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HD Exam 1 > Lectures 5 and 6, IG/TCR Variability Devo > Flashcards

Lectures 5 and 6, IG/TCR Variability Devo Flashcards

1
Q

In B lymphocytes, what is the name of the chains that undergo rearrangement?
What specific parts of each chain rearrange?

A

Heavy and light chains

  • Light: V J
  • Heavy: D J followed by V DJ
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2
Q

What is the name of the process whereby germline DNA rearranges?

A

Somatic recombination

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3
Q

What occurs after somatic recombination and prior to translation?

A

Splicing

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4
Q

Describe the path from HSC to mature B cell

A

HSC -> Pro-B cell -> Pre-B cell -> Immature B cell -> Mature B cell

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5
Q

*How do we know, during B cell development, that the cell has become a Pre-B cell?

A

Mew heavy chain is expressed

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6
Q

*How do we know, during B cell development, that the cell has become an immature B cell?

A

Surface IgM expressed

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7
Q

How do we know, during B cell development, that the cell has become an mature B cell?

A

Surface IgM and IgD expressed

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8
Q

*When, during B cell development, does heavy chain (D-J and V-DJ) rearrangement occur?

A

During pro-B cell stage

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9
Q

*When, during B cell development, does light chain (V-J) rearrangement occur?

A

During pre-B cell stage

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10
Q

What is allelic exclusion? Why does it occur?

How does it to occur?

A

Only 1 of the 2 alleles (chromosomes) is rearranged (you only want 1 heavy and 1 light chain to be rearranged)

  • As a result of allelic exclusion, all the antigen receptors on an individual lymphocyte will have the same AA sequence in the variable domain of the heavy chain
  • RAG
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11
Q

What protein cuts during light and heavy-chain gene rearrangement?

A

RAG-1/2

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12
Q

*How does RAG know where to cut?

A

Binds at a conserved sequence known as Recombination Signal Sequence (RSS)

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13
Q

During light chain gene rearrangement, where would RSS’s be found?

A

Downstream of V’s, upstream of J’s

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14
Q

During Ig gene rearrangement, what are the names of the fragments that form via RAG in B cells? T cells?

A

BRECs and TRECs
(B cell Recombination Excision Circle)
(T cell Recombination Excision Circle)

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15
Q

How could BRECs and TRECs be important clinically?

A

BRECs and TRECs indicate that new cells are being made. They dilute out over many cell divisions
- Important info to know for marrow transplants

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16
Q

*What mechanism allows for creation of Ig’s w/same variable domains that can be either secreted or membrane bound?

A

Alternative RNA splicing

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17
Q

Where is the most downstream place that RNA cleavage occurs, and is crucial for whether an IG is secreted or membrane-bound?

A

Poly-A tail

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18
Q

What’s a solid estimate of the amount of different epitopes we need?

A

~10 million (10^7)

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19
Q

What are the 3 methods by which such a large AB repertoire is generated?

A
  1. Combinatorial V(D)J gene joining
  2. N nucleotide addition by TdT (Terminal deoxynucleotidyl Transferase)
  3. Combinatorial association of H and L chains
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20
Q

How does TdT act to enhance AB diversity?

How many NT’s does it typically add?

A

After excision by RAG, rather than simple ligation TdT adds NTs b/w V(D)J segments randomly.
- Typically adds 1-20 NTs

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21
Q

How could TdT NT addition lead to problems?

A

If NTs aren’t added in units of 3, you would have a frameshift.

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22
Q

What happens to the cells if V(D)J rearrangements are nonfunctional?

A

They die

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23
Q

*What if V(D)J rearrangements react w/a multivalent self molecule?
What if they react w/ soluble self molecules?

A
  • They apoptose or undergo receptor editing

- They migrate to periphery and become anergic

24
Q

What happens to an immature B cell that does not react to self?

A

Migrates to periphery and become a mature B cell

25
Q

Where does receptor editing take place?

A

Bone marrow

26
Q

What is receptor editing?

What part of the B cell does it affect?

A

If B cell reacts to multivalent self molecule but doesn’t apoptose (because it hasn’t left marrow?), RAG is reactivated and light chain rearrangement continues
- Likely will no longer react to self

27
Q

*What are the names of the TCR chains? Compare them to BCRs/IGs.

A

Alpha and beta chains

  • Alpha similar to light chain (V + J)
  • Beta similar to heavy chain (V(D)J)
28
Q

Do T cells express Ig’s on their surface like B cells?

A

No

29
Q

Can T cells express Ig’s in membrane-bound and in secreted form?

A

No

30
Q

In the HSC, what is the state of the genes considered?

A

Germline (no rearrangements)

31
Q

T/F? A single pentameric IgG will express both kappa and lambda light chains?

A

False

32
Q

Do gamma-delta and alpha-beta T cells share rearranged TCR genes or not?

A

No–Both T cells, but have separate gene segments

33
Q

T/F, B and T cell leukemias express multiple TCR/BCR?

A

False–they are monoclonal

34
Q

*When only the heavy chain is expressed on a B cell’s surface, what stage is the cell at?
A type of IgM is still seen on the surface- What is this called?
What is the Ig/receptor called?

A
  • Pre-B cell stage
  • A surrogate light chain is expressed
  • Pre-B cell receptor
35
Q

*What is the purpose of having a pre-B cell receptor?

A

To shut off RAG, thus preventing further heavy chain gene rearrangement (important for allelic exclusion)

36
Q

What are the names of the 2 different light chains that can be made?
Which is made first?
What is the typical ratio in humans?

A
  • Kappa and lambda
  • Kappa is rearranged 1st
  • 65:35 kappa:lambda
37
Q

*How could the V(D)J rearranged heavy chain segment possibly lose it’s D?

A

If the V(D)J rearrangement leads to a (multivalent) self-reactive AB, receptor editing occurs if the cell survives. During receptor editing, a new V J rearrangement can occur that would delete out the D segments in a BREC, forming only a V-J segment.
(but doesn’t only the light chain undergo receptor editing?)

38
Q

If a heterozygote w/1 parent that passed on x-heavy chain and 1 parent that passed on y-heavy chain genes, which heavy chain would be expressed in a single Ig?
Would all Ig’s have x or y, or could some be x and some be y, or would most be mixed x and y?

A
  • Either all x or all y heavy chain would be expressed in each Ig due to allelic exclusion
  • Across all Ig’s, there could be some that are all x and some that are all y, but no mixed Ig’s.
39
Q

What is myeloma?

A

A type of cancer that begins in the bone marrow. It is a cancer of plasma cells (a type of B cell)
- Multiple myeloma is most common form

40
Q

What is leukemia?

What’s a major side effect?

A

A malignant progressive disease in which the bone marrow and other blood-forming organs produce increased numbers of immature or abnormal leukocytes.
- These suppress the production of normal blood cells, leading to anemia and other symptoms.

41
Q

What mechanism is responsible for an Ig’s w/ the same variable domains to have different constant domains? (e.g. IgA vs. IgD)

A

Alternative splicing (at RNA level)

42
Q

Once AB is already formed (e.g. IgM or IgD in B cell), how could these Ig’s become others such as IgG, IgE, or IgA? (Overall name of the process)

A

Isotype switching

43
Q

Where does isotype switching occur?

A

Secondary lymphoid tissue

44
Q

What protein is involved in isotype switching?
What is this analogous to in B cell gene rearrangements?

What is the site that this protein recognizes?
What is this analogous to in B cell gene rearrangements?

A

AID (analogous to RAG)

Switch regions (analogous to RSS)

45
Q

If an IgM undergoes isotype switching to become an IgG, could it ever go back to IgM?
Could it go on to become an IgA/IgE?

A

No (that segment has already been excised/used)

Yes

46
Q

Do IgM (produced first) and IgD on the surface of the same B cell have the same or different V regions?

A

Same (just different C regions)

47
Q

How can μ and δ heavy chains arise from the same transcript of a B cell?

A

Mew and delta (heavy) chains with the same Vh domain result from alternative splicing of primary transcripts (nuclear RNA).

48
Q

How do you calculate the maximum possible number of combinations (VDJ rearrangements) in a B cell?

A

V x #D (if present) x #J

product

49
Q

What % of T cells are gamma-delta (vs. alpha-beta)?

A

Only ~5%

50
Q

Identify the approximate number of heavy chain V, D and J gene segments in the B cell germline.
Identify the approximate number of light chain V and J gene segments in the B cell germline

A

Heavy: ~40V, ~25D, ~6J

Light (kappa and lambda): ~70V, 4-5J

51
Q

Immature B lymphocytes are called immature B lymphocytes because why?

A

They do not proliferate and differentiate in response to antigens.

52
Q

The RSS are highly conserved stretches of __-__ nucleotides separated by nonconserved ___ or ___ nucleotide spacers.

A

7-9

12 or 23

53
Q

T/F: In pre-B cells, both heavy and light chain genes are rearranged.

A

False- Light chain genes are in germline configuration (recall: pre-TCR)

54
Q

Do T cells do receptor editing?

A

No

55
Q

Which has a larger total diversity- TCRs or IG’s?

A

TCRs (10^18 vs. 10^13)

56
Q

T/F: At the immature B cell stage, once a B cell expresses a complete heavy or light chain, it cannot produce another heavy or light chain containing a different V region.

A

True. (but it can do receptor editing of the same chain)

HD Exam 1 (15 decks)

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