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CMB2004 > L2 - Genetics of antigen recognition receptors (antibodies) > Flashcards

L2 - Genetics of antigen recognition receptors (antibodies) Flashcards

1
Q

What are the V & C regions of antibody & TCR polypeptide chains are encoded by?

A

Separate gene segments that rearrange during lymphocyte differentiation

Domains are encoded by very small mini genes

There are bits in-between V & C

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2
Q

What are the bits in-between V & C?

A

D = diversity

J = joining

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3
Q

What is the V region of H chains & TCR-beta encoded by?

A

V
D
J

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4
Q

What is the V region of L chains & TCR-alpha encoded by?

A

V

J

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5
Q

What do V, D & J encode?

A

V region of H chains & TCR-beta

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6
Q

What do V & J encode?

A

V region of L chains & TCR-alpha

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7
Q

Rearrangement of Ig genes in B cells

A

Genes rearrange during B cell development to form a functional gene

The genes in B cells are closer than in every other type of cell in the body

DNA is different in B cells than every other cell

B cells break their DNA in a way no other cells do (apart from T cells) & move genes so they are closer

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8
Q

How do B cells produce a functional immunoglobulin?

A

Involves recombination to bring gene segments together

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9
Q

Light chain of an antibody

A

After DNA breaks, a single V & a single J gene segment are joined together to encode the V region of the light chain

The 2 exons come together

DNA is broken randomly to bring 2 of each together randomly

Leads to different BCRs in every cell

B cell has to decide to break its DNA at one locus – either lambda or kappa

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10
Q

What happens once V & J are next to each other for the light chain?

A

It gets transcribed into RNA like a normal gene making the light chain – can then fold up to form a unique antigen binding site

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11
Q

Heavy chain of an antibody

A

Similar mechanism but extra sequence section with the D region

2 breaks needed

A single V, D & J gene fragment are joined together to encode the V region of the heavy chain

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12
Q

Order of breakage in the heavy chain

A

Each B cell first breaks between D & J to bring them together

Then is sequentially broken again & the DJ joins the V

Lots of combinations – every V can go with every D & J

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13
Q

What forms the binding site?

A

Variable regions of H & L chain

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14
Q

Hierarchy of rearrangements for both heavy and light chains

A

First H chain genes – D-J then V-D

Then light chain genes – kappa first (V-J)

If kappa rearrangement unsuccessful then lambda genes rearrange

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15
Q

What chain has greater variability?

A

Greater variability in H chain as V, D & J

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16
Q

What loci are the H, kappa & lambda chains encoded?

A

H chain – chromosome 14

Kappa chain – chromosome 2

Lambda chain – chromosome 22

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17
Q

What isotope are most antibodies at the start?

A

IgM

18
Q

What does RSS stand for?

A

Recombination signal sequences

19
Q

What are RSS?

A

DNA rearrangement is guided by special sequences flanking the V, D & J regions = RSS

Involves a complex of enzymes = V(D)J recombinase (recombination activating gene – RAG)

20
Q

What are RAG genes?

A

Recombination activating gene

21
Q

What are the 2 types of RAG genes?

A

RAG-1 & RAG-2

Encode lymphoid-specific components of the recombinase

22
Q

Where are RAG genes expressed?

A

Only in B & T cells
Recognise the RSS to do the breaking

Can put RAG genes into cells that don’t express them to show they break DNA

23
Q

What happens if theres mutations in the RAG genes?

A

Immunodeficiency

24
Q

How is the DNA broken and then reassembled to increase variability?

A

RSS are recognised by RAG

DNA is then bent & broken & reassembled

When its reassembled the enzyme TDT randomly puts a few base pairs on before it reassembles it – increases variability even more

All get reassembled slightly differently – encodes a slightly different variable region

25
Q

What is allelic exclusion?

A

When a B cell makes a heavy chain, it tells the other chromosome not to do the same process again

Also turns off further light chain rearrangement once a light gene rearranges successfully

Each B cell only has 1 BCR – isn’t made on both chromosomes

26
Q

How does allelic exclusion turn the gene off in 1 chromosome?

A

Turns of the RAG genes in that chromosome

Ensures every B cell only has 1 L chain & 1 H chain

All time dependent – heavy chain goes first & then the light chain

27
Q

Mechanisms for generation of antibody diversity

A

Multiple germ line genes

Combinatorial diversity

Junctional diversity

Combinations of H & L chains

Somatic hypermutation

28
Q

Multiple germ line genes

A

Multiple VH, V-kappa & V-lambda

Also multiple D & J

29
Q

Combinatorial diversity

A

Different V, D & J segments recombine to produce different sequences

Eg. 40V x 25D x 6J = 6,000 combinations

H chains potentially more diverse than L chains

30
Q

Junctional diversity

A

Includes:
– Imprecise joining – small differences in position of V-D & D-J join
– N regions – random addition of nucleotides at junctions of V-D & D-J by terminal transferase

31
Q

Combinations of H & L chains

A

Eg. 106 H and 104 L would give 1010 possible antibodies

32
Q

Somatic hypermutation

A

Mutation frequency in antibody VH genes orders of magnitude higher than normal spontaneous mutation rate

Occurs in germinal centres as B cells recognise Ag & proliferate/become activated

33
Q

What does somatic hypermutation involve?

A

Involves the enzyme AID – activation-induced deaminase

AID acts on DNA to de-aminate cytosine to uracil

Uracil is then recognised by error-prone DNA repair pathways leading to mutations

Leads to even more variation in the receptors

34
Q

Membrane (BCR) vs secreted antibody

A

As individual B cells differentiate, they start to secrete their unique BCR as antibody (soluble form)

Secreted form has an alternative hydrophilic C-terminus but same specificity as membrane Ig (BCR)

Membrane & secreted forms produced by alternative RNA processing

If the BCR binds to the antigen we want it to on the surface, then we can release the BCR as an antibody

35
Q

What is the heavy chain in IgM?

A

Mu

36
Q

What is the heavy chain in IgD?

A

Delta

37
Q

What is the heavy chain in IgG?

A

Gamma

38
Q

What is the heavy chain in IgA?

A

Alpha

39
Q

What is the heavy chain in IgE?

A

Epsilon

40
Q

Why is IgM the first isotype expressed by each developing B cell?

A

C-mu is physically the closest to the V,D and J genes

C-delta is then next to C-mu: hence IgD can be co-expressed with IgM by differential processing of the RNA from the two C region genes

41
Q

What does switching to other classes require?

A

Recombination

Guided by switch regions & DNA breakage

Also involves AID

Cytokines & pathogens cause the switch

CMB2004 (12 decks)

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