L19: Introduction to Immunological disorders

Question 1

List the different mechanisms of immunological tolerance

Answer 1

1. central
2. peripheral

Question 2

explain what tolerance is

Answer 2

the education of the immune system to recognise self

Question 3

Where does education / tolerance take place

Answer 3

lymphoid tissue - where lymphocytes are found

Question 4

Where are the major sites of tolerance for central tolerance

Answer 4

thymus and bone marrow

Question 5

what are the major sites of peripheral tolerance

Answer 5

spleen, lymph nodes, tonsils, adenoids

Question 6

explain how central tolerance occurs

Answer 6

1. immature lymphocytes specific for self antigens may encouter these in the lymphoid organs
2. self-reactive immature cells are deleted, change their specificity (B cells), develop into regulatroy lymphocytes

too strong binding, no binding 203

Question 7

explain how peripheral tolerance works

Answer 7

1. Some self-reactive lymphocytes mature and enter peripheral tissues.
2. There they may be inactivated or deleted by encounter with self antigens in these tissues, or are suppressed by the regulatory T cells
   (peripheral tolerance).

anergy, apoptosis, suppression

Question 8

what are the three mechanisms of central tolerance?

Answer 8

non-selective (death by neglect)
positive selection
negative selection

Question 9

What is central tolerance based on?

Answer 9

mature T cells recognising both MHC and peptide - refers to the strength of binding

Question 10

explain death by neglect

Answer 10

TCR that fail to bind self MHC - 80%

aka non selection

Question 11

explain the term negative selection

Answer 11

TCR that bind too strongly to MHC - 20%

Question 12

explain the term psositive selection

Answer 12

1-2% lymphocytes whose TCR recognise self MHC not too strong/weak - displays non-self peptides in the periphery

Question 13

how do T-cells encounter self-antigen in the thymus?

Answer 13

1. thymic epithelial cells (TECs) express extra-thymic antigens
2. ETA are usually expressed in other tissues/organs
3. lymphocytes negatively selected when their affinity with self antigen-MHC complexed presented to TEC is very high - apotptotic death

Question 14

TEC

Answer 14

thymic epithelial cells

Question 15

how are Tregs developed?

Answer 15

some self reactive thymocytes are not deleted by differentiate into Tregs

Question 16

why are Tregs important

Answer 16

important for peripheral tolerance - otherwise you can get autoimmunity

Question 17

Explain the process of central tolerance in B cells

Answer 17

1. Immature B-cells recognise self antigens present at high concentration then B-cells edit sequence of BCR
2. If editing fails B cells maybe deleted (mechanism not well understood)
3. If self antigen recognition is weak the B cells become
   unresponsive and exit bone marrow in an ‘unresponsive’ state (anergic)

Question 18

What are the three mechanisms of peripheral tolerance

Answer 18

1. clonal anergy
2. suppression
3. immunological tolerance

Question 19

clonal anergy

Answer 19

Self-reactive lymphocytes still exist, but are
inactivated and are resistant to antigen stimulation.

Question 20

Suppression

Answer 20

Tregs control the activation of self-reactive lymphocytes

Question 21

Immunological tolerance

Answer 21

Self-reactive lymphocytes are present, but do not mount a pathological response

a) Antigens are sequestered in immunologically “privileged” sites (eg the anterior chamber of the eye or the testis)
b) B cells lacking adequate T cell help
c) Lack co-stimulation by other molecules

Question 22

explain peripheral tolerance in B cells

Answer 22

B cells require help form T-cells to triger antibody secretion
- t cell tolerance therfore leads to B cell tolerance

Question 23

define autoimmunity

Answer 23

failure of an organism to recognise its own molecules as “self” - loss of tolerance

Question 24

List the requirements for AID

Answer 24

1. Escape of autoreactive clones from thymus or bone marrow
2. Autoreactive clones encounter self-antigens
3. Peripheral tolerance failure
4. Autoreactive tissue damage

Question 25

explain the mechanism for AID

Answer 25

1. genetic susceptibility
2. infection or injury
3. influx self reactive lymphocytes
4. activation of self reactive lymphocytes

Question 26

how does genetic susceptibility affect AID

Answer 26

disrupt self tolerance mechanisms

Question 27

How does infection/injury affect AID

Answer 27

alter the way seld antigens are displayed

Question 28

Explain how an influx of self reactive LC affect AID

Answer 28

infection or injury induces inflammation

Question 29

What is molecular mimicry

Answer 29

component of pathogen has an epitope (small peptide piece) that resembles a self epitope. T and B cells think they look the same

Question 30

How does molecular mimicry occur (genetically)

Answer 30

The antigens/proteins on pathogen and self
are NOT the same, but they have stretches of
sequence that ARE the same

Question 31

give examples of AID

Answer 31

• ARF
• MS
• T1D
• Rheumatoid Arthitis
• Coeliac Disease

Question 32

what is the relenvance of genetics in developing and AID

Answer 32

• suscetibility can increase
• polgenic - many genes invoved in suceptibility
• environmental factors involved too

Question 33

Give some examples of genes involved in AID development

Answer 33

antigen presentation genes (MHC)
antigen receptr genes (TCR)
complement genes
regulatory genes (Cytokines)

Question 34

What are the treatment types for T1 AID

Answer 34

palliative - treat resulting deficits
- replacement (lost secretions)
- infection treamtnet (AB)
- remove trigger (gluten)

Question 35

What are the treatment types for T2 AID

Answer 35

• suppress immunity
• corticosteroids, NSAIDS, DMARDs