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3s2: Infection and Immunity > Week 4 > Flashcards

Week 4 Flashcards

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1
Q

What is a problem with current antibody generation?

A

10^10 to 10^11 different antibodies but only 21,000 genes

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2
Q

What is an overview of the steps from lymphoid cell to Pre-B cell?

A

Lymphoid cell –> Pro-B-cell via partial heavy-chain gene rearrangement
Pro-B-cell –> Pre-B-cell via complete heavy-chain gene reagrrangement

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3
Q

What is an overview of the steps from Pre-B cell to mature B cells?

A

Pre-B-cells –> Immature B cell via light-chain gene rearrangement
Immature B cell –> Mature B cell via change in RNA processing

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4
Q

What happens to mature B cells?

A

Antigen stimulation
Class switching between the different Ig cells
Some make memory B cells

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5
Q

What is needed of Ig models?

A

Vast diversity of antibodies specificities
Heavy and light chains of a variable region at the amino-terminal end with constant region at carboxyl-terminal end
Existance of isotypes with the same antigenic specificity

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6
Q

How can different isotypes have the same anitgenic specificity?

A

A given variable region with different heavy chain constant regions

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7
Q

What were the two orginal models to explain antibody diversity?

A

Germ-line theories - one gene coding for each antibody (impossible)
Somatic-variation theories - large number from small No of genes due to mutation or recombiaton (problem with regions staying constant)

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8
Q

What is the model for the generation of antibody diversity?

A

1965- Dreyer and Bennett suggest the two gene model
A recombination model

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9
Q

What is the two gene model?

A

Two seperate genes code for the varibale and constant parts of the heavy and light chains
Genes come togther at DNA level
100s or 1000s of V-region genes, with only a single C-region gene for each class

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10
Q

What was the work of Tonegawa and Hozumi in 1976?

A

The first direct evidence for separate gene segments encoding the V and C regions of Igs, which are rearranged durign cell differentiation

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11
Q

What is an overview of gene segments of alpha chain T cell receptors?

A

Variable - 50 genes
Diveristy - 0 genes
Joining - 70 genes
Constant - 1 gene

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12
Q

What is an overview of gene segments of delta chain T cell receptors?

A

Variable - 3 genes
Diveristy - 3 genes
Joining - 13 genes
Constant - 1 gene

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13
Q

What is an overview of gene segments of beta chain T cell receptors?

A

Variable - 57 genes
Diveristy - 2 genes
Joining - 13 genes
Constant - 2 genes

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14
Q

What is an overview of gene segments of gamma chain T cell receptors?

A

Variable - 14 genes
Diveristy - 0 genes
Joining - 5 genes
Constant - 2 genes

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15
Q

How are alpha chain T cell receptors made?

A

One variable and one joining domain are selected with constant
The mRNA is spliced to make this sequence
This is translated to produce mature alpha chain

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16
Q

How are beta chain T cell receptors made?

A

One variable, one diversity and one joining domain are selected with constant
The mRNA is spliced to make this sequence
This is translated to produce mature beta chain to complement the alpha chain to make mature T cell

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17
Q

What is similar abouth gamma and delta recombination?

A

They undergo a similar process
Alpha = Gamma
Beta = Delta

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18
Q

What is an approximate for TCR and b cells?

A

TCR alpha chain is approximate to the Ab light chain
TCR beta chain is approximate to the Ab heavy chain

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19
Q

What is an overview of antibody gene transcription location?

A

Kappa light chain - chromsome 2
Lambda light chain - chromosome 14

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20
Q

What is an overview of antibody gene transcription in germ-line DNA?

A

Each mutligene family contains several coding sequences, called gene segemnts, seperated by non-coding DNA

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21
Q

What is a breakdown in gene regions in the Lambda light chain region?

A

Variable - 31
Joining - 4
Constant - 7
Ordered to mixed, not all togetehr

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22
Q

What is a breakdown in gene regions in the Kappa light chain region?

A

Variable - 40
Joining - 5 (one is a pseudogene)
Constant - 1
All sections all together

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23
Q

What is a breakdown in gene regions in the heavy chain region?

A

Variable - 51
Diversity - 27
Joining - 6
Constant - 9

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24
Q

What is the leader sequence?

A

Guides peptide through ER cleaved off before assembly of finished Ig molecule
At start of every V gene

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25
How are Kappa anitbodies produced?
One varitation and joining gene is almost randomly selected, where the seperating DNA is removed or moved Typical transcription and splicing making mature mRNA which is translated The leader sequence is removed
26
How are heavy chain anitbodies produced?
D-J joining, with seperating DNA removed D-J segment is joined to V, and again seperating removed, creating VDJ DNA segment It is transcriped, alternate splicing of constant domain ie mew domain to make IgM or delta to make IgD Polyadenaylation and RNA splicing -> mRNA which is translated to make IgM or IgD domain
27
What are RSSs?
Recombination signal sequences which flank each germ-line V,D and J gene segment Conserved palidromic heptamers and AT-rich nonamer sequence
28
What is an overview of the location of RSSs?
One RSS is located 3' to each V gene segment One RSS located 5' to each J gene segment One on both sides of each D gene segment
29
What are the different types of RSSs?
One turn - 12 bp sequence Two turn - 23 bp sequence
30
What is the one-turn/two-turn joining rule?
Gene segments with a one turn signal sequence can only join to gene segment with a two-turn signal sequence
31
Why is the one-turn/two-turn joining rule importnant?
Ensures that a V segment only joins to a J segment and not another V segment for each light/ heavy chain
32
What is the function of RAG enzymes?
Involved in the recombination-activating genes (cleave DNA)
33
What is the function of TdT enzyme?
Terminal deoxynucleotidyl transferase )adds N nucleotides)
34
What is the function of HMGB1/2 enzymes?
High mobility group B proteins (stabilse RAG1/2 to RSSs)
35
What is the function of Ku70/80 enzymes?
WIth DNA-PKcs - binds DNA at DS breaks
36
What is the function of artemis enzymes?
Opens hairpins
37
What is the function of DNA ligation complex enzymes?
Ligats coding and signal joints
38
What is step 1 of recombination?
RAG1/2 and HMGB1/2 ind to the RSS and catalyse synapse formation between a V and J gene segement
39
What is step 2 of recombination?
RAG1/2 performs a single stranded nick at the exact 5' border of the heptameric RSSs bordering both the V and the J segments
40
What is step 3 of recombination?
The hydroxyl group that was liberated by the nick at the 3' end of the coding strand attacks the corresponding phosphate group on the noncoding strand of V and J segment This creates a covently sealed hairpin coding end and a blunt signal end
41
What is step 4 of recombination?
Signal end joining ligates the ends of the two RSS heptameric sequences that were originally in contact with the V and J coding sequences
42
What is step 5 of recombination?
Opening of the hairpin can result in a 5' overhang, a 3' overhang or a blunt end Artemis most commanly creates a 3' overhang
43
What is step 6 of recombination?
Cleavage of the hairpin generates sites for P nucleotide addition
44
What is step 7 of recombination?
Ligation of light chain V and J regions
45
What is important about step 8 - 10 of recombination?
They only occur in Ig heavy chains In TCRs where they occur in both alpha and beta chains
46
What is step 8 of recombination?
Exonuclease cleavage can result in the loss of nucleotides on either or both sides of the coding joint
47
What is step 9 of recombination?
Nontemplated nucleotides are added to the coding joint by TdT or occasionally by pol µ
48
What is step 10 of recombination?
Ligation of the heavy chanin by NHEJ DNA ligase complex
49
What is the end result of recombination?
The formation of a coding joint and a signal joint beteeen RSSs
50
What happens after the joining of the P and N nucleotides?
When VDJ recombination is complete, the sequence of each junciton is different from that predicted from the simple joining of the segments
51
What are Pnucleotides?
P nucleotides are 5' GA and opposite which are ligased togetehr
52
What is a overview fo N nucleotides?
Random nucleotides added by TdT in addition to P nucleotides
53
What is junctional flexibility?
Introduction of novel DNA sequences introducted at VDJ junctions (P and N nucleotides)
54
What is non-productive rearrangement?
A danger of the imprecise joining, the triplet reading frame of the joined Ig gne might be disrupted by generating premature stop codons
55
What can counter non-productive rearrangement?
B-cells are diploid, so if one allele rearranges non-productively the other allele may rescue the cell
56
What happens if both alleles are non productive?
Apoptosis Each VJ, DJ and VD joining reaction only 1 in 3 reactions result in productie rearrangement
57
How often to pre-B celll progress to maturity?
Only ~8% progress to maturity (this is reduced when they undergo tolerance mechanisms to remove self-reactive B cells, like T cells)
58
What is allelic exlcusion?
B cells only express the rearranged heavy and light chains from one chromosome eg do not rearrange two antibdy alleles independantly
59
What is the mechanism for allelic exlcusion?
Heavy chain rearrangement first sucessfully it inhibits rearrangement of the second allele, though fails second is attempted Also stimulates the rearrangement of light chain genes When both sucessful switches off all furhter rearrangments
60
What is a mechanism for antibody diverisity not seen in TCRs?
Somatic hypermutation
61
WHen does somatic hypermutation occur?
Occurs after rearrangement and after antigen stimulation As individual nucleotides in VJ or VDJ units are replaced (substiutions not indels) Mechanism not fully understood
62
What is the time frame of somatic hypermutation?
Occurs within the germinal centres in secondary lymphoid organs within a weekk of immunisation with antigen
63
What is the frequency of somatic hypermutation?
Every 10^-3 per base pair per generation Normal rate is 10^-8
64
Why does somatic hypermutation occur?
Hypermutations occur randomly throughout V(D)J, though some areas are more susceptible to increase affinity (affinity maturation)
65
What is a CDR?
Complementary determining region
66
What is key about CDR3?
Contain both P and N nucleotides With somatic hypermutations
67
What is a possible number of light and heavy chain associations in humans?
Heavy chains - ~8262 Light chains - ~320 Total - ~2,644,240
68
What can increase the number of possible chain combinations?
~2,644,240 doesnt consider P, N nucleotides and somatic hypermutation
69
What can decrease the number of possible chain combinations?
Not all heavy and light chains cna physically interact with one another Recombination process is not entirely random, so not all gene segments are used at the same frequency
70
What is class switching?
Only secreted antibodies After antigentic stimulation hevay chain DNA can undergo further rearrangement in which the VDHJ unit stay the same but constant domain changes Also called isotype switching
71
What is the first antibody produced?
IgM is first antibody produced VD is spliced to constant Mu region in mRNA Can switch to other constant regions - only constant region of heavy chain involved
72
What is the switch region?
DNA flanking sequence - 2-3Kb upstream from constant heavy chain which recombination enzymes recognise except delta chain
73
What is an overview of the switch region structure?
Vary in length, but contain groups of short repeated DNA sequences
74
What is an overview of switch recombinase?
Carries out the activation-induced cytidien deaminase This recombination results in the intervening DNA being lost making it irrevesible, though multiple switching events can occur
75
What are switch factors?
T helper cells make these TGFBeta (Mu to Alpha) IL-4 (Mu to Gamma 1 or Epsilon
76
How does class switching occur?
The switch factor will trigger the bringing in the Mu gene segment to the chosen one
77
What happens when the switch regions are brought togetehr?
Folding of DNA to bring the switch regions together DNA cleavage at that event, no P or N nucleotides Ligation of switch regions together, and removal of inbetween regions into circular region and degraded
78
Why can't you go back when class switching?
Heavy chain M and D are removed, though the other possible regions are still present to be switched too
79
What regulated class switching?
Through promoters, enhancers and sliencers So only occurs after rearrangement in B-cells and not in other somatic cells that have undergone rearrangement
80
How does the enhancer regulate class switching?
In non-rearranged DNA they are two far away to activate promoters Though after VJ or VDJ recombination has occured the enhancer is close to the promoter increasing expression by ~10,000 fold
81
What is an overview of oct-2?
Transcription factor oct-2, only found in B cells, binds to promoter elements in rearranged loci
82
What cause the change in secreted or membrane bound antibody?
4 poly-A sites If polydenation occurs at site 1 then encodes for secreted chain If polydenation occurs at site 2 then encodes for membrane chain due to having 2 poly-A segments

3s2: Infection and Immunity (12 decks)

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