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Combating Disease > B & T cell development & mechanisms of immunological tolerance > Flashcards

B & T cell development & mechanisms of immunological tolerance Flashcards

1
Q

What is Bone structure and contain ?

A

Bone marrow structure is dynamic & complex containing Hematopoietic stem cells that differentiate into many cell types

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2
Q

B-cell development takes place?

A

Entirely in bone marrow

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3
Q

T cell progenitors begin ?

A

In bone marrow & complete development in thymus

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4
Q

What in the bone marrow provide support & growth

factors for lymphocyte development ?

A

Stromal cells and thymic

epithelial cells

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5
Q

Hematopoiesis stages are defined by ?

A

Cell-surface markers, transcription factor expression & receptor gene rearrangements

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6
Q

Central tolerance of T cells in thymus ?

A

Positive selection: MHC restriction

AND negative selection

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7
Q

Central tolerance of B cells in bone marrow ?

A

No need for MHC restriction

Only negative selection

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8
Q

B Lymphocytes derive from?

A

Hematopoietic stem cells in the bone marrow

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9
Q

B-cell development begins by?

A

Rearrangement of the heavy-chain locus

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10
Q

The pre-B-cell receptor tests for ?

A

Successful production of a complete heavy chain and signals for the transition from the pro-B cell to the pre-B cell stage

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11
Q

Pre-B-cell receptor signalling inhibits ?

A

Further heavy-chain locus rearrangement and enforces allelic exclusion

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12
Q

Pre-B cells rearrange the ?

A

Light-chain locus and express cell-surface immunoglobulin.

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13
Q

Immature B cells are tested for?

A

Autoreactivity before they leave the bone marrow – via central tolerance

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14
Q

B Lymphocytes that encounter self antigens for the first time in the periphery are ?

A

Eliminated or inactivated - via peripheral tolerance

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15
Q

B cell development ?

A

1st checkpoint: no more Heavy-chain gene rearrangements
- Allelic exclusion enforced
2nd checkpoint: Repeated attempts at Light-chain
rearrangements
Central Tolerance: B cell tested for self-reactivity (negative selection) before leaving

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16
Q

Negative selection purges B cells that are self-reactive?

A

3 different mechanisms:

  1. Receptor editing of V & J genes Light chain
  2. Anergy (inactivation)
  3. Clonal deletion (apoptosis)
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17
Q

What do Immature B cells arriving in the spleen do ?

A

Turn over rapidly and require

cytokines and positive signals through the B-cell receptor for maturation and long-term survival

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18
Q

T-cell progenitors originate in?

A

The bone marrow, but all the

important events in their development occur in the thymus

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19
Q

Commitment to the T-cell lineage occurs in the thymus following ?

A

Notch Signalling

20
Q

Where do T cells proliferate ?

A

Extensively in the thymus, but most die there

21
Q

Successive stages in the development of thymocytes are marked by ?

A

Changes in cell-surface molecules

22
Q

Thymocytes at different developmental stages are found in ?

A

Distinct part of the thymus

23
Q

T cells with α:β or γ:δ receptors arise from ?

A

A common progenitor

24
Q

Successful synthesis of a rearranged β chain allows?

A

The production of a pre-T-cell receptor that triggers cell proliferation and blocks further β-chain gene rearrangement

25
Q

T-cell α-chain genes undergo?

A

Successive rearrangements until positive selection or cell death intervenes

26
Q

Only thymocytes whose receptors interact with self peptide:self MHC
complexes can ?

A

Survive and mature

27
Q

Positive selection acts on?

A

A repertoire of T-cell receptors with inherent specificity for MHC molecules

28
Q

Positive selection coordinates?

A

The expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell

29
Q

Thymic cortical epithelial cells mediate ?

A

Positive selection of developing thymocytes

30
Q

T cells that react strongly with ubiquitous self antigens are deleted ?

A

In the thymus – this is negative selection and is driven most efficiently by bone marrow-derived antigen-presenting cells

31
Q

Thymic epithelial cells express?

A

High MHC I & II

32
Q

Developing T cells “browse” possible ?

A

Self-peptide/MHC complexes on thymic epithelial cells

33
Q

What does Transcription factor AIRE (autoimmune regulator) permit ?

A

Expression of hundreds of self antigens

34
Q

Positive selection detrmines?

A

Expression of either CD4 or CD8

35
Q

Negative selection of T cells?

A

TCRs bind too strongly so negative selection (deletion) occurs

36
Q

Positive selection of T cells?

A

TCRs bind “just right” so it progresses to single-positive stage
- These cells are MHC restricted

37
Q

T cells specific for self-antigen are removed in the thymus by negative selection via DC?

A

Tissue-specific proteins are expressed in on thymic dendritic cells & participate in negative selection:

  1. Strong binding leads to apoptosis
  2. Intermediate binding by Tregs
  3. No binding but can bind MHC by periphery
38
Q

Autoimmune regulator (AIRE) protein induces ?

A
  • Expression of tissue-specific proteins in thymic cells

- New T cells can be screened against these antigens safely in the thymus

39
Q

Most new T cells will die because ?

A

The signals from MHC:TCR are not strong enough (neglect)

40
Q

Some T cells will be positively selected because ?

A

MHC:TCR signals generate strong enough survival signals. From these cells, some will be negatively selected if the bind too strongly to MHC/self antigen. A small subset of these with slightly weaker interaction will become Tregs

41
Q

3 fates of peripheral T cells when they react strongly to self-antigen ?

A
  1. Negative selection by Apoptosis – Activation Induced Cell Death AICD - usually as a result of repeated antigen stimulation (evolved to deal with repeatedly meeting ‘self’ antigen in the periphery via Fas-FasL)
  2. A small population might become Anergic – due to a lack of co-stimulation. Normally during immune response, APCs will upregulate co-stimulation via pattern recognition. CTLA-4 rather than B7 induces anergy
  3. Tregs keep potentially self-reactive cells in check
42
Q

Explain the exposure of sequestered antigens ?

A

Some antigens never appear in thymus but can be later released into the circulation & potentially treated as foreign

43
Q

Underlying cause of autoimmunity can be through?

A

A fault in T-cell education & tolerance in the thymus

44
Q

Loss of tolerance: neoantigens?

A

A normal self antigen becomes modified & appears as a non-self antigen e.g. Infections, burns, uv exposure, drugs e.g. penicillin

45
Q

Loss of tolerance: Molecular Mimicry ?

A

Microbial antigens can have protein sequences that exactly

match human self antigens

Combating Disease (11 decks)

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