Lecture 19 - intro to immunological disorders

Question 1

what is immune discrimination?

Answer 1

between self and non-self
aka immunological tolerance

Question 2

what is immune system education?

Answer 2

the process of the IS learning tolerance

Question 3

where does the immune system education take place?

Answer 3

in the lymphoid tissue (primary and secondary lymphoid organs

Question 4

what is central tolerance and peripheral tolerance?

Answer 4

central = eliminates clones that recognise self
peripheral = silences anything that escapes the central tolerance

Question 5

describe the mechanism of central toelrance

Answer 5

immture lymphocytes with specificity for SELF antigens are either deleted (apoptosis) change their specificity (B cells only) or develop into Treg lymphocytes (CD4+ only)

Question 6

describe peripheral tolerance mechanism

Answer 6

some self reactive lymphocytes mature and enter peripheral tissues. lack of co-stimulation leads to an anergic cell, or apoptosis can happen

Question 7

what are the three mechanisms for T cell central tolerance?

Answer 7

• non-selection
• positive selection
• negative selection

Question 8

what is non-selection?

Answer 8

central tolerance mechanism when T cell receptors fail to bind with self MHC or do so very weakly
- aka death by neglect

Question 9

what is negative selection?

Answer 9

central tolerance mechanism when T cell receptors bind too strongly to self MHC peptides and are removed (otherwise could cause autoimmune)

Question 10

what is positive selection?

Answer 10

the 1-2% of T cells with the perfect TCR-MHC binding affinity and will display non-self peptides in the periphery

Question 11

how are T-cells educated on all self-antigens while remaining in the thymus?

Answer 11

thymic epithelial cells express extra-thymic antigens (outside-thymic antigens) so immature T cells can learn self antigens

Question 12

what event in the thymus causes an immature T cell to be negatively selected against?

Answer 12

when they bind very strongly to thymic epithelial cells presenting self antigens (very high affinity)

Question 13

what happens when an immature T cell is recognised as too self reactive/negative selection in the thymus

Answer 13

leads to apoptosis, but some can escape and instead differentiate into Treg cells (peripheral tolerance)

Question 14

what is the affinity model of T-cell selection?

Answer 14

model suggests that T cells with slightly higher affinity for self peptide/self MHC may be the ones selected to become Treg cells

Question 15

what is the main mechanism of central tolerance in B cells, and what does the cell end up like?

Answer 15

receptor editing
- can cause anergic B cell if affinity for self antigen is too low
- may cause apoptosis
- new non-self reactive B cell most times

Question 16

what is the process of receptor editing in B cells

Answer 16

• BCR receptor is endocytosed, the gene is modified and then receptor is re-expressed at the cell surface

Question 17

what are the three main mechanisms of peripheral tolerance?

Answer 17

• clonal anergy (the self reactive cells still exist but are inactivated - lack of co-stimulation maybe)
• suppression (the self reactive cells are present and potentially active but are monitored by Treg cells)
• immunological ignorance (self reactive cells are present but no not mount a pathological response)

Question 18

what is an immunologically privileged site?

Answer 18

a place where immune responses are naturally limited or suppressed to reduce risk of autoreaction

Question 19

true or false, B cell tolerance leads to T cell tolerance

Answer 19

false, its the other way round

Question 20

what happens when a normal B cell undergoes peripheral tolerance due to a faulty T cell, and how?

Answer 20

apoptosis. two mechanisms are:
- No CD4+ helper signal (no T cell, no TCR or no CD40L to bind CD40)
- Angergized T cell (TCR binds MHC, but there is no CD40L to CD40)

Question 21

what is autoimmunity due to?

Answer 21

a breakdown in tolerance

Question 22

what are the requirements for an autoimmune disease?

Answer 22

1: central tolerance mechanisms fai’
2: autoreactive clones bind self antigen
3: peripheral tolerance mechanisms fail
4: must lead to autoreactive tissue damage to cause disease.

Question 23

what normally contributes to autoimmune diseases?

Answer 23

genetic and environmental susceptibility paired with an infection or injury

Question 24

what happens in the beginning of an autoimmune disease?

Answer 24

1: infection or injury leads to an influx of self reactive lymphocytes leading to inflammation
2: autoreactive lymphocytes are activated and cause clinical damage

Question 25

what is sympathetic opthalmia?

Answer 25

damage to the eye after trauma releases 'immune privileged' antigens, leading to autoimmune disease on the eye

Question 26

how does molecular mimicry cause autoimmune diseases?

Answer 26

B and T cells cross-react with self peptides that look similar to a bacterial peptide after an infection

Question 27

how does multiple sclerosis happen?

Answer 27

human myelin protein in neural tissue looks very similar to Epstein-Barr virus protein (molecular mimicry) and cross-reacting antibodies cause damage to nerves

Question 28

how does type I diabetes work as an autoimmune disease?

Answer 28

the immune sytem attacks the beta-islet cells of the pancreas and insulin can't be produced. - poorly functional Treg response we dont know the driver behind this - TREATMENT WITH INSULIN INJECTIONS

Question 29

what is rheumatoid arthritis?

Answer 29

autoimmune attack on synovial tissue where rheumatoid factor binds patients own IgG - Treg functionality decreased - TREATMENT WITH LONG ACTING PENICILLIN

Question 30

what is coeliac disease?

Answer 30

reaction to gliadin from wheat leads to autoimmune inflammatory reaction in intestines, damages villi and reduces nutrient absorption - frequently leads to anemia

Question 31

what are common susceptibility genes that more often lead to autoimmune disease than normal?

Answer 31

polygenic traits within immune system - some types of HLA genes - some types of IgG and TCR genes - some types of complement genes - some regulatory genes (cytokines, costimulatory molecules)

Question 32

which gender more commonly gets autoimmune diseases and what does this tell us?

Answer 32

women are more likely to get autoimmune diseases this tells us that sex hormones may play a role

Question 33

what are the three mechanisms of disease specific autoimmune disease treatments?

Answer 33

- replacement (e.g diabetes with insulin injections and monitoring carb intake) - infection treatment (e.g monthly penicillin injections for rheumatic fever) - remove trigger (e.g coeliac disease - remove gluten)

Question 34

what kind of treatment is required for autoimmune disorders that can't use disease specific treatments?

Answer 34

most of them are palliative, so they act to dampen the inflammatory and immune responses.

Question 35

what are the three mechanisms to suppress immunity to treat autoimmune disorders?

Answer 35

- corticosteroids (inflammatory) - NSAIDs e.g ibuprofen (block pain and swelling symptoms - DMARDs (disease-modifying antirheumatic drugs, slow acting immunosuppressants such as methotrexate)

Question 36

what is a biologic treatment for autoimmune disease?

Answer 36

more specific treatment (but not disease specific), and acts on components of the immune response and not the whole immune response (e.g using TNF antagonists to prevent TNF driven inflammation in rheumatoid arthritis)

Question 37

what are the drawbacks of an autoimmune disease treatment and what recent event complicated this?

Answer 37

treatments can cause immune supression which increases susceptibility of people to other diseases. very hard to manage in global pandemics such as covid