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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
What does the VDJ region constitute to?
Constitutes to highly diverse 3rd hypervariable region Ig CDR3 = complimentarity determining region Loops pop out of binding site Ab + allows recognition of Ag
26
Describe the light chain
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
Light chain rearrangement
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
What chromosome is the Lambda light chain on and how many segments of each region are there?
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
How is extra diversity generated?
By imprecise joining
30
How does recombination occur?
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
What are the function of the RSS segments?
Bring different components gene into mix - flanks all VDJ segments Ensure that correct joining of the segments occur via 12/23 rule
32
What is the 12/23 rule?
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
How are the segments chosen?
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
Where are double stranded breaks generated?
At the RSS junction by RAG1/RAG2 complexes via VDJ recombinase Creates hairpin end on coding region
35
What enzyme opens up the hairpin loops?
Artemis
36
How is extra diversity added into the hairpin loops?
Get addition or removal of bases using TdT
37
What is the role of DNA ligase and other factors?
Rejoin coding ends
38
What is deletion recombination?
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
Describe deletion recombination mechanism (same as earlier)
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
What is combinational diversity?
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
What is junctional diversity?
Addition and removal bases V,D,J junction | Largest contribution to diversity
42
Describe the specificities of junctional diversity
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
Describe the development of B cells
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
When do B cells become responsive to Ag?
At the immature B cell stage, NOT prior to that
45
How is self-recognition avoided?
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
When are B cells able to be activated?
Once in periphery, mature B cells capable being activated --> proliferation + differentiation into plasma + memory cells
47
What is an idiotype?
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
How are idiotypes clinically significant in SLE?
Idiotype 16/6 - unique to SLE .˙. can be used diagnostically
49
Describe SCID
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
What are autoimmune B cells?
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
How can autoimmune B cells occur?
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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