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Immunology > Lecture 6 > Flashcards

Lecture 6 Flashcards

1
Q

What is somatic diversification? What are the 3 steps?

A

Somatic diversification = altering Ig/TCR gene segments in a NON-heritable way

  1. Gene rearrangement (VDJ recombination)
  2. Somatic hypermutation
  3. Class switch recombination
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2
Q

Which region of the receptor gene does NOT undergo recombination?

A

C - constant region!

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3
Q

Which Ig/TCR chains have VD and J genes?

A

Heavy chain
Beta
Delta

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4
Q

Which Ig/TCR chains have V and J genes only?

A

Light chain (kappa and gamma)
Alpha
Gamma

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5
Q

Which Ig/TCR chains undergo recombination first?

A

Heavy chain, beta, delta

Makes sense - why these chains present first in the preT/B cell receptors!

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6
Q

Where does most diversity in receptors come from?

A

Junctional deletions/additions
Limited number of V, D, J genes - unlimited options for adding/deleting random nucleotides to the junctions between those genes

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7
Q

Does the V, D, or J gene code for CDR2 and 1? How does this affect the Ig/TCR function?

A

CDR1 and 2 - V gene
Directly coded for by this gene
Limited number of V genes in the DNA - limited diversity
Therefore, CDR1 and 2 interact with the MHC - less variable region

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8
Q

What is CDR3 coded by? How does this affect the Ig/TCR function?

A

V-J (D if there) junction
Junction = most diversity possible
Interacts with antigen bound by MHC

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9
Q

What molecules make up VDJ recombinase enzyme?

A

RAG 1 & RAG 2

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10
Q

What flanks either side of V/D/J genes?

A

RSS = recombination signal sequence
On either side of any gene that can undergo recombination
Heptamer - 12/23 bp - nonamer

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11
Q

What part of the RSS is highly conserved?

A

Heptamer - identical
Some nonamer variability
Lots of variability in the spacer

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12
Q

What is the difference betwe 12/23 spacer?

A 
12 = 1 alpha helix turn in the CDR
23 = 2 turns
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13
Q

What is the point of having RSS?

A

Prevents recombination within the same locus

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14
Q

What is the 12/23 rule?

A

Rearranging gene segments are always flanked by different RSS lengths

12 matches with 23

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15
Q

Of the RAGs, which:

  • Binds the RSS directly?
  • Is catalytic?
  • Facilitates binding via changes in affinity?
A

RAG 1 = binds RSS, cuts

RAG 2 = facilitates RAG1

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16
Q

Why is VDJ recombination cell specific?

A

B/c RAG1/2 only in IMMATURE lymphocytes

17
Q

What are the 5 steps of VDJ recombination?

A
  1. RAG1/2 binds RSS - 2 RAG complexes total, 1 for each RSS
  2. RSS synapsis
  3. DNA cleavage
  4. Signal end joining
  5. Coding end joining
18
Q

Explain RAG’s “two step” cleavage.

A

Cleavage in trans
1. Nick top strand
2. Hairpin formation
RAG stays bound to cut RSS

19
Q

What are the 3 steps of coding joint formation? Think ENZYMES.

A
  1. Bind broken DNA ends via DNA-dependent protein kinase + ku70 + ku80
  2. End processing (additions or deletions to joint)
  3. DNA end ligation via DNA ligase 4
20
Q

What is the DNA signal joint product that is cut out?

A

TREC = extrachromosomal circle

21
Q

Which 2 enzymes can make additions to the joint?

A 
Artemis 
- via hairpin or asymmetric opening 
- +s P nucleotides = DNA repair filling in short ends of uneven break with sequence that is palindromic to the original coding end
Tdt
- Non-templated addition
22
Q

What aspect of NHEJ is unique to immature lymphocytes?

A

Tdt

23
Q

What enzymes can make deletions to the joint?

A

DNA POL mu or gamma

24
Q

What is the accessibility hypothesis?

A

Recombinase alone is not enough to initiate gene rearrangement
Needs access to the target genes
RAG2 has affinity for Ig/TCR loci - binds histones to open specific aspects of the DNA for RAG1

25
Q

What are the general differences between RAG and NHEJ mutations/defects?

A

RAG mutation = defect in initiation of recombination

NHEJ mutation = defect in completion

26
Q

What is Omenn syndrome? What do you see clinically in these patients?

A 
RAG mutation - autosomal inheritance 
SCID + hyper-allergic reaction symptoms
- RAG1/2 is diminished but not 100% gone 
- Biased few cells get made 
-->  Th2 bias --> inflammation
--> preferred B cell switch to IgE
27
Q

How do you get SCID with radiation sensitivity?

A

Artemis/DNA ligase 4 mutations

No NHEJ in any cells

28
Q

Do Ig or TCR genes undergo hypermutation and class switch? When do these occur?

A

Ig ONLY

Mature B cells - once bind antigen

29
Q

What is somatic hypermutation? What is the goal of this process?

A

Point mutations in heavy or light chain V genes
Changes to the variable region
GOAL = Ab affinity maturation

30
Q

What is class switch? What is the goal of this process?

A

Recombination of heavy chain C genes
Changes to constant region
GOAL = different Ab isotypes

31
Q

Which enzyme initiates both SHM & CSR?

A 
AICDA - induces DNA damage
DNA repair:
- BER 
- NMR = nucleotide mismatch repair
- NHEJ
32
Q

How do you get primary adult immunodeficiency?

A

Defected SHM & CSR

  • AICDA mutation
  • BER mutation
  • NHEJ or DNA damage response gene mutations
33
Q

What is AICDA’s mechanism?

A

Cytidine –> uridine

Creates C –> T transition

34
Q

After AICDA, which is more likely to fix the damage vs propagate the error?

A

Fix = BER

Keep error intentionally –> point mutation to improve Ab binding site = NMR

35
Q

What Ab isotype CANNOT undergo CSR?

A

IgD

36
Q

What disease results from AICDA deficiency?

A

Type 2 hyper IgM syndrome

  • autosomal
  • mutations that inactivate AID
  • recurrent bacterial infections, survive them but keep getting them b/c only making primary Ab
  • No switching isotypes or high affinity Abs
37
Q

What is type 1 hyper IgM syndrome?

A

CD40 or CD40L gene mutation
B cells can’t interact with T cells to induce AID expression
Symptoms:
- Repeated bacterial infections
- No germinal centers
- Immune deficiency b/c also lacking CD40 on macrophages

38
Q

What disease could be attributed to VDJ recomb and CSR?

A

Cancer mutations - LEUKEMIA & LYMPHOMA

Due to chromosome translocations

Immunology (25 decks)

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