Tolerance And Regulation Of Lymphocyte Responses (16)

Question 1

What is the importance of immune regulation?

Answer 1

• to avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
• to prevent inappropriate reactions against self antigens

Question 2

What is autoimmunity?

Answer 2

• immune response against self antigen–> imbalance between immune activation and control
• disorders classified as “immune-mediated inflammatory diseases”
• systemic e.g. lupus or organ-specific e.g. Grave’s disease
• must have susceptibility genes and environmental trigger

Question 3

What are immune-mediated inflammatory diseases?

Answer 3

• chronic disease w/ prominent inflammation, often caused by failure of tolerance or regulation
• e.g. rheumatoid arthritis, IBS, MS etc…
• may result from immune responses against self antigens or microbial antigens in gut (Crohn’s?)
• systemic or organ specific
• may be caused by T cells or antibodies

Question 4

What is allergy?

Answer 4

• harmful immune response to non-infectious antigens that causes tissue damage and disease
• can be mediated by antibody (IgE) and mast cells–> acute anaphylactic shock
• or by T cells–> delayed type hypersensitivity

Question 5

What is hypercytokinemia and sepsis?

Answer 5

• too much immune response (systemic)
• often in a positive feedback loop
• triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate the response correctly

Question 6

What is the 3 signal model of licensing a response?

Answer 6

1. antigen recognition: cell sees antigen
2. co-stimulation: cell to cell contact–> molecules on APC clear a space called ‘immune synapse’ on T cell membrane, bringing all TCRs together, enabling them to crosstalk and activate cascade
3. cytokine release

Question 7

Why are immune responses self-limiting?

Answer 7

principal mechanism: immune response eliminates antigen that initiated the response, so the first signal for lymphocyte activation is eliminated

Question 8

What are the 3 phases of cell mediated immunity?

Answer 8

1. induction: MHC w/epitope on DC recognised by TCR and T cell activated
2. naive T cell becomes effector cell–> performs function and proliferates
3. memory: effector pool contracts to memory

Question 9

What is a resolution of an infection?

Answer 9

• no tissue damage- returns to normal

- phagocytosis of debris by macrophages

Question 10

What is repair?

Answer 10

healing w/ scar tissue and regeneration

- fibroblasts and collagen synthesis

Question 11

What is chronic inflammation?

Answer 11

active inflammation and attempts to repair damage are ongoing

Question 12

What molecule is a marker that makes immune cells inert/tolerant to persistent antigens (active control mechanism)?

Answer 12

PD-L1

T cells become harder to activate

Question 13

What is immunological tolerance?

Answer 13

specific unresponsiveness to an antigen, induced by exposure of lymphocytes to that antigen

N.B. all individuals are tolerant of their own antigens (self-tolerance)–> breakdown in self-tolerance leads to autoimmunity

Question 14

What is central tolerance?

Answer 14

• self-reactive T or B cells in lymphoid organs destroyed before they enter circulation
• if B cell recognises a (self) antigen in bone marrow, it dies by apoptosis
• T cell needs to be able to bind to self-MHC, but not too strongly (otherwise apoptosis is triggered)

Question 15

What is peripheral tolerance?

Answer 15

self-reactive T or B cells in the circulation are destroyed or controlled by the way that antigen is presented to them

N.B. some B cells change their specificity and some T cells develop into Tregs (suppress immune response and prevent autoimmunity)

Question 16

What is autoimmune regulator protein (AIRE)?

Answer 16

• a specialised transcription factor that produces the entire repertoire of human proteins by thymus cells–> and all loaded up onto self MHC
• promotes self tolerance
• mutations in AIRE lead to multi-organ autoimmunity, but better at responding to infections (as similar to self)

Question 17

What is anergy?

Answer 17

• mechanism of peripheral tolerance
• when a naive T cell sees its MHC/peptide ligand without appropriate co-stimulatory protein–> becomes anergic/tolerised

Question 18

What is ignorance?

Answer 18

• mechanism of peripheral tolerance
• antigen conc. too low or not enough T cells to get activated
• immunologically privileged sites (T cells cannot access) e.g. eye

Question 19

What is antigen-induced cell death?

Answer 19

• mechanism of peripheral tolerance
• death ligand, Fas induces apoptosis
• anergy but DEATH instead

Question 20

What are the subsets of CD4 Th cells?

Answer 20

• Th1: produce interferon gamma–> boosts intracellular immune response (anti-viral)
• Th2: produce IL4, IL5, IL13–> boosts anti-multicellular organism response e.g. against parasite
• Tfh (follicular helper T cells): produce IL21, activate B cells
• Th17: secrete IL17 in autoimmune disease e.g. arthritis; important for control of bacteria
• regulatory T cells (Treg): necessary to maintain tolerance to self antigens

Question 21

What is cross regulation by T cell cytokines?

Answer 21

one type of cytokine shuts down other pathways and boosts own, so no 2 type of CD4 helper response at same time

Question 22

What are T regulatory cells?

Answer 22

• subset of Th cells
• inhibit other T cells by producing IL10 (anti-inflammatory cytokine)
• make transcription factor Foxp3 that drives IL10 production (absence leads to broad systemic autoimmunity- IPEX syndrome)

Question 23

What are the different types of Tregs?

Answer 23

• nTreg (natural)

- iTreg (inducible) induced during immune response

Question 24

How can you lose tolerance?

Answer 24

• exposure to environmental antigens or self-antigens in the context of infections can alter tolerance–> e.g. bacteria Streptococcus pyogenes antigen looks like antigen on heart muscle
• exposure in the wrong place

Question 25

What is class switching under T cell influence?

Answer 25

• keep variable region the same, but antibody type changes
• cytokine production by T cell leads to different constant immunoglobulin genes being linked to variable region
• cytokine depends on type of Th cell