mutation?

Answer 7

autoimmunity. Autoreactive CD8+ T-cells escape to periphery, and cause APECED (autoimmune polyendocrinopathy candadiasis ectodermal dystrophy)

loss of function

Question 8

what are the receptors on regulatory T cells?

Answer 8

CD25 - high affinity IL-2 Receptor
CD4
TCR
CTLA4-binds to b7 costimulatory molecules on APC’s

Question 9

what is the definitive marker of Treg

Answer 9

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

Question 10

What results from FOXP3 dysfunction?

Answer 10

IPEX syndrome

• no Tregs
• allergy
• severe autoimmunity
• female carriers
• males affected

Question 11

how do Treg promote tolerance?

Answer 11

1. Treg locates APC displaying Self-antigen
2. Treg is activated but does not proliferate
3. 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

Question 12

how are Tregs generated?

Answer 12

Thymic Tregs arise during positive selection in thymus

induced Tregs differentiate in periphery

Question 13

Describe establishment of Anergy in t-cell tolerance

Answer 13

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.

Question 14

Describe inhibition of T-cell activation as means of tolerance

Answer 14

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

Question 15

describe belatacept

Answer 15

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

Question 16

ipilimuma

Answer 16

an anti-ctla-4 antibody that binds CTLA-4 on the T-cell, prvents B7 binding which would inhibit

increases T-cell activation

Question 17

Overview of Negative selection (3)

Answer 17

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)

Question 18

Overview of regulatory T cells

Answer 18

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

Question 19

clonal anergy

Answer 19

if a T-cell doesnt receive a co-stim signal from APC, cell becomes unresponsible to activation

Question 20

b cell tolerance (4)

Answer 20

clonal deletion
b cell anergy
functional deletion
suppression of activation

Question 21

clonal deletion

Answer 21

BCR binds self antigen in bone marrow, does not leave. some die, but not all. some do receptor editing

Question 22

b cell anergy

Answer 22

b cell anergy prevents immunity against soluble antigens. Will express IgD but not IgM

Question 23

functional deletion is.

Answer 23

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

Question 24

pre-existing antibodies

Answer 24

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

Question 25

hemolytic disease of newborn

Answer 25

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.

Question 26

treatment/prevention of hemolytic disease of newborn?

Answer 26

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

Question 27

Anargy b-cell overview

Answer 27

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

Question 28

overview of antibody suppression

Answer 28

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

Question 29

in general, what makes the best immunogens/antigens?

Answer 29

proteins

1. they get bound to BCR
2. antigen internalized and processed
3. peptide fragment loaded onto MHCII
4. t-cell recognizes specific peptide in MHCII
5. t cell help initiates an effective antibody response

only proteins can be presented on MHC to T cells

Question 30

larger antigen =

Answer 30

more b cell epitopes on antigen, more t-cell peptides, greater immune response

Question 31

what do adjuvants do?

Answer 31

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

Question 32

even among protein antigens, factors including __________________ determine degree of immunogenecity

Answer 32

size (bigger, more immunogenic), route of exposure (subdermal more immugenic) and foriegnness (more different from self = more immunogenic)

Question 33

adjuvants are important for..

Answer 33

immune stimulation and vaccine effectiveness

Question 34

uncontrolled expansion of activated T-cells is prevented by the interaction of..

Answer 34

CLTA-4 on activated T-cell and b7 molecules on the APC