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IMM Exam 1 > Antibody Diversity > Flashcards

Antibody Diversity Flashcards

1
Q

chains of antibodies

A
  • 2 heavy chains
  • 2 light chains
  • identical
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2
Q

domains of antibodies held together by

A
  • disulfide linkage
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3
Q

secreted IgG antibody:

  • L chains
  • H chains

How many Ig Domains?

A
  • 2

- 4

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4
Q

variable region

A
  • sequence varies among different antibodies

- antigen binding pocket

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5
Q

constant region

A
  • sequence is the same among different antibodies
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6
Q

light chains (VL and CL)

A

1 VL + 1 CL for each chain

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7
Q

heavy chain (VH and CH)

A
  • 1 VH + 3 or more CH
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8
Q

CL domain functions

A
  • no effector functions
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9
Q

hypervariable regions

A
  • CDR1
  • CDR2
  • CDR3 (most variability)
  • complementarity-determining regions
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10
Q

how do hyper variable regions interact with antigen

A
  • stick away from the protein so they can contact antigen
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11
Q

each antigen binding pocket consists of

A
  • VH and VL chain
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12
Q

each antibody has how many antigen binding pockets?

A
  • 2
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13
Q

IgA in what form?

A
  • dimer

- connect by J chain

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14
Q

H chain isotypes

A
  • IgG
  • IgA
  • IgM
  • IgE
  • IgD
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15
Q

L chain isotypes

A
  • kappa

- lambda

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16
Q

secreted and membrane associated antibodies differ how

A
  • at the C-terminal tail
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17
Q

chain structure of T cell receptor

A
  • has two chains
    • alpha-beta
    • gamma-delta
  • each chain has a V and C region
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18
Q

CDRs in variable region of T cell receptor

A
  • bind antigen
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19
Q

T cell receptor recognizes antigen in what context

A
  • context of MHC
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20
Q

mechanisms of antibody diversity

A
  • Multiple VH and VL genes
  • combinatorial association of different V,D, and J gene segments
  • junctional diversity by nucleotide addition
  • combinatorial association of VH and VL regions
  • somatic hypermutation
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21
Q

heavy chain gene

A
  • V
  • D
  • J
  • C
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22
Q

light chain gene

A
  • V
  • J
  • C
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23
Q

VH CDR1,2 derived from

A
  • VH segment
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24
Q

VH CDR3 derived from

A
  • DH and JH segments
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25
Q

VL CDR1,2 derived from

A
  • VL segment
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26
Q

VL CDR3 derived from

A
  • JL segment
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27
Q

leader sequence on each V gene segment

A
  • codes for N-terminal signal peptide

- targets the proteins to the ER

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28
Q

VDJ recombination

A
  • two gene segments brought together and double strand break made
  • somatic recombination of V-D-J joining
  • N and P nucleotides added or removed and ends ligate together
  • C regions separated from variable regions by introns
  • DNA splicing of introns bring exons back together
29
Q

what mediates the recombination

A
  • recombination signal sequences
  • heptameter separated by 12 or 23 nt spacer
  • followed by AT-rich nonamer
30
Q

prime ends of gene segement

A
  • 3’ end of V segment
  • 5’ end of J segment
  • both sides of D segment
  • think 3’VDJ5’
31
Q

which segments can pair up

A
  • only 12 bp segment with a 23 bp segment
32
Q

V(D)J recombination by deletion

  • deleting D in this case
A
  • 12 bp segment synapses with 23 bp segment
  • ensure D segment not skipped or that two of the same segment don’t join together
  • cut between gene segment and heptamer
  • ligate gene segments together
33
Q

V(D)J recombination by inversion

A
  • intervening DNA not removed by a circle but remains present
  • RNA splicing remove intervening sequences
34
Q

rearrangement and transcription

A
  • rearrangement brings enhancers close to promoter allowing transcription to occur
  • enhancer can be at 3’ end or in intervening sequence
35
Q

non-homologous end joining

A
  • uses 1-3 nt single stranded regions of homology to enhance repair
36
Q

non-homologous end joining synapsis

A
  • chromatin opens in developing lymphocyte to allow recombination enzymes access to DNA
  • chromosome looping brings gene segments together
37
Q

RAG1 and RAG2 in synapsis

A
  • form a complex and recognize RSS sequences

- RAG2 binds to hypermethylated H3K4 sites in chromatin and recruits/activates RAG1

38
Q

non-homologous end joining; cleavage

A
  • RAG1 nicks one strand

- single stranded DNA forms hairpin with other strand

39
Q

non-homologous end joining; hair pin opening end processing an joining

A
  • Ku70/80 binds to break
  • recruits DNA-PK (protein kinase)
  • DNA-PK phosphorylates and activates Artemis endo-exonuclease
  • Artemis endonuclease opens the hairpins
  • DNA polymerase fills in nucleotides (P nucleotides)
  • TdT (terminal transferase) adds nucleotides onto broken ends (N nucleotides)
  • DNA ligase joins ends together
40
Q

P nucleotide addition

A
  • hairpin cleavage and repair

- allows nucleotides to be added to junction by DNA polymerase

41
Q

N nucleotide addition

A
  • terminal transferase adds additional nucleotides at junction
42
Q

why is there greater diversity at CDR3

A
  • junctional diversity

- multiple gene segments

43
Q

importance of CDR3

A
  • most important region for antibody binding specificity
44
Q

allelic exclusion

A
  • if one chromosome undergoes rearrangement successfully, it inhibits rearrangement on the other chromosome
  • each B cell makes only one antibody
45
Q

allelic exclusion: chromatin on the successful chromosome

A
  • open

- acetylated

46
Q

allelic exclusion: chromatin on excluded locus

A
  • heterochromatized

- methylated

47
Q

light chain isotype exclusion

A
  • if the kappa locus undergoes a productive rearrangement, it inhibits lambda rearrangement
48
Q

how does higher affinity arise

A
  • due to somatic hypermutation in V region by CD40:CD40L signaling
  • at DNA level
  • during an immune response, B cells produce antibodies that progressively have a higher affinity for antigen
49
Q

mechanism of class switching

A
  • cytokine stimulation triggers transcription through I exon, switch region, and CH exons
  • different cytokines dictate which CH gene is switched to
  • double stranded breaks occur at mu switch region and downstream switch region
  • intervening DNA lost
  • RNA splicing yields transcript with new CH
50
Q

activation-induced cytidine deaminase activated by

A
  • activated by CD40
51
Q

activation-induced cytidine deaminase process

A
  • R loop on nontemplate strand
  • AID converts C’s to U’s by deamination
  • Uracil-N-glycosylase removes U residues
  • Ape1 endonuclease nicks regions without bases
  • some nicks generated on the template strand
  • double strand breaks into two switch regions and repair by non-homologous end joining
52
Q

in proliferating B cells, mutation rate for which genes is 1000x higher than for other genes

A
  • V genes

- due to somatic hypermutation

53
Q

As somatic mutation of antibody increases

A
  • Kd decreases

- which means affinity for antigen increases

54
Q

mechanism of somatic mutation

very similar process to isotype switching

A
  • AID converts C-> in U in V region
    MECHANISM
  • U’s changed to T’s (C->T mutation)
    OR
  • Uracil-N-glycosylase exists bases and repairs with an error prone repair system
    OR
  • mismatch repair enzymes remove the U nucleotides and replaces surrounding DNA using an error prone DNA polymerase which generates mutations
55
Q

why do membrane versus secreted forms of antibodies differ in C terminal tails?

A
  • due to RNA splicing
56
Q

antibody membrane form structure

A
  • Cu4 followed by hydrophobic tail and cytoplasmic tail
57
Q

antibody secreted form structure

A
  • Cu4 followed by hydrophilic tail piece
  • utilizes a poly A cleavage site before the exons encoded the hydrophobic and cytoplasmic tail so those exons aren’t included in primary transcript
58
Q

difference of T cell receptor diversity and antibody diversity

A
  • T cell receptors DO NOT UNDERGO SOMATIC MUTATION
59
Q

severe combined immunodeficiency (SCID) caused by

A
  • mutations in recombination enzymes
  • RAG
  • Artemis
  • DNA-PK
  • DNA ligase 4
60
Q

SCID result

A
  • complete loss of B and T cells
61
Q

Omenn syndrome

A
  • less severe than SCID

- due to mutations with reduced function of RAG and Artemis genes

62
Q

Hyper IgM syndrome caused by

A
  • genetic defects in AID or uracil-N-glycoslyase
  • defective in class switching and somatic mutation
  • ALSO CAUSED BY DEFECTS IN CD40
63
Q

Hyper IgM syndrome result

A
  • all antibody is IgM

- susceptibility to infection

64
Q

AID deficiency in somatic mutation

A
  • completely defective
65
Q

AID deficiency in UNG deficiencies

A
  • preserved but reduced
66
Q

lymphoid tumors and translocations

A
  • B and T cell tumors commonly have translocations of oncogenes into antibody loci

OR

  • RAG-RAG and RAG-AID translocations
67
Q

lymphoid tumors and translocations process

A
  • oncogenes suffer double stranded break by AID at sequences related to switch site
  • join to AID induced class switch recombination break in antibody gene locus
68
Q

lymphoid tumors and translocations result

A
  • over expression of oncogene in B or T cells due to active antibody or TCR promoters

IMM Exam 1 (20 decks)

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