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Infection and Immunity > Antibody genetics 1 > Flashcards

Antibody genetics 1 Flashcards

1
Q

Where are B cells derived?

A

Directly from bone marrow

Originally develop in foetal liver @ 8-9wks gestation

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2
Q

Which 2 sets of organs make up the lymphoid system?

A
  1. Primary lymphoid organs - bone marrow = thymus

2. Secondary lymphoid organs - bone, spleen, liver, lymph nodes etc

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3
Q

Describe the maturation of lymphocytes

A

Pluripotent stem cells replicating in bone marrow
Develops into lymphocyte precursor

Mature B cells derive from lymphocyte precursor
Immature T cells derive from lymphocyte precursor + move out of bone marrow to thymus

In thymus become mature T cells via thymic education

Mature T cells move into circulation + mature B cells move into circulation

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4
Q

What are the 2 populations of mature lymphocytes in the circulation?

A

i. B cells from bone marrow

ii. T cells from bone marrow via the thymus

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5
Q

What is significant about these cells?

A

Each cell has its own specificity, produces >10^8 different cells - each with different specificity

Whole system to develop high numbers of different specificities of cell

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6
Q

What type of cells line the bone endosteum (inner surface of bone)?

A

Progenitor cells

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7
Q

What cells do progenitor cells associate with?

A

Associate with stromal reticular cells

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8
Q

What phenotypes are included in the umbrella of stromal reticular cells?

A

Lots of different phenotypes:
Fibroblasts
Endothelial cells
Myofibroblasts

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9
Q

What do SRC secrete and how does this aid B cell differentiation?

A

Secrete IL-7 which sustains B cell differentiation - recombination of receptors

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10
Q

How many progeny are produced from each progenitor and where do they migrate to?

A

64 different progeny which migrate to spongy centre of the bone

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11
Q

What happens after recombination of receptors and migration to the centre of the bone?

A

If receptor doesn’t work, cleared by macrophages

If productive BCR, adventitia reticular cells aid egression of mature B cells into central sinus -> sinusoids

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12
Q

How does B cell selection occur?

A

75% B cells don’t make it out of the bone - undergo apoptosis or phagocytosed by macrophages

B cells have survived have successful rearranged Ig gene

Auto-reactive B cells deleted by -ve selection

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13
Q

How many B cell genes are there and what is the B cell diversity?

A

35,000 genes

10^8 B cells

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14
Q

What was Paul Ehrlich’s Side chain hypothesis?

A

Each cell had multiple specificities but each receptor had 1 specificity
When a receptor binds the cognitive Ag, it dominates
Isn’t completely correct but did predict clonal selection and expansion

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15
Q

What is diversity amongst the B cell population?

A

Each cell has one specificity .˙. 1 receptor

When it binds Ag, that clone is identified and is proliferated

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16
Q

How is the diversity generated with such few genes?

A

1 gene not equal to 1 protein

Somatic recombination limited number of genetic segments can give many permutations

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17
Q

How was somatic recombination confirmed?

A

1976 by Tonegwa
Did southern blot analysis Ig gene in myeloma cell line compared with embryonic tissue (which was yet to rearrange B cell receptors)

Became evident that V+C regions were distant in embryonic cell, were close together in myeloma cells - suggests something removed from genetic material

Indicating recombination of genes

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18
Q

What are the mechanisms of diversity used by lymphocytes?

A

Somatic recombination - allows joining of one gene segment to another

Somatic mutation allows the sloppy joining of those segments with the addition of extra nucleotides

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19
Q

What do the mechanisms of diversity produce?

A

Heavy and light chains of Ig

B cell produces heavy + light chain independently - unique pairing of these = another level of diversity

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20
Q

What is the order of diversity generation?

A

Heavy chain rearrangement
If successful followed by K light chain
If unsuccessful followed by Lambda light chain

Hence many chances to produce a productive arrangement

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21
Q

On which chromosome are the VDJ segments found?

A

Chromosome 14

Components of Ig diversity region

22
Q

List the 3 genetic libraries and the number of segments they include

A

V region - 80 ( approx. 50 functional)
D region - 23 Dh segments
J - region 6 segments

Combo any 1 V w/ any 1 D and any 1 J forms functional heavy chain VDJ

23
Q

What is the function of the V region?

A

Codes for signal peptide which directs polypeptide to RER, golgi then out of cell/ onto cell surface

24
Q

How does VDJ recognition occur?

A

From germline DNA, developing B cell joins V region (V2) to D (D2) and J region (J3)
Gives functional VDJ region will bind to constant region
Cu (IgM) - naive B cell
or different (Ig isotype) later on immune response

First have joining Jh - Dh
Dh highly variable, both number of codons and sequence
3 possible reading frames - adds more diversity
can be used singly or used in combo

If Jh - Dh produces productive rearrangement heavy chain, B cell will add V region
DhJh signals rearrangement to Vh gene segment
Forms contiguous sequence ending in VhDhJh protein sequences

VDJ recombines to Cu if naive B cell/ 1 of other 8 C regions, after Ag experience eg. Cgamma, C epsilon, C alpha

25
Q

What does the VDJ region constitute to?

A

Constitutes to highly diverse 3rd hypervariable region Ig
CDR3 = complimentarity determining region
Loops pop out of binding site Ab + allows recognition of Ag

26
Q

Describe the light chain

A

Human K light chain on chromasome 2
31-35 functional Vk segments with promoter sequences 5’ to each one - no germline transcription

No Dk segments
5 Jk segments, 1 Ck segment

Additional diversity generated by sloppy end joining

27
Q

Light chain rearrangement

A

Germline DNA (rearranged to produce BCR) -> B cell DNA contains J region -> recombined to produce primary RNA transcript
Spliced to remove extra J regions (because primary nuclear RNA has additional J regions) to give mRNA
Transcribed to form K light chain

If non-productive VJ rearrangement created, other K allele used
Non-productive -> rearrangement of Lambda light chain

After Vlambda, Jlambda is combined, introns between VJ&clambda are cleaved out from 1 RNA transcript

28
Q

What chromosome is the Lambda light chain on and how many segments of each region are there?

A

Chromosome 22

V - 29-33 functional V lambda segments
J - 7-11 each linked to C lambda

Number of Jlambda Clambda sequences depend on haplotype

29
Q

How is extra diversity generated?

A

By imprecise joining

30
Q

How does recombination occur?

A

Occurs through utilisation highly specific signal sequences - RSS = recombination signal sequences

RAG1/RAG2 - recombination activating genes
Responsible for splicing out different part of gene segments

N-region junctional diversity by TdT - terminal deoxynucleotidyl transferase
Gives additional diversity

31
Q

What are the function of the RSS segments?

A

Bring different components gene into mix - flanks all VDJ segments
Ensure that correct joining of the segments occur via 12/23 rule

32
Q

What is the 12/23 rule?

A

In front of the segments are RSS sequences as follows:
Downstream (3’) of Vh, Vl, Dh will get:
Heptamer, 12 or 23 non-conserved base spacer, nonamer

Upstream (5’) of Jh, Dh, Jl are corresponding nonamer, spacer followed by a heptamer sequence

12/23 base-pair spacer corresponds to 1 or 2 turns of the double helix

12 only combines with 23, NOT with another 12
.˙. VJ cannot recombine in heavy chain without D in between ˙.˙ 12/12 don’t join

33
Q

How are the segments chosen?

A

Unknown
Portions of genes are made available to recombination machinary
2 selected coding segments and their RSS’s are bought together forming a chromosomal loop

34
Q

Where are double stranded breaks generated?

A

At the RSS junction by RAG1/RAG2 complexes via VDJ recombinase
Creates hairpin end on coding region

35
Q

What enzyme opens up the hairpin loops?

A

Artemis

36
Q

How is extra diversity added into the hairpin loops?

A

Get addition or removal of bases using TdT

37
Q

What is the role of DNA ligase and other factors?

A

Rejoin coding ends

38
Q

What is deletion recombination?

A

Major mechanism for most Ig + TCR recombination
Can get inversion in K chain V region (V+J in same orientation)
It is the process described

39
Q

Describe deletion recombination mechanism (same as earlier)

A

In germline Ig/TCR locus:
RAG1/RAG2 complexes bind to signal sequences of appropriate gene segments
Bring to segments together to form RAG synaptic complex

Double stranded breaks are generated @ RSS junction by RAG1/2 via VDJ recombinase
Creates hairpin end on coding region

Hairpins opened by Artemis and then TdT adds/removes bases to give extra diversity

Coding ends are then rejoined by number of factors including DNA ligase - have imprecise joining where nucleotides are added
Signal joint which is removed is a precise junction

40
Q

What is combinational diversity?

A

The fact that V(D)J regions can combine randomly creating many Ag specificities + have random pairing of VH + VL
Not all pairings will form functional receptors

41
Q

What is junctional diversity?

A

Addition and removal bases V,D,J junction

Largest contribution to diversity

42
Q

Describe the specificities of junctional diversity

A

RAG1/RAG2 breaks down DNA strands + Artemis open hairpin loop - done assymetrically .˙. 1 DNA loop larger than the other
Shorter strand extended w/ complimentary nucleotides to longer strand before ligation - P nucleotides

TdT then adds more N nucleotides
Adds non-germline sequence to mix
TdT mediated N-region diversity more common in heavy chains than light

Junctional sequence form CDR3 - 3rd hypervariable region

43
Q

Describe the development of B cells

A

Bone marrow stem cells develop into pro-B cells
Pro-B cells have limited phenotype - express little CD19+CD10
In bone marrow = Pre-B cell
Begins to rearrange heavy chain, express TdT + RAG enzymes - responsible for rearrangement BCR

Forms immature B cell - expresses heavy + light chain
RAG, CD19, Surface expression IgM = BCR

Then B cell leaves bone marrow into periphery where mature B cell expresses u chain + delta chain
B cell expresses surface IgM + IgD, light chain CD19 + mature B cell circulates in periphery

44
Q

When do B cells become responsive to Ag?

A

At the immature B cell stage, NOT prior to that

45
Q

How is self-recognition avoided?

A

In bone marrow get negative selection + receptor editing
If it binds self Ag rearrange the receptor
If rearranged receptor binds self Ag (ie. anything in bone marrow) - these B cells are deleted

46
Q

When are B cells able to be activated?

A

Once in periphery, mature B cells capable being activated –> proliferation + differentiation into plasma + memory cells

47
Q

What is an idiotype?

A

Region specific for Ab - could be its binding site
All Ab binding same epitope may share idiotype
Would be a novel structure and so may be recognised as non-self by rest of immune system

Could represent control system - idiotypes recognise idiotypes, Id anti-Id

48
Q

How are idiotypes clinically significant in SLE?

A

Idiotype 16/6 - unique to SLE .˙. can be used diagnostically

49
Q

Describe SCID

A

Severe combined immunodeficiency syndrome
Mostly male, affects approximately 1/50,000
Mutation in RAG1/2 meaning can’t rearrange either T/B cell receptor
Causes major compromise in immune response - most forms affect T cells but some affect both lymphocyte populations

50
Q

What are autoimmune B cells?

A

BCR editing occurs during B cell maturation bone marrow
Allows non-functional BCR to be deleted or replaced
If productive B cell receptor binds self Ag, B cell driven into apoptosis or doesn’t leave bone marrow
But some autoimmune B cells may leave

51
Q

How can autoimmune B cells occur?

A

B cells change receptors by affinity maturation
In 2 response improves - high affinity Ig dependent on T cell help from thymus

T cells educated in thymus and autoimmune T cells deleted - v. few auto-reactive T cells

B cells recognising auto-antigens don’t get help required to develop high affinity autoimmune response
.˙. auto-reactive IgM doesn’t cause issues

If IgM class switches to IgG with T cell help, this can become pathogenic
eg. rheumatoid arthritis - Ab against Ab
IgG rheumatoid factor pathogenic not IgM

Infection and Immunity (8 decks)

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