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Intergrated Cell Biology > Immunology 4- Diversity In Immunoglobulins > Flashcards

Immunology 4- Diversity In Immunoglobulins Flashcards

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1
Q

Other B cell lineages in a given human all be derived from the same allele or either the father or the mother, true or false?

A

False, allelic exclusion only occurs on a cell to cell basis, so other B cells in a given person may silence or promote the other allele

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2
Q

A B Cell cannot express both alleles of its Ig genes at the same time, true or false?

A

True

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3
Q

After allelic exclusion what is the first step of the early lymphoid cell in becoming a PRO-B cell ?

A

To make a functional Heavy chain via somatic rearrangement of the genes corresponding to the Variable domain, with the constant domains having to be IgM or IgD

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4
Q

What is the second task, taking a the Pro-B cell (with a functional heavy chain) into a Pre-B cell ?

A

Light chain somatic rearrangement. With Kappa isotopes tried first, and Lambda if not

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5
Q

If any somatic rearrangement, junction joining, alternative splicing, hypermutation or class switching mechanisms result in a non-functional or undesired Immunoglobulin then what is the fate of the B-cell?

A

Apoptosis

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6
Q

Kappa light chain genes and Lambda genes are within the same loci, true or false?

A

False, Kappa genes are on chromosome 2, and Lambda genes are on chromosome 22

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7
Q

Lambda light chain combinations are tried ahead of Kappa light chain combinations, resulting in 60 and 40% human serum fractions, true or false (?: remember what chromosome each is on!)

A

FALSE, kappa (chromosome 2) is tried first, if unsuccessful then Lambda genes are tried. Kappa makes 60% of Igs resultingly, and Lambda makes 40%

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8
Q

VDJ recombination refers to what portion of the Ig? And what does VJ recombination refer to?

A
  1. Somatic rearrangement of the VDJ genes that comprise the variable region of heavy immunoglobulin chain
  2. Somatic rearrangement of the VJ genes that comprise the variable region of the light immunoglobulin chain
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9
Q

What is the consequence of the light chain not joining a D (diversity genes)?

A

It has no junctional diversity, after RAG excises unselected D and J genes and so with V and D joining

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10
Q

What does VDJ stand for?

A

Variable, diversity, joining

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11
Q

What is found downstream ( and upstream) of VDJ genes?

A

Recombination signal sequences (RSS)
Found downstream of each V segment
Found up and downstream of D segments
And found upstream of J segments

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12
Q

What is the structure of RSSs and what is the 12/22 rule?

A 
A Heptamer (7) and nonomer (9) nucleotide sequence separated by either 12 or 22/23 nucleotides 
RAG can only bind and bring together one gene of each of the VDJ regions, and the RSS must not be both 12 or 22 must be 12-22 or 22-12
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13
Q

What is RAG?

A

Recombination activating gene, RAG1 and RAG2 exclusively expressed in lymphocytes

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14
Q

More than one V, D or J gene can be selected and expressed in a B cell, true or false?

A

False, only one of each can be selected, the rest are excised and lost forever

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15
Q

Somatic rearrangement/ V(d)J rearrangement is reversible, true or false?

A

False, it is irreversible, once a B cell is committed to the selection of genes to make its antigen binding domain this cannot be undone. Meaning every immunoglobulin it expresses has the same antigen binding site Fab

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16
Q

what nucleotide lengths can RSS be?

A 
7+12+9= 28 bp
7+22+9= 38 bp
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17
Q

What is the importance of the 12/22 rule

A

It prevents recombination within VDJ regions and encourages recombination between, generating new variable domains

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18
Q

How many possible VDJ combinations can be made on the heavy chain?

A

40 genes for V, 20 for D and 6 for J make 4800 possible combinations

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19
Q

How many RSS flank a D gene?

A

Two

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20
Q

If the RSS of a D gene has a 12bp gap then what must the gap length of the RSS of the selected J gene be?

A

22 bp

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21
Q

V and D somatic rearrangement occurs first, true or false (?: make the DJ first, then he becomes THEE DJ)

A

False, D and J are combined first, then V. Unless it concerns light chains, in that case V and J are the first and only recombination

22
Q

What pair of scientists worked on the SOMATIC ARRANGEMENT MECHANISM to account for immunoglobulin diversity? What dogma did this go against and what did they use to prove this?

A

Dreyer and Bennett, they used restriction endonucleases and this went against the dogma- one gene= one polypeptide

23
Q

VDJ rearrangement is random, true or false?

A

True

24
Q

Draw the entire mechanism of VDJ recombination, with all enzymes and steps

A

Seriously

25
Q

RAG nicks both strands of DNA, t or f?

A

False, it nicks only one

26
Q

What occurs when RAG binds RSS of VDJ gene segments, brings them together and nicks them?

A

A free OH is formed and attacks then opposite strand forming a hairpin loop on both end of the selected gene segments. The gene segments in between are excised, along with the remaining RSS and RAG enzymes, lost to the B/T cells genome forever

27
Q

RAG nicking is imprecise and source for sequence diversity? True or false

A

False, nicking of the RSS is precise, it is the ARTEMIS nicking of the hairpin loops and subsequent non germ line nucleotide additions by TERMINAL-deoxynucleotidyl-transferase (TdT) and polymerase that accounts for junctional diversity in the heavy chain

28
Q

What is ARTEMIS?

A

It is a endonuclease that causes a single strand nick in the hairpin loops, following RAG binding and gene segment excision.

29
Q

What are P and N nucleotides? And what enzymes are involved

A

Upon ARTEMIS nicking, Palindromic overhangs are created, TdT and polymerase work to remove nucleotides or inject non-germ line nucleotides between the D and J (or V and D) gene segments

30
Q

What follows the work of RAG, ARTEMIS, TdT and DNA polymerase?

A

Ligase, to seal the gene segments

31
Q

How many V and J gene segments are there on the light chain variable domains and what possible combinations of each can be achieved? When combined with those of the heavy chain VDJ combinations what does this give?

A

K- V=35 J=5
=175

Lambda= V=30 J=4
=120

When combined with VDJ of heavy chain the number of successful recombinations equates to approximately 800,000 (approx 1million) many more unsuccessful ones but they aren’t selected

32
Q

How many gene segments are in the constant region of Lambda?

A

4

33
Q

At what region is somatic hypermutation focused?

A

The 3 CDR regions of the light and heavy chains.

34
Q

At what point does somatic hypermutation occur?

A

Once the mature B cell enters a peripheral (secondary lymph organ) and encounters a Follicular dendritic cell presenting a given antigen. Upon interaction of its membrane bound IgM or IgD specific signals are transmitted to the B cell causing IgM secretion and somatic hypermutation

35
Q

What is the propose of somatic hypermutation?

A

To fine tune the antigen binding domains of the immunoglobulin to give the highest possible affinity to the exposed antigen

36
Q

What causes IgM to be membrane bound and what causes it to be secreted, what are the mechanisms of selection for these forms?

A

IgM membrane mRNA transcript contains Membrane coding exons (M1 and M2) at the end of C(Mu) which code for hydrophobic Amino acids at its C terminus, allowing for membrane intergraiton. Alternative splicing thorough alternative poly A site causes excision of the secretory coding exon

Upon activation by a APC, alternative splicing now excises the the two membrane coding exons by selecting alternative poly A site, leaving the Secretory coding exons which code for hyphillic amino acids

37
Q

What drives somatic hypermutation to its end point?

A

Clonal selective, of the better fitting mutants

38
Q

What enzymes catalyses somatic hypermutation and what is the general mechanism?

A

Activating induced Deanimase (AID) targets CDR
Take amine group from Cytosine, creates Uracil which doesn’t pair with Guanine
DNA Repair enzymes excise the non-pairing nucleotides and replace with possible non-germline nucleotides, providing even further diversity at the variable region, either bettering or worsening the ability of the antigen binding site

39
Q

What range does Somatic hypermutation bring immunoglobulin diversity to?

A

In the order of billions

40
Q

IgDs function seems solely to be a receptor for B cells, true or false?

A

True

41
Q

How does IgG come about?

A

Through Class switching

42
Q

In what order are the gene segments of a typical heavy chain immunoglobulin ? And how many are there for the constant region?

A

VDJ—- constant—Mu–delta–gamma4,3,2,1–elipson–alpha1-alpha2

9 altogether

43
Q

What enzyme is responsible for class switching and what is the consequence of class switching (?once you got IgA you never go back!)

A 
AID again! (Activating Inducing Deanimase) 
As the B cell class switched downstream to other classes it cannot revert to the genes that once lied upstream, so a plasma cell expressing IgA can never differentiate into IgG but the reverse can happen due to the arrangement of genes
44
Q

The VDJ/VJ REGION stays the same but the constant region that determines the class of immunoglobulin can change and this is because the antigen target remains the same but the biological function of the immunoglobulin is different. True or false?

A

True

45
Q

What chemical class determines class switching?

A

Cytokines

46
Q

What gene sequence lies upstream of the constant region gene segments?

A

Switch sequences, which is targeted by AID

47
Q

If the pathogen is a helminth (parasitic worm) what is the appropriate class switch to? And what cytokine does this?

A

IgE and cytokine IL-4

48
Q

What Ig is achieved under interaction of IL-5 and where is this Ig usually found (?: ?)

A

IgA and the gastrointestinal tract or any other mucosal surface

49
Q

What Ig classes are appropriate for combating viruses?

A

IgM and IgG1

50
Q

What Ig class is appropriate for Bacterial pathogens?

A

IgG3 (better at complement fixation, yet more susceptible to digest at flexible hinge region)

51
Q

When are memory cells selected for creation?

A

During class switching, a proportion will be dedicated to forming memory B cells of each isotype

52
Q

Allelic exclusion of Ig genes of maturing B cells occurs in the bone marrow, and is the first step in the development of B cells, true or false?

A

True

Intergrated Cell Biology (8 decks)

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