9-immunological Tolerance And Autoimmunity Flashcards Preview

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Flashcards in 9-immunological Tolerance And Autoimmunity Deck (43):

Tolerogenic vs immunogenic antigens

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


List the 6 layers of tolerance

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


What is central tolerance?

#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


What is peripheral anergy?

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


What is antigen segregation?

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


How do regulatory T cells contribute to tolerance?

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


What is functional deviation

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


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

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


What is anergy?

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


What does AIRE do again?

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


Once lymphocytes are mature and circulating...

Any antigen has the POTENTIAL to activate the lymphocytes


Explain concept of costimulation

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)


Difference between the two pathways in T cell peripheral tolerance?

What is the inhibitory receptor?

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


What is the inhibitory receptor of T cell peripheral tolerance?

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


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

1) Recognizing self antigen without costimulation
2) Making inhibitory receptor/signaling block (CTLA-4) (if CTLA4 binds CD80 on APC


How is a T cell suppressed?

No costimulation, regulatory T cell blocks activation


Four things that can happen in T cell peripheral tolerance

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


Where can B cell anergy occur?

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


3 things that can happen in B cell peripheral tolerance

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


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

What can cause barrier breakdown?

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


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

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)


What is unique about IPS communication and the body?

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!)


What does FAS ligand do and where is it expressed?

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


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

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)


What are the two forms of regulatory T cell action?

Extrinsic (cell acting on another cell)

Intrinsic (signal from within the cell)


What is the extrinsic function of regulatory T cells?

Cell acting on another cell

Includes regulatory T cells exerting effects on activated t and B cells and APCs


What is the intrinsic function of regulatory T cells?

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


When are regulatory T cells generated?

During negative selection


What is foxP3 and its function

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


What happens to T cells once the antigen is eliminated?

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


What competition occurs between love and die signals?

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


Which cells remain after immune response?

Memory cells


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

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)


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

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)


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

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


Describe the two main processes that can lead to autoimmunity

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


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

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


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

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)


Which defect causes ankylosing spondylitis? What kind of allele is it?

When matching diseases with an allele and relative risk, what should you remember?

HLA-B27 (nearly a garuntee) (MHC allele)

Closer to 100 = closer to 1:1 causal effect


What happens if central tolerance fails? Peripheral tolerance?

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


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



Define tolerance

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


What is the difference between central and peripheral tolerance?

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