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MD1 Neuroscience > Self, Non-Self Discrimination > Flashcards

Self, Non-Self Discrimination Flashcards

1
Q

What is the site for central tolerance?

A

Thymus for T cells

Bone marrow for B cells

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2
Q

What is the site for peripheral tolerance?

A

Secondary lymphoid organs

Peripheral tissues

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3
Q

What are the mechanisms that induce tolerance?

A

Deletion
Anergy
Ignorance
Regulation

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4
Q

Which uncommitted progenitor gives rise to the development of B cells?

A

Common lymphoid progenitor (CLP)

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5
Q

Where do B cells develop?

A

Bone marrow

Also in neonatal spleen and liver

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6
Q

When does the generation of new B cells end?

A

Continues through life

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7
Q

What is the configuration of the BCR in a CLP?

A

In germline configuration

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8
Q

What happens in BCR development during the early pro-B cell stage?

A

DJ heavy chain rearrangement

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9
Q

How are genes chosen to make a BCR/TCR?

A

Enzymes come in and randomly chop DNA

Recombined via RAG

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10
Q

What happens in BCR development during the pre-B cell stage?

A

Heavy mu chain produced by combining V, D, and J segments

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11
Q

How many chances does a pre-B cell get to make a functional heavy mu chain?

A

2 because of 2 alleles

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12
Q

What happens to a pre-B cell that cannot make a functional heavy mu chain?

A

Die

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13
Q

How is a pre-B cell saved from death?

A

Heavy mu chain tested for functionality by pairing with surrogate chains > pre-BCR
Functional pre-BCR signalling engaged by dimerisation/oligomerisation - no Ag needed

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14
Q

What is the significance of pre-BCR testing?

A

Important checkpoint for transition of pro-B cell to pre-B cell

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15
Q

What enzyme is needed for pre-BCR signalling, and what disease occurs when this enzyme is not present?

A

Bruton’s tyrosine kinase

Disease: Bruton’s X-linked agammaglobulinaemia

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16
Q

How many chances does an immature B cell get to make a functional light chain?

A

4 because of 2 loci: kappa and lambda - on 2 alleles

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17
Q

Do BCRs on a B cell express both a kappa and lambda light chain?

A

No, only one type is used by a single B cell = isotypic exclusion

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18
Q

What is the transition between a small pre-B cell to an immature B cell?

A

Light chain and heavy chain forming IgM

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19
Q

What is the default response of lymphocytes during development?

A

To die - must be actively saved from apoptosis via signals

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20
Q

How does central tolerance of B cells work?

A

No self reaction in bone marrow > migrate to periphery > mature B cell
Multivalent self molecule binding > clonal deletion/receptor editing > apoptosis/generation of non-autoreactive mature B cell
Soluble self molecule binding (smaller signal) > migrates to periphery > anergic B cell
Low-affinity non-cross-linking self molecule binding > migrates to periphery > mature B cell (clonally ignorant)

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21
Q

Are there any self-reactive B cells in the periphery?

A

Yes, a little bit of self-reactivity goes through because of low signal or low affinity binding

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22
Q

Why is an anergic state of lymphocytes maintained in the periphery?

A

In case receptor strongly recognises foreign molecule

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23
Q

Is B cell central tolerance of equal stringency as T cell central tolerance?

A

No, B cell tolerance less stringent

24
Q

By when does the thymus fully develop?

A

Fully developed by birth

25
Q

When does the thymus start to involute?

A

During puberty

26
Q

What effect does DiGeorge syndrome have on the thymus?

A

Thymic aplasia because 3rd and 4th pharyngeal arches don’t develop properly

27
Q

Does T cell development continue throughout life?

A

Yes, but it sharply drops during puberty when thymus starts to involute

28
Q

What are the three main fates of thymocytes entering the thymus?

A

Alpha/beta T cells
Gamma/delta T cells
Invariant NKT cells

29
Q

What are alpha/beta T cells?

A

Conventional T cells

Further differentiate into CD4 helper T cells and CD8 killer T cells

30
Q

What are gamma/delta T cells?

A

Primarily located in epithelial and mucosal sites
Don’t have CD4 and CD8
Don’t undergo positive and negative selection
Produced earlier in embryonic development than conventional T cells

31
Q

What happens to double negative (DN)1 thymocytes?

A

TCR genes still in germline configuration

32
Q

What happens to DN2 thymocytes?

A

Become responsive to IL-2

Beta chain rearrangement starts

33
Q

What happens to DN3/4 thymocytes?

A

Rearrangement of beta chain continues

Pre-TCR testing determines whether cell expresses CD4 and CD8

34
Q

What happens to double positive (DP) thymocytes?

A

Rearrangement starts at alpha chain locus

Single beta chain can associate with many different alpha chains

35
Q

How many times can a thymocyte try and make a functional beta chain?

A

2 times because of 2 alleles

36
Q

What is positive selection?

A

Ensures thymocytes can recognise and bind to MHC

Determines whether or not cell will be CD4 or CD8

37
Q

Which cells do thymocytes bind to in negative selection?

A

Professional antigen presenting cells expressing self-Ag

38
Q

What is negative selection?

A

Thymocytes that recognise self-Ag strongly are deleted

39
Q

What does death by neglect involve in the thymus?

A

Thymocytes bind too weakly to MHC so they die because of too weak a signal

40
Q

What is the role of Tregs in peripheral tolerance?

A

Have intermediate self-reactivity

Suppress function of other T cells

41
Q

What do Tregs express?

A

CD25

Foxp3

42
Q

What do Tregs secrete?

A

IL-10

TGF-beta

43
Q

What is the defect in immunodysregulation polyendocrinopathy X-linked syndrome (IPEX)?

A

Foxp3

44
Q

What happens to mice who don’t express Foxp3, and what does this illustrate?

A

Develop autoimmune diseases

Removing just one peripheral tolerance mechanism causes autoimmunity > peripheral tolerance important

45
Q

What are the symptoms of Grave’s disease?

A 
Tachycardia
Loss of weight
Heat intolerance
Exophthalmos = abnormal protrusion of eyeballs
Sleep disturbances
Hot flushes
Agitated nervousness
46
Q

How is Grave’s disease mediated?

A

Autoimmune Abs produced against TSH receptor on thyroid gland > stimulates thyroid to produce hormone
Thyroid hormones shut down TSH production but have no effect on autoAb production > excessive thyroid production > hyperthyroidism

47
Q

How is myasthenia gravis mediated?

A

Ab blocks Ach receptor at NMJ

48
Q

What are the symptoms of myasthenia gravis?

A

Progressive weakness following diurnal pattern

49
Q

Why does decreasing the amount of Ach activity at the NMJ have such profound effects?

A

Small minute changes in fine control muscles have large effects
Eg: levator palpebrae superioris > person can’t keep eye open when looking up after a while

50
Q

What is the treatment in severe cases of myasthenia gravis?

A

Can elute Abs from blood but it’s not Ag specific

Danger of becoming vulnerable to other infections and diseases

51
Q

What is multiple sclerosis (MS)?

A

Loss of myelin sheath through autoimmune process
Debilitates nerve conduction
Can affect any part of CNS > people present with variety of symptoms

52
Q

Which immune cell is believed to be implicated in MS?

A

Th17 cells

53
Q

What is one possible treatment in development for MS?

A

Trying to trap autoreactive T cells in periphery

54
Q

What is molecular mimicry?

A

Pathogen derived Ags resemble self tissues

55
Q

What are two examples of where molecular mimicry occurs?

A

Rheumatic feveer

Guillain-Barre syndrome

56
Q

What are some possible environmental risk factors that cause tolerance failures?

A 
Industrialisation
Small family sie
Affluent, urban homes
Stable intestinal microflora
High antibiotic use
Low/absent helminth burden
Good sanitation > low orofaecal burden

MD1 Neuroscience (55 decks)

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