Central And Peripheral Tolerancre

Question 1

What is immune tolerance?

Answer 1

State of specific immunological unresponsiveness to substances that have the capacity to elicit an immune response

Question 2

What are the 2 layers of immune tolerance?

Answer 2

Central - during development
Peripheral - mature cells

Question 3

Why do we need immune tolerance?

Answer 3

To prevent autoimmunity
For pregnancy - fetus expresses foreign antigens.
Prevent allergy - harmless environmental antigens

Question 4

Immunogens vs Toleragens

Answer 4

Immunogens are substances that favour attack - immunogenicity
Toleragens are substances that favour tolerance

Question 5

Immunogens vs Toleragens dose level

Answer 5

Immunogens are optimal dose
Toleragens have either a very high or low dose

Question 6

Immunogens vs Toleragens persistence

Answer 6

Immunogens are short lived and Toleragens are prolonged

Question 7

Immunogens vs tolerances levels of co stimulation

Answer 7

Immunogens have high levels of co stimulation whereas Toleragens dont due to absense of danger

Question 8

Immunogens vs Toleragens portal of entry

Answer 8

Immunogens is subcutaneous or intradermal
Toleragens is oral or intravenous

Question 9

Central tolerance location

Answer 9

Primary lymphoid organs -
thymus for T cells
Bone marrow for B cells

Question 10

Central tolerance timing

Answer 10

Occurs during the early development of immature lymphocytes

Question 11

Central tolerance mechanism

Answer 11

‘The first filter’
Eliminates developing clones that react strongly to self-antigens before they enter the blood stream

Question 12

Peripheral tolerance location

Answer 12

Secondary lymphoid organs -
Spleen, lymph nodes
Also peripheral tissues

Question 13

Peripheral tolerance timing

Answer 13

Occurs continuously throughout life,
Acting on mature lymphocytes

Question 14

Peripheral tolerance mechanism

Answer 14

‘The safety net’
Silences or deletes self-reactive cells
That have escaped the central filter
This prevents tissue damage

Question 15

2 signal hypothesis for naive T cell activation

Answer 15

Signal 1 - TCR binds to MHC peptide on APC
Signal 2 - CD28 on T cell binds to CD80/86 on APC - co stimulation
Result = activation, proliferation (IL-2 production), + survival

Question 16

What happens if there is signal 1 (antigen) but not signal 2 (co stimulation)?

Answer 16

The T cell isn’t activated
It enters anergy
Even if it sees the antigen later with co stimulation it will remain unresponsive
This process is CRUCIAL for tolerance to self antigens on non professional APCs

Question 17

Anergy - what is it?

Answer 17

A state of long term functional unresponsiveness.

Question 18

Process of central tolerance for T cells

Answer 18

Progenitor cells arise in bone marrow + migrate to thymus
In thymus they rearrange TCR genes and undergo +ve and -ve selection
Only around 5% survive and exit as mature, self tolerant T cells

Question 19

Positive selection in the thymus for T cells

Answer 19

Occurs in cortex
Cortical epithelial cells present self peptides on MHC I + II
If the naive T cell recognises the self peptide on the MHC molecule it survives.
If the naive T cell doesn’t recognise and doesn’t bind it dies by apoptosis

Question 20

Result of +ve selection

Answer 20

Ensures T cells can interact with hosts own MHC molecules

Question 21

Negative selection in the thymus for T cells

Answer 21

Occurs in the medulla
Medullary epithelial cells + dendritic cells present seld antigens.
If the affinity of binding fro T cell is too strong ie high affinity there is CLONAL DELETION ie apoptosis

Question 22

Goal of -ve selection

Answer 22

Removes T cell with high potential to cause autoimmunity

Question 23

What is AIRE protein?

Answer 23

Transcription factor expressed in medullary thymic epithelial cells

Question 24

AIRE protein function

Answer 24

Forces expression of thousands of tissue specific antigens within thymus.
Exposes developing T cells to peripheral self antigens to ensure deletion of autoreactive clones

Question 25

What is a deficiency in AIRE called?

Answer 25

APECED autoimmune polyendocrinopathy candidiasis ectodermal dystrophy APS-1

Question 26

What is deficiency in AIRE caused by?

Answer 26

Mutations is AIRE gene

Question 27

What does APECED or APS-1 cause/

Answer 27

T cells specific for endocrine glands eg pancreas, adrenal are not deleted in thymus Patients then develop multi organ autoimmunity

Question 28

Central tolerance for B cells

Answer 28

Bone marrow checkpoints Immature B cells express membrane IgM. If they encounter multivalent self antigen in the bone marrow - receptor editing will occur.

Question 29

What happens if receptor editing fails?

Answer 29

Clonal deletion - apoptosis Anergy - for soluble, weak antigens

Question 30

Mechanism of receptor editing for B cell central tolerance

Answer 30

Strong self binding signals the cell to reexpress RAG1/RAG2 enzymes This causes the light chain to be rearranged again This creates a new BCR with new specificity

Question 31

Outcome of receptor editing of B cells.

Answer 31

If the new BCR is non autoreactive - survival and export If it is still autoreactive - apoptosis

Question 32

What does central tolerance miss?

Answer 32

Some antigens arise only during puberty or aging, after the T cell repertoire is established.

Question 33

What is Clonal ignorance?

Answer 33

Autoreactive T cells exist in periphery. They dont cause disease because they never encounter their specific antigen.

Question 34

Why do some autoreactive T cells never encounter their antigen ie Clonal ignorance?

Answer 34

Anatomic barriers - antigen is behind a barrier Low concentration - antigen levels too long to trigger signalling

Question 35

What are some immunoprivileged sites ie protected zones?

Answer 35

Brain Eye Testis Uterus These are sites where immune responses are restricted to prevent damage to vital organs.

Question 36

Mechanisms of protection of immunoprivileged sites

Answer 36

Physical barriers Anti inflammatory cytokines - TGF-b Constituitive expression of Fas ligand - induces apoptosis of entering T cells

Question 37

Mechanisms of peripheral tolerance

Answer 37

Anergy and checkpoints Deletion - AICD Suppression by Tregs

Question 38

Anergy and checkpoints

Answer 38

CTLA-4 = competes with CD28 for CD80/86 binding. Has higher affinity for it and sends a -ve signal PD-1 = binds to PD-L1 on tissues/tumours. Delivers inhibitory signals to prevent killing These are essential for preventing uncontrolled inflammation

Question 39

Deletion - AICD

Answer 39

Activation induced cell death This is how immune responses is turned off after infection clears. Repeated stimulation of T cells increases expression of Fas and Fas ligand. Fas ligand binding to fas triggers the caspase pathway which is apoptosis

Question 40

Suppression by T regs

Answer 40

These are specialised subset of CD4+ T cells. They actively inhibit activation and proliferation of other T cells They are crucial for maintains tolerance to self antigens and gut microbiota

Question 41

Types of T regs

Answer 41

Natural Tregs Induced Tregs

Question 42

Natural t regs

Answer 42

generated in the thymus during development Specific for self antigens

Question 43

Induced t regs

Answer 43

Generated in the periphery from naive T cells Induced by TGF-B and IL-2 Crucial for mucosal tolerance ie gut/lungs

Question 44

how do Tregs suppress?

Answer 44

Inhibitory cytokines - IL-10, TGF-b antiinflam Cytolysis - by granzyme/perforin Metabolic disruption - IL-2 sink starves other cells Targeting dendritic cells - CTLA-4 on Tregs removes CD80/86 for DCs

Question 46

Breg cells

Answer 46

Produce IL-10 Suppresses Th1 and Th17 responses Important in recovery from autoimmune inflammation

Question 47

Oral tolerance favouring tolerance

Answer 47

Gut = major site of tolerance Antigens administered orally tend to induce tolerance rather than immunity

Question 48

Low zone tolerance

Answer 48

Low levels and persistent levels of antigen T cells constantly stimulated but lack sufficient costimulation or inflammation Causes anergy or t reg induction

Question 49

High zone tolerance

Answer 49

Extremely high levels of antigen Causes exhaustion or deletion Immune paralysis System is overwhelmed and shuts down specific clones to prevent massive damage