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Immunology > B cell development > Flashcards

B cell development Flashcards

1
Q

Where do B cells originate and mature?

A

Bone marrow

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2
Q

What are B cells? What are their general functions/

A

-They are a subset of lymphoid

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3
Q

What are B cells? What are their general functions/

A
  • They are a subset of lymphoid cells
  • they are anigen presening cells
  • when activated they are plasma cells
  • become memory cells
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4
Q

What are B cells? What are their general functions/

A
  • They are a subset of lymphoid cells
  • they are antigen presenting cells
  • when activated they are plasma cells
  • become memory cells
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5
Q

What determines the specificity of the antibodies?

A

The BCR-Ig receptor is the same specificity of the secreted antibody.

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6
Q

Describe the experiment in 1954 that lead to the discovery of role of B cells

A

Chicken’s small organ Bursa of Fabricius was removed, and chicken could not make antibodies to Salmonella.

In humans, we have bone marrow and secondary lymphoid tissues: spleen and lymph node.

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7
Q

Where is B cell development co-ordinated?

A

A complex genetic program in the bone marrow; there must be a single specific Ig BCR.

This is regulated.

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8
Q

What does humoral mean?

A

Soluble response.

B cells are known to link humoral and cell mediated responses of the adaptive system.

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9
Q

When in the B cell development do the different gene recombinations?

A

In PRO-B cells heavy chain is rearranged

In later PRE-B cells light chin is rearranged.

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10
Q

When in the B cell development do the different gene recombinations?

A

In PRO-B cells heavy chain is rearranged: V-D-J

In later PRE-B cells light chin is rearranged.: V-J

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11
Q

Where is B cell development co-ordinated?

A

A complex genetic program in the bone marrow; there must be a single specific Ig BCR.

This is regulated to avoid mutation causing immunodeficiency, and B cell malignancies and change in B cell tolerance.

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12
Q

Calculate diversity of heavy and light chains?

A

Heavy chain diversity 46 V genes multiplied by 23 D genes, multiplied by 6J genes = 6,348

Same with light chains types: (33 Vx5 J) + (38 Vx5 J) = 355
Combinatorial diversity:Total heavy chain x total light chain = 6,348 x 355 = 2.3e6.

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13
Q

What can add to combinatorial diversity?

A
  • Junctional diversity: nucleotides are added/removed
  • Receptor editing
  • Somatic hypermutation
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14
Q

What is X-linked Agammaglobulinemia?

A

A mutation on the Bruton’s tyrosine kinase (Btk) gene on the X chromosome (essential for B cell maturation) blocks this early maturation. No B cells mean antibody production is stopped. CD19 used as a B cell marker.

This causes recurrent bacterial infections

Treatment: Replace gamma globulin gene or prophylatic antibodies

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15
Q

What is Burkitt’s Lymphoma?

A

A condition where Ig heavy chain gene segment is fused with a protooncogene called MYC (a gene that regulates cell cycle)

This is caused deregulated DNA breakage and repair at Ig gene loci during rearrangements which brings MYC gene is close proximity to heavy chain.

Overexpression of MYC which may result in deregulated cell growth

Treatment: cytotoxic chemotherapy and Rituximab drug

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16
Q

What is Burkitt’s Lymphoma?

A

A condition where Ig heavy chain gene segment is fused with a protooncogene called MYC (a gene that regulates cell cycle)

This is caused deregulated DNA breakage and repair at Ig gene loci during rearrangements which brings MYC gene is close proximity to heavy chain.

Overexpression of MYC which may result in deregulated cell growth

Treatment: cytotoxic chemotherapy and Rituximab drug: to kill B cells.

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17
Q

What is Asplenia?

A

Where the spleen is missing. This means the patient is susceptible to encapsulated bacterial infections

Treatment: vaccination, and prophylactic antibodies.

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18
Q

What are some important roles of the spleen/

A
  • site of B cell final maturation
  • site of RBC development
  • it is a filter for the blood to remove damaged cells, or pathogens in the blood.
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19
Q

Where is B cell development co-ordinated?

A

A complex genetic program in the bone marrow; there must be a single specific Ig BCR.

This is regulated by signals from extracellular environment and BCR to avoid mutation causing immunodeficiency, and B cell malignancies and change in B cell tolerance.

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20
Q

The pathway of B cell development.

A

1) Hematopoietic stem cells: Before in yolk sac or fetal liver/spleen is where hematopoietic activity occurs. After birth, it is the bone marrow that contains stem cells.
2) there are a number of precursor cell types
3) First wave of Rag genes peaks means rearrangement of heavy chain at pro-B cell , then it declines
4) Large proliferation at large pre B cell due to BCR signalling.
5) Second wave of Rag genes rearranges light chain.

21
Q

What are the properties of a stem cell

A

1) differentiate into any cell

2) SELF-RENEWAL.

22
Q

List the cell types of B cell precursors that develop in the bone marrow in order

A

1) hsc
2) early B
3) Pro
4) Pre
5) large pre: recombines heavy chain and expressing heavy chain protein which forms the BCR
6) small pre- signalling from BCR causes downregulate previous BCR so heavy chain is inside cell where it combines with recombined light chain which forms a new mature, functional BCR on surface.
7) immature
8) mature which exit bone marrow as functional B cells.

23
Q

Describe an experiment to analyse B cell presursors

A

Each stage can be broken down by looking at membrane bound antigen.

Isolate Bone marrow cells, Stain the cells with various florescent antibodies and use flow cytometry to differentiate between each type of cell

24
Q

What do all B cells express on cell surface? What antigens define all the different stages of B cell development on a Fax plot?

A

B220+ on all cells

CD43, IgM, IgD

25
Q

Where is B cell development co-ordinated? What regulation is associated with this development?

A

A complex genetic program in the bone marrow; there must be a single specific Ig BCR.

This is regulated by signals from extracellular environment and BCR to avoid mutation causing immunodeficiency, and B cell malignancies and change in B cell tolerance.

Specific check points at specific stages in B cell development so damaged cells are eliminated early on to save energy taking them through full development.

26
Q

What environmental signals control B cell development? What does it control?

A

Bone marrow stromal cells lie directly beneath B cel with specific cell-cell contacts between the two.

The stromal cells secrete cytokines which control proliferation, survival and differentiation of B cells

Different cytokines and different cell contacts at different stages of differentiation.

27
Q

Describe stromal cell influence on HSC?

A

The FLT3 receptor on HSC precursor receives stromal cell FLT3 cytokine

FLT3: instructs HSC to maintain stemness properties and begins HSC down B cell pathway.

28
Q

Describe stromal cell influence on early Pro B cells?

A

early Pro-B cells express another receptor called C-kit with binds to stromal cell ligand stem cell factor (SCF)

Signals activate further proliferation, survival and differentiation.

29
Q

Describe stromal cell influence on late Pro B cells to Pre B cells ?

A

The late pro B cell now expresses IL-7 receptor.

Stromal cells produce IL7 which bind to Pro B cell receptor and it becomes a Pre B cell.

This means there is a large population expansion.

30
Q

What is the role of each stromal cell secretions on B cell development?

A

FLT3 ligand: ensures HSC survival

Stem cell factor: survival of HSC and proliferation to early Pro- B cells

IL7: Causes proliferation of Pro-B and Pre-B cells.

31
Q

What is Flt3 ligand? Why is it important?

A

A growth factor secreted by BM stromall cells that stimulates proliferation of HSC/early progenitors when it binds to tyrosine kinase receptor on B cell.

Without Flt3 receptor gene, patients don’t respond to ligand cytokine which decreases B cell progenitors and therefore mature B cells; it is needed to commit stem cells.

32
Q

What is Stem cell factor? Why is it important?

A

It binds to tyrosine kinase receptor C-kit and acts to increase survival of HSC, self renew and maintain HSC.

It is important because it induces IL7 receptor expression

33
Q

What is IL7 and why is it important?

A

Interleukin-7 B cell precursor growth promoting factor produced by stromal cells. It regulates thymocyte survival of mature T cells too.

34
Q

Describe the IL-7 receptor on B cell and the impact of binding to IL7.

A

It is a dimeric polypeptide containing an alpha chain and a common gamma chain.
- Binding of IL7 activates Jak kinases which phosphorylate transcription factor STAT5 which induces transcription of target genes. This leads to proliferation.

  • Promotes survival of B cells via transcription of pro-survival genes like BCL2.
  • PIK Kinase signalling induces RAG gene expression and V-D-J recombination and therefore determines differentiation. Here it specifically inhibits the light chain loci so RAG genes cannot access until the correct stage in development
35
Q

What is the combined action of all the released cytokines , FLT3, SCF, IL7 and adhesion CAM?

A

To generate movement of cells from HSC (pluripotent potential) into a committed pro-B cell stage starting to recombine V-D-J. (B cell lineage genes switched on and other lineages are maintained OFF)

36
Q

What are the two checkpoints of B cells that check the gene recombination?

A

Checkpoint 1: Is there a functional heavy chain (V-D-J)? In the late PRO b cell. This is mediated by a functional pre-BCR

Checkpoint 2: Is there a functional light chain (V-J) At the SMALL PRE-cell. This is mediated by the final mature BCR

37
Q

What is the purpose the the two checkpoints?

A

The recombination process is not precise; if unproductive there will be no Ig chains and therefore no B cells.

there must only be one (of two loci) to recombine. If rearrange both loci differently, there will be antibodies with two different antigen specificity

38
Q

Describe checkpoint 1

A
  • Heavy chain rearrangement D-J on BOTH chromosomes at EARLY PRO b cell
  • at LATE PRO b cell, one of D-J rearrangements undergoes V-D-J recombination
  • non-productive rearrangments of second D-J chromosome dies via apoptotis
  • productive V-D-J chromosome forms chains with temporary V-preB/lamda5 light chain.
  • This forms functional pre-BCR
  • This allows cell to survive and differentiate into pre-B cells.
39
Q

How many cells manage to pass checkpoint 1? What can be done to change this?

A

50% cells manage to make functional rearrangements/heavy chain and functional PRE BCR.

There is a second chromosome however, per cell, so this can be used as a second attempt to

40
Q

What is the purpose of allelic exclusion?

A

Only one specific antigen receptor expressed with allows for high affinity binding; one copy heavy chain locus, one copy light chain locus.

It is caused by the downregulation of RAG1/2 after the expression of a functional pre-BCR (containing recombined heavy chain) so no recombination of second loci

41
Q

Describe the surrogate light chain. What happens when ligand binds?

A

-VpreB/lamda 5 do not have hypervarible regions so independant of antigen. They do have extended terminal tail domains which interact with ligands. This is needed for preBCR signalling.

Ligand binds:

42
Q

What happens when ligand binds to preBCR? What is the stages of development after this point?

A

1) Suppression of H chain rearrangment so only one AB specificity
2) Triggers entry into cell cycle so large Pre-B cells with PRE-BCR are clonally expanded containing identical heavy chains
3) proliferation stops and pre-BCR is lost when lamda5/VpreB are downregulated
4) Re-expression of Rag1/2 so intracellular V-J rearrangment of one light chain locus
5) final BCR specific for one antigen on surface of an immature B cell

43
Q

Describe checkpoint 2

A

Here the functional BCR is checked; no BCR cell dies therefore it selects for functional light chains.

one kappa Light chain and one lamda chain is rearranged which can form full BCR.

44
Q

Describe checkpoint 1

A

If not preBCR, cell dies, therefor it selects for functional heavy chains

  • Heavy chain rearrangement D-J on BOTH chromosomes at EARLY PRO b cell
  • at LATE PRO b cell, one of D-J rearrangements undergoes V-D-J recombination
  • non-productive rearrangments of second D-J chromosome dies via apoptotis
  • productive V-D-J chromosome forms chains with temporary V-preB/lamda5 light chain.
  • This forms functional pre-BCR
  • This allows cell to survive and differentiate into pre-B cells.
45
Q

How many cells manage to pass checkpoint 1? What can be done to change this?

A

50% cells manage to make functional rearrangements/heavy chain and functional PRE BCR.

There is a second chromosome however, per cell, so this can be used as a second attempt to make preBCR.

46
Q

Describe the surrogate light chain.

A

-VpreB/lamda 5 do not have hypervarible regions so independant of antigen. They do have extended terminal tail domains which interact with ligands. This is needed for preBCR signalling.

47
Q

Describe negative selection of the immature B cells

A

This is needed for self tolerance; early in development B cells are self-reactive, and polyreactive to lots of antigens, negative selection causes immature cells to not be polyreactive.

48
Q

Describe selection in terms of signal strength

A

To strong signal: Deletion of receptor editing

Weak binding: anergy

49
Q

What are three mechanisms of negative selection if cells are self reactive?

A

1 )Deletion

2) Anergy results when cell recognises soluble antigen not on a surface: although cell survives, cells do not function/not responsive due to weak signal, and no cross linking with antigen.
3) Receptor editing: where the specificity of variable region segments is altered.via arrest of self recognition BCR, followed by the reactivation of RAG1/2 so rearrangement of loci that recognise different antigen.

If cell is incorrect after this, it is inactivated or killed

Immunology (19 decks)

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