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Infection and Immunity > 5 Antibody diversity > Flashcards

5 Antibody diversity Flashcards

1
Q

Amino acid isotopic variability in immunoglobulins

A

IgG antibody - heavy chain class (and subclass where applicable) is used, light chain (kappa or lambda)

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2
Q

Amino acid allotypic variability in immunoglobulins

A

allelic variations across populations - associated with heavy and light chains. Some have effect on overall physiochemical properties of antibody

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3
Q

example of allotypic variability in immunoglobulins

A

altering small amino acid changes that have effect on glycosylation patterns

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4
Q

Amino acid idiotypic variability in immunoglobulins

A

purely on the antigen binding area
identifying unique structure and sequence that makes a particular antibody (applies to TCR too) different from any other antibody, associated with variable of heavy and light chains. CDRs of variable regions.

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5
Q

Heavy and light Ig chains/T-cell receptor genes - germline sequences

A

Germline sequences are not functional

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6
Q

Heavy and light Ig chains/T-cell receptor genes - functional genes

A

functional genes are a result of somatic recombination - only occurs in B and T cells

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7
Q

Heavy and light Ig chains/T-cell receptor genes - germline genes

A

large cluster of gene segments in a multigene family

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8
Q

Heavy and light Ig chains/T-cell receptor genes - regions

A
  • Variable region (V) segments (start at 5 prime) need a leader sequence upstream of all the variables
  • Diversity (D) segments (Ig heavy & TCR beta chains – not light)
  • Joining (J) segments
  • Constant (C segments)
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9
Q

light chain rearrangement

A

random V & J segments recombine, make gene encoding VL domain
Specific recombinase system recognises (discrete signals within the gene) DNA recombination signal sequences (RSS) = joining, cut out the DNA in chromosome between

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10
Q

where are recombination signal sequences

A

present at the end of V and start of J regions

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11
Q

effect of recombination signal sequences

A

signalling for those pieces need to come together

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12
Q

how is diversity produced in B cells

A

Have coding joint – V and J segment joint in the chromosome DNA - totally imprecise, another way Ig can increase their diversity = 90% diversity in B cells when you make them

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13
Q

12/23 rule

A

only an Ig gene segment with a random 12 base spacer

RSS can be joined to an Ig gene segment with a 23 base spacer

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14
Q

effect of 12/23 rule on diversity region

A

When add diversity region – D region, still follows the same rule

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15
Q

12/23 light chain joins

A

light chain can only join V to J

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16
Q

12/23 heavy chain joins

A

Heavy chain can only join V to D and D to J

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17
Q

B cell development cell stages

A

Start with a stem cell, progress through series of stages: early pro-B cell, late pro-B cell, large pre-B cell (has a partial immunoglobin not fully functional), small pre-B cell then immature B cell

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18
Q

which chain is made first in B cell development

A

heavy then light

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19
Q

when is the B cell checked for self-reactivity

A

Once gets to having a mature antibody on its surface

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20
Q

what genes are expressed at different points throughout the B cell development process

A

RAG 1 and 2

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21
Q

when are RAG 1 and 2 expressed

A

only expressed during B cell and T cell development

expressed during B cell development of heavy chain then during the development of light chain

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22
Q

what are RAG 1 and 2 known as

A

proteins Recombination activating genes 1 &

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23
Q

what are RAG 1 and 2 essential for

A

somatic recombination

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24
Q

RAG 1 and 2 regulation

A

highly regulated, switched on and off at different stages

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25
Q

what happens if don’t have RAG 1 and 2

A

Without RAG 1 and 2 cannot make B or T cells – immune deficiency

26
Q

what is Terminal deoxynucleotidyl transferase

A

(TDT) is a non-templated DNA polymerase which acts on the cleaved DNA ends and adds additional DNA bases

27
Q

progression of rearrangement to form B cells - how is a signal formed to stop heavy chain rearrangement

A

Start with heavy
D-J rearrangement on both chromosomes at same time
After triggers late pro-B cell heavy chain gene rearrangement on only one chromosome (V to DJ region that’s already been made)
If make heavy chain and gets on surface of cell = signal to come down off cell surface and stop rearranging the heavy chain genes,

28
Q

what happens if doesn’t make successful rearrangement

A

cell rearranges the second chromosome – if this one is non-functional too the cell will die

29
Q

when is light chain rearrangement triggered

A

after heavy chain has been successfully rearranged and signal sent to stop

30
Q

light chain rearrangement for B cells

A

kappa chain rearranged first on one chromosome (if successful and creates surface IgM, cell will no longer rearrange) if doesn’t will rearrange second kappa chain gene, if that fails will rearrange the two lambda – plenty of goes at making light chain gene

31
Q

what is created at end of rearrangements

A

Immature B cell will either be IgM kappa or IgM lambda

32
Q

why can light chains rearrange multiple times

A

Receptor editing can rescue B cells which have generated a self-reactive antibody – will try to rearrange to see if can make it not self-reactive
V-J configuration, can potentially have another go to rearrange until run out of V and J regions to join

33
Q

when can’t light chain rearrange again

A

if use very first V region and very last J region first time round then don’t get a second chance

34
Q

what is the joining of Coding Joint DNA like

A

imprecise

35
Q

Joining of Coding Joint DNA for light chain

A

V-J

36
Q

Joining of Coding Joint DNA for heavy chain

A

V-D and D-J

37
Q

result of joining of Coding Joint DNA

A

joining can result in additional nucleotides added to the joint

38
Q

what are the additional nucleotides in Joining of Coding Joint DNA

A
  • Non-templated addition by Terminal deoxynucleotidyl transferase (TdT): Termed N region additions
  • Palindromic additions by template directed fill in by DNA polymerases: Termed P-region additions
39
Q

effect of adding more nucleotides in the joining of coding joint DNA

A

alter the potential peptide reading frame - As random they do not meet, some changes of removal ‘nibbles’ till they can come together

40
Q

what occurs during N and P region addition

A

RSSs brought together
RAG complex generates DNA hairpin at coding ends
artemis: DNA-PK complex opens DNA hairpins generating palindromic P-nucleotides
N-nucleotide additions by Tdt
pairing of strands
unpaired nucleotides removed by exonuclease
gaps filled by DNA synthesis and ligation = coding joint

41
Q

what causes variability in antibodies

A

Between D and J DNA is not encoded in chromosome

42
Q

Allelic exclusion

A

Single T or B cell will only express product of a single allele for each of its relevant antigen receptor genes
B-cell will express a single specificity of IgH chain and a single specificity light chain

43
Q

what causes mono-specificity

A

A single T-cell will express either a unique α and β, or a unique γ and δ TCR pair
Allelic exclusion leads to monospecificity of BCR

44
Q

what is monspecificity

A

same antibody

45
Q

if crossed animal with alpha and beta B cell what is expressed

A

heterozygous, has genetic material of both, only one – a or b is expressed on the surface of T cell

46
Q

what does somatic hypermutation do

A

refines the immune response

Recognises the epitope and fine tuning it

47
Q

where does somatic recombination occur

A

only in B cells and the secondary lymphoid organs

48
Q

somatic recombination and mutations

A
  • Targeted mutations in the DNA encoding the rearranged VJ or VDJ segment
  • altered DNA sequence may encode different amino acids
  • some mutations will improve binding to antigen.
  • Occurs simultaneously with class switching
49
Q

Somatic hypermutation results

A

small alterations in amino acid sequence within the Variable domains of immunoglobulins

50
Q

Known details of somatic hypermutation

A
  • Not random mutations - transitions >transversions
  • especially serine codons AGC and AGT
  • Activation induced cytidine deaminase (AID) is induced
51
Q

Mechanisms for generation of diversity

A
  • choice of multiple genes – multifaceted
  • random recombination of gene segments
  • V-J (light) and V-D-J (heavy)
  • imprecise junction when they join, allows for P and N addition
  • (N region addition, P region addition)
  • Combination of heavy and light chain proteins
  • somatic hypermutation
52
Q

Refining the antibody o self-reactive

A

tend to die fairly rapidly – clonal deletion

53
Q

Refining the antibody soluble self-molecule

A

can get out to periphery, they’re usually very unresponsive to any normal stimuli for B cells (anergic), don’t enter lymph nodes so die fairly rapidly

54
Q

Refining the antibody no self-reaction

A

No self-reaction to self or soluble self = migrate to periphery and then become naïve B cell, when meet antigen = mature B cell

55
Q

where does clonal deletion occur

A

All in the bone marrow

56
Q

what does Isotopes (class) switching affect

A

the heavy chain genes only

57
Q

Isotopes (class) switching - initial isotopes made

A

IgD and IgM are made (cell surface)

58
Q

how are more isotopes produced

A
  • Further class switching involves a second specific recombination system
  • gives a switch to IgG, IgA, IgE
  • occurs after antigen stimulation
59
Q

how are IgM and IgD made

A

generated by RNA splicing – depends on RNA splicing whether end up with IgM or IgD

60
Q

what enzymes are involved in isotope switching

A

activation-induced cytidine deaminase (AID)

61
Q

what enzymes are involved in somatic recombination

A

activation-induced cytidine deaminase (AID)

Infection and Immunity (29 decks)

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