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IHO Week 2 - WLB > Antibodies I & II - Diebel > Flashcards

Antibodies I & II - Diebel Flashcards

1
Q

What is the H chain?

A
  • 2 identical residue chains
  • linked by disulfide bonds at the hinge region
  • 5 kinds that define the class of antibody:
    • gamma
    • alpha
    • mu
    • epsilon
    • delta
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2
Q

What is the L chain?

A
  • 2 identical residue chains
  • linked to heavy chain by disulfide bonds
  • Two different types:
    • kappa
    • lambda
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3
Q

What is a variable domain?

A
  • domain that is different in sequence between antibodies of different specificities
  • N-terminal of both heavy chain (VH) and light chain (VL)
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4
Q

What is a constant domain?

A
  • region of each chain type that is essentially identical no matter what the specificities of the antibodies are
    • 1 in light chains
    • up to 4 in heavy chains
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5
Q

What are hypervariable regions?

A
  • most amino acid sequence variability in the V domain is in 3 areas = hypervariable regions
    • amino acids in the hypervariable regions comprise the actual antigen-binding site
    • Complementarity-determining regions (CDRs)
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6
Q

What is the Fab?

A
  • 2 identical branches (split pieces of the “Y”) of an antibody cut at hinge region
  • not linked
  • Includes
    • 2 heavy chains
    • 2 light chains
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7
Q

What is the FC?

A
  • bottom trunk/stalk of antibody if cut at the hinge region with papain
  • Composed of:
    • 2 heavy chains
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8
Q

What is the F(ab’)2?

A
  • two antigen-binding F(ab) portions linked together by disulfide bonds
    • retain some of hinge region
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9
Q

What are the five classes of antibodies?

A
  • IgG - three constant domains in heavy chain
  • IgA - three constant domains, forms dimer connected by J-chain, with secretory portion
  • IgM - four constant domains, forms pentamer
  • IgD - three constant domains, only in B-cells
  • IgE - four constant domains
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10
Q

What is the function of IgG?

A
  • neutralizes toxins and blood-borne viruses
  • binds bacteria & facilitates their destruction by:
    • activating complement
    • binding them to phagocytic cells
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11
Q

What is the function of IgA?

A
  • present in mucosal areas
  • secretory component protects it from proteolysis
    • allows for translocation of the dimer through epithelial layers
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12
Q

What is the function of IgM?

A
  • neutralizes toxins and blood-borne viruses
  • binds bacteria & facilitates their destruction by:
    • very efficient complement activator
  • first antibody to appear in serum after immunization
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13
Q

What is the function of IgD?

A
  • Uncertain
    • possiby functions mainly as a receptor on naïve B-cells
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14
Q

What is the function of IgE?

A
  • confers resistance to worms and other parasites
  • causes Type I Immunopathology = immediate hypersensitivity/allergy
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15
Q

What is antibody valence?

A
  • number of antigenic determinants (epitopes) an antibody molecule can theoretically bine
    • IgG = 2
    • IgA = 4 (because it is a dimer)
    • IgM = 10 (because it is a pentamer)
    • Fab = 1
    • F(ab’)2 = 2
    • isolated VL = 0 (does not fxn alone)
    • isolated VH = 0 (does not fxn alone)
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16
Q

What are antibody isotypes?

A
  • subclasses of antibodies
    • e.g. IgG1, IgG2, IgG3, IgG4
  • constant domain regions are slightly different, but the variable domain stays the same
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17
Q

How many antibody isotypes are there all together in all five classes of antibodies?

A

10

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18
Q

What are antibody allotypes?

A
  • minor allelic differences in the sequence of immunoglobulins between individuals
  • determined by the allotypes of your parents (Mendelian fashion)
    • e.g. comparing two IgG1 molecules, but one is from a gene from one parent, and the other is from a gene from the other parent
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19
Q

What are antibody idiotypes?

A
  • unique combining region (variable regions)
  • made up of the CDR amino acids of its Light and Heavy chains
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20
Q

What is the relative concentration of IgG in the serum?

A

1000 mg/dL

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21
Q

What is the relative concentration of IgA in the serum?

A

200 mg/dL

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22
Q

What is the relative concentration of IgM in the serum?

A

100 mg/dL

23
Q

What is the relative concentration of IgD in the serum?

A

5 mg/dL

24
Q

What is the relative concentration of IgE in the serum?

A

0.02 mg/dL

25
Q

What part of antibodies does kappa and lambda refer to?

A

kappa refers to one of the constant light chain possibilities

lambda refers to the other constant light chain possibility

26
Q

Which antibody isotypes have the highest serum half life?

A
  • IgG = 8-23 days
  • IgA = 6 days
  • IgM = 5 days
27
Q

Which antibody isotype can cross the placenta?

A

IgG

28
Q

Which antibody isotype is the largest (molecular weight)?

A

IgM = 900 kD

(IgA = 150-600kD, IgE = 190kD)

29
Q

Which antibody isotype is the best for complement fixation?

A

IgM

30
Q

Which antibody isotype is the best for mast cell/basophil degranulation?

A

IgE

31
Q

Which antibody isotype is the best for bacterial lysis?

A

IgM

32
Q

Which antibody isotype is the best for antiviral activity?

A

IgA

33
Q

Which two antibody isotypes are best at toxin neutralization?

A

IgG & IgA

34
Q

What do elevated levels of IgM indicate?

A
  • recent infection
  • other exposure to antigen
35
Q

Which antibody can be used as a blocking antibody to block TNF production (as in rheumatoid arthritis) or to block allergens (can out-compete IgE to desentize a hypersensitivity reaction?

A

IgG

36
Q

Which antibody has a greater daily production than any other Ig isotype?

A

IgA

37
Q

Which antibody is present at very high levels in colostrum, is present in breast milk, and provides an excellent level of protection to newborns against respiratory and intestinal infections?

A

IgA

38
Q

What gene segments code for the variable domain region of heavy chain genes?

A
  • V
  • J
  • D
39
Q

What gene segments code for the variable domain region of light chain genes?

A
  • V
  • J
40
Q

Where does the constant region of the light chain come from in light chain synthesis?

A
  • lambda light chain - only one C domain
    • chromosome 22
  • kappa light chain - only one C domain
    • chromosome 2
41
Q

How is a heavy chain synthesized?

(Hint: 5 steps)

A
  • bring one random D segment close to one J
    • DNA is cut
    • intervening DNA is discarged
    • remaining ends joined
  • bring a V segment up to the recombined DJ
    • DNA is cut
    • intervening DNA is discarged
    • remaining ends joined
  • entire VDJ region is assembled
  • VDJ region is joined with constant region of particular antibody through splicing
  • final mRNA product can be transcribed
42
Q

What are the two enzymes that do the recombination of antibody and T-cell receptor DNA?

A

RAG-1 and RAG-2 recombinases

43
Q

How do RAG recombinases recombinate heavy chain DNA?

A
  • recombinases first bind splice signals to the right of a D segment and the left of a J segment
    • pull them together (synapsis)
    • cut (cleavage)
    • splice (joining)
  • recombinases bind splice sequence to the right of a V segment and the left of a D segment
    • pull them together
    • cut
    • splice
44
Q

Why do B-cells have randomizing mechanisms like Somatic Variation?

A

production of the V-D and D-J joints are “sloppy”

45
Q

What happens in Somatic Variation?

A
  1. Exonucleases chew away a few nucleotides after the DNA is cut but before two gene segments are joined (before D joined to J, or before V joined to DJ)
  2. Cell can add a few nucleotides with an enzyme terminal deoxynucleotidyl transferase (TdT), which doesn’t use a template so its additions are random
46
Q

What is the downfall of Somatic Variation?

A
  • create a frame-shift mutation
  • abortively rearrange chains
  • incomplete antibody causes cell to die
47
Q

How does variation through Somatic Hypermutation work?

A
  • Activation-Induced Deaminase (AID) converts random cytosines→uracil in the CDR gene regions of one individual antibody
    • C:G pair becomes uracil:guanine mismatch
  • Uracil bases are excised by the repair enzyme uracil-DNA glycosylase
  • DNA polymerases then fill in the gap
    • create mostly single-base substitution mutation
  • One daughter makes different antibody at the end of cell division
    • might be better OR worse
48
Q

When does class switching occur?

A
  • After activation:
    • B-cells switch from membrane-bound IgM and IgD to → secreted IgM by differential splicing
  • As B-cells continue to divide:
    • class switch to production of IgG by DNA rearrangement
  • Any time:
    • activated B-cells may continue to class switch to produce IgE or IgA by further DNA rearrangement.
49
Q

How does class switching occur?

A
  • Cell with particular H-chain VDJ combination + mu (IgM) and delta (IgD) genes goes back to its DNA form
  • loops-out mu and delta
  • puts the H-chain VDJ combination next to different C region gene (gamma (IgG), epsilon (IgE), or alpha (IgA))
  • excises/discards intervening DNA
    • cannot go back and express the constant regions of IgM or IgD anymore
  • The L-chain and the VH domain stays the same, but the C region of the heavy chain changes.
50
Q

What is allotypic exclusion?

A
  • Only one heavy chain (maternal/paternal) and one light chain (either kappa/lambda, either maternal/paternal) are synthesized in any one B-cell.
    • All the other genes are silenced.
    • Though the person can make two allotypes, each individual B-cell makes only one.
  • In somatic variation, sloppy recombination often ends up with a frame-shift mutation
    • cell can “try again” with the other allele
    • even though any single B-cell is theoretically capably of making 2 heavy chains (maternal/paternal) and 4 light chains (maternal/paternal & kappa/lambda), that never happens
    • it makes only one of each and all other alleles are excluded
51
Q

What is the role of allotypic exclusion in the generation of a functional B cell receptor (BCR)?

A
  • allows progenitor B-cell to make two attempts at producing a productive allele
    • progenitor B-cell x2 attempts (ma/pa)
    • pre-BCR (mu) x2 attempts (ma/pa)
    • IgM (mu + kappa) x2 attempts (ma/pa)
    • mu + lambda x2 attempts (ma/pa)
  • if cell still not successful (all four combinations failed) → leads to cell death
52
Q

How does RNA splicing and polyA site selection dictate what isotype of antibody is produced and whether that antibody is membrane bound or secreted?

A
  • As mature B-cells are activated to divide and differentiate by their cognate antigen
  • they switch from membrane-bound IgD and IgM to → secretory IgM
    • switch occurs at the level of processing mRNA transcripts
    • splice out “M1/M2” Poly-A site #2 (membrane-bound gene)
    • instead use “S” Poly-A site #1 (secretory)
53
Q

What are the 12 stages of Ig expression and B-cell maturation?

A
  • Stem Cell (μ germline, κ/λ germline)
  • Early pro-B cell (μ germline, κ/λ germline)
  • Late pro-B cell (μDJ, κ/λ germline)
  • Large pre-B cell (μVDJ, κ/λ germline)
  • Small pre-B cell (μVDJ, κ/λ germline)
  • Immature B-cell (μVDJ, κ/λ VJ)
  • Imature B-cell: IgM+, IgD-​
    • leaves bone marrow and enters peripheral circulation
  • Immature B-cell: IgMhigh, IgDlow
    • alternative splicing to give both delta and mu chains
    • gains access to primary lymphoid follicle and matures
  • Mature naive B-cell: IgMlow, IgDhigh
    • enters circulation and binds specific antigen in lymphoid tissue draining infection
  • Antigen-activated B-lymphoblast
    • Alternative splicing to secrete Ig
    • Isotype switching
    • Somatic hypermutation
  • Antibody-secreting plasma cell
    • fighting the current infection
  • Memory cell
    • preparing for future infection

IHO Week 2 - WLB (10 decks)

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