9-immunological Tolerance And Autoimmunity

Question 1

Tolerogenic vs immunogenic antigens

Answer 1

Immunogenic: foreign antigen, only present in periphery (not primary lymph) and blood, encountered WITH co-stimulation, short lived and usually not around

Tolerogenic: self antigens/present during development, in generative organs (negative selection and central tolerance process), always there at high levels, exposure in primary lymph during maturation is assumed to be self–>tolerogenic, w/o co-stimulation (unless deficiency) lead to tolerance if activated

Question 2

List the 6 layers of tolerance

Answer 2

1) central tolerance
2) peripheral anergy
3) antigen segregation
4) regulatory T cells
5) functional deviation
6) activation-induced cell death

Question 3

What is central tolerance?

Answer 3

1 layer/most critical

Negative selection in bone marrow and thymus during b and T cell development (in primary lymph)

All other layers help to catch cells that escape central tolerance (in secondary lymph)

If B cell binds weakly to antigen= anergy

Question 4

What is peripheral anergy?

Answer 4

2nd most important
Location: secondary lymph

If fully mature T cell binds antigen in secondary lymph, strongly recognizes, but NO co-stimulation–> cell turned OFF= ANERGY

Cell eventually dies

Cellular inactivation by weak signaling without co-stimulation

Question 5

What is antigen segregation?

Answer 5

Physical barriers that separate immune cells from specific antigens that are kept away from lymph so they are not screened against

Physical barrier to self-antigen access to lymphoid system

(Ex: eye antigens)
If T cells are activated: they can enter any tissue they want

If barrier is compromised during injury, immune system can attack healthy eye

Question 6

How do regulatory T cells contribute to tolerance?

Answer 6

If they bind to self, they turn off everything else in the area

Question 7

What is functional deviation

Answer 7

Regulatory T cells telling other cells to switch what they are doing (limit inflammatory cytokines secretion)

Question 8

What is activation of induced cell death in terms of tolerance?

Answer 8

All activated lymphocytes are primed to die, the “live” signal is there while fighting, but once antigen is eliminated, effector cells die b/c the live signal is no longer overpowering die signal

Cells apoptose

Question 9

What is anergy?

Answer 9

Anergy is a PERMANENT state of unresponsiveness–> will NOT activate if it binds to antigen no matter how strongly it binds to antigen, no longer has ability to activate

B cells: if they bind weakly to antigen–>anergy

Question 10

What does AIRE do again?

Answer 10

Allows expression of antigens from other areas of the body in the maturation process in maturation tissues

Question 11

Once lymphocytes are mature and circulating…

Answer 11

Any antigen has the POTENTIAL to activate the lymphocytes

Question 12

Explain concept of costimulation

Answer 12

If there is no costimulation, it means the innate cells cannot recognize it and it is self antigen

(There are not receptors for self antigens in innate response)

Question 13

Difference between the two pathways in T cell peripheral tolerance?

What is the inhibitory receptor?

Answer 13

1) normal response: activation with costimulation= effector response
2) T cell anergy: if cell is missing costimulation or the cell is making inhibitory receptor= anergic next time it engages

CTLA-4= inhibitory receptor

Question 14

What is the inhibitory receptor of T cell peripheral tolerance?

Answer 14

CTLA-4 (on T cell, T cell is inhibited if CTLA4 binds CD80)

Question 15

What two things lead to anergy in T cell peripheral tolerance?

Answer 15

1) Recognizing self antigen without costimulation

2) Making inhibitory receptor/signaling block (CTLA-4) (if CTLA4 binds CD80 on APC

Question 16

How is a T cell suppressed?

Answer 16

No costimulation, regulatory T cell blocks activation

Question 17

Four things that can happen in T cell peripheral tolerance

Answer 17

1) normal response with costimulation
2) anergy: functional unresponsiveness (lack of costimulation or signal block)
3) suppression: via regulatory T cell (also blocks activation)
4) deletion: apoptosis

Question 18

Where can B cell anergy occur?

Answer 18

In bone marrow during negative selection if they have weak binding while maturing, they become responsive if bind to self

Question 19

3 things that can happen in B cell peripheral tolerance

Answer 19

Anergy (functional inactivation)
Deletion: apoptosis
Regulation by inhibitory receptors

Question 20

If anything causes breakdown of the barrier of antigen segregation what can happen?

What can cause barrier breakdown?

Answer 20

Can release segregated antigens and lead to autoimmunity: need the barrier to heal/rebuild so that there is no longer a source of that self/segregated antigen

Trauma or chronic infection that long term leads to tissue barriers being broken

Question 21

What are IPS (immune privileged sites)? And list them

Answer 21

Sites that are protected from immune response that are structured in a way that immune response doesn’t normally have access to it (trauma to gain access)

Include: brain, eyes, testes, uterus (fetus)

Question 22

What is unique about IPS communication and the body?

Answer 22

1) no lymph drainage
2) can exclude lymphocytes
3) tissues can express FAS ligand: triggers death pathway within cells (if lymphocyte binds tissue–> die lymphocyte die!)

Question 23

What does FAS ligand do and where is it expressed?

Answer 23

Expressed in IPS and triggers death pathway within cells (if lymphocyte binds tissue–> die lymphocyte)

Question 24

How do you tell the difference between bacterial and viral meningitis?

Answer 24

Meningitis is an infection of the brain/spinal fluid.
CSF should be clear in normal individuals

viral of this is still clear

bacterial has inflammatory response and is turbid: because Glucose levels decrease if bacterial (bacteria eat the glucose)

Question 25

What are the two forms of regulatory T cell action?

Answer 25

Extrinsic (cell acting on another cell) Intrinsic (signal from within the cell)

Question 26

What is the extrinsic function of regulatory T cells?

Answer 26

Cell acting on another cell Includes regulatory T cells exerting effects on activated t and B cells and APCs

Question 27

What is the intrinsic function of regulatory T cells?

Answer 27

Signal from within the cell Limits the size and duration of the immune response if clones of lymphocytes that are inherently programmed into cells. Activated lymphocytes are sensitive to apoptosis. Natural tendency of responding cells to die. Mediated by inherent death pathways and FAS

Question 28

When are regulatory T cells generated?

Answer 28

During negative selection

Question 29

What is foxP3 and its function

Answer 29

T.F. To associate with regulatory T cells: suppress the immune response like breaks on a car Inhibits T cell activation or inhibits T cell effector functions

Question 30

What happens to T cells once the antigen is eliminated?

Answer 30

They are no longer needed and only the death signal is left--> primed to die and apoptose

Question 31

What competition occurs between love and die signals?

Answer 31

Love overrides die while antigen is still present. When it is gone, did signal causes T cell apoptosis Death via death receptor or deficiency of survival signals

Question 32

Which cells remain after immune response?

Answer 32

Memory cells

Question 33

What two things must happen for an autoimmune condition to develop?

Answer 33

1) genetic predisposition: allows for more self-reactive cells to escape tolerance: failure of tolerance (more cells= more chance for self-reactive to react to self antigen), usually due to defect in single or multiple genes, higher rate of production of self reactive cells 2) environmental stimulus: usually infection *wrong cell* *wrong place* *wrong time* (Costim: wrong cell: self reactive lymphocyte) (site of inflammation) (costimulators present)

Question 34

Normal immune system process versus autoimmunity: type of antigen? Time to eliminate? Mediated by which cells? Abundance of antigen? Can any self reactive cell lead to autoimmunity?

Answer 34

Normal: trying to destroy a pathogen--> pathogen eliminated, IS ceases, memory cells develop and almost all activated immune cells die Auto: self antigen (which is ubiquitous and in excess) is not easily eliminated, takes time to develop, can be mediated by T Cells B cells or antibodies Note: activation of auto reactive lymphocytes does NOT mean autoimmunity (this happens frequently and is transient and nondestructive)

Question 35

Which two things can lead to autoimmunity? Which leads to tolerance?

Answer 35

1) Self-tolerance: leads to anergy or delection of self reactive cell 2) Induction of costimulators in APCs: leads to autoimmunity 3) Molecular mimicry: leads to autoimmunity

Question 36

Describe the two main processes that can lead to autoimmunity

Answer 36

1) Induction of costimulators on APCs: dendritic cells have both MHC classes so they can display costimulators for self antigen and activate the bad lymphocytes, thus leading to autoimmunity 2) Molecular mimicry: some of our antigens look very similar to foreign antigens, usually they use it to hide from us, but if we activate against that which looks like our own, we will cross react against our own similar antigen, thus leading to autoimmunity

Question 37

Which group of genes are most associated with self-reactivity?

Answer 37

MHC, because if you mess with MHC you mess with T cells

Question 38

Name four genes that contribute to genetic predisposition to autoimmunity when mutated

Answer 38

1) MHC: messes with T cell activation 2) AIRE: if you cannot express non thymic antigens in thymus--> more self reactive lymphocytes escape tolerance 3) FOXP3: (t.f. For main class of reg T cells) if no reg T cells or less reg T cells, don't have breaks on the car so self reactives can escape 4) FAS: if cells don't respond to death signals, more likely to damage host (mutation increases amount of self-reactive cells)

Question 39

Which defect causes ankylosing spondylitis? What kind of allele is it? When matching diseases with an allele and relative risk, what should you remember?

Answer 39

HLA-B27 (nearly a garuntee) (MHC allele) Closer to 100 = closer to 1:1 causal effect

Question 40

What happens if central tolerance fails? Peripheral tolerance?

Answer 40

If central tolerance fails: cells escape without undergoing negative selection--> crank out self reactive cells. More self reactive cells escape and enter periphery If peripheral tolerance fails: increases likelihood/allows for self-reactive cells to activate

Question 41

T/F we all make self-reactive cells, but layers of tolerance prevent autoimmunity

Answer 41

TRUE :)

Question 42

Define tolerance

Answer 42

The process used by the body, in particular the adaptive IS, to tolerate self antigens

Question 43

What is the difference between central and peripheral tolerance?

Answer 43

Central= activities that occur in central/primary lymph DURING MATURATION of lymphocytes (testing that occurs: b bone marrow and t thymus) Peripheral= activities that occur in peripheral lymph and occur AFTER LYMPHOCYTE HAS FULLY MATURED. To prevent mature lymphocytes from activating when they shouldn't