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Immunology 7070 > Lecture 8 - First of Final Material > Flashcards

Lecture 8 - First of Final Material Flashcards

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1
Q

What is the problem around which the immune system must work to function properly?

A

It needs to react to a huge variety and newly-arising pathogens all the time and can react to virtually anything. How can it recognize/respond to to many pathogens?

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2
Q

What were the two theories of Ag recognition proposed in the 50s?

A

Instructionist theory

Selectionist theory

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3
Q

Define the instructionist theory.

What are the problems with it?

A

The Ag acts as a template that molds and directs the formation of specific immune recognition receptors from a generic and precursor protein.
It would then be able to mold to anything and cause a reaction.

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4
Q

Define the selectionist theory.

What are the problems with it?

A

Specific immune recognition receptors for all antigens which are able to SOMEHOW exist in the body which are able to activate the receptor causing it to replicate within generic Ab producing cells. Specific recognition receptors are clonally distributed within immune cell populations so they each have specificity to this.
HOW could all of these receptors be available in the body at once?

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5
Q

What was the main issue with the selectionist theory and how was it overcome?

A

Not enough room in the genome for billions of distinct recognition receptors.
Burnet proposed in 1959 a randomization of pattern amongst differentiating lymphoid cells. VDJ recombination ended up being correct.

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6
Q

How does the structure of the IgG molecule help solve the problems of specific immune recognition?

A

It is a dual function molecule with:

1) variable Ag binding domains
2) constant domain to trigger immune effector mechanisms

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7
Q

Describe the main antibody domain structure and functions.

A
  • 4 protein subunits (2 heavy, 2 light chains) each with multiple Ig domains
  • Ig domains (folds) provide stable scaffolding
  • Ig domains act in many receptors in immune cells as well as outside the immune system
  • Each Ig molecule specifies antigen recognition/immune function
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8
Q

What is the “Ig super-family” of receptors?

A

The receptors that are able to bind and recognize Ig domains to drive an immune response.

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9
Q

Describe the variable regions of the heavy and light Ig domains.

A

Each heavy and light chain variable region has hyper-variable regions. There are four FR regions and 3 hyper-variable regions in both heavy and light chains

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10
Q

Where are Ig hypervariable regions located in linear and conformational peptides?

A

In 3D conformational: HV regions are at the tip of the variable Ig domain where binding occurs.
Linearly they are spread out evenly with less variable regions.

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11
Q

Where on/in a protein does Ag binding occur?

A

In a pocket, groove, cup, or even around protruding surfaces. There is extreme flexibility.

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12
Q

Define affinity of an Ab.

A

The strength with which one Ag binding surface of an Ab binds with one epitope of an Ag.

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13
Q

Define avidity of an Ab.

A

The total binding strength of an Ab binding to Ag.

Abs have 2-10 binding sites each and some Ags have repeating epitopes.

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14
Q

How is affinity often expressed? Define this.

A 
Dissociation constant (Kd).
The molar concentration of an Ag required to occupy half of the available antibody molecules in a solution.
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15
Q

How does the constant Kd work?

A

The lower the Kd the higher the affinity.

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16
Q

How is anti-microbial effectiveness of a given Ab determined?

A

By affinity, avidity, and which microbial molecule/epitope is bound.

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17
Q

Which has more powerful binding affinities, TcRs or BcRs?

A

BcR binding > TcR binding

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18
Q

When were TcRs identified and by whom?

A

1970s/1980s by three guys simultaneously (one was Canadian)

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19
Q

How do cell surface receptors mediate clonal selection?

A

They trigger intracellular activation signals. Membrane Ig and TcRs are able to both create signal transduction (Remember! TcRs themselves cannot, they have to do so via CD3 etc.)

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20
Q

How are TcRs similar to BcRs?

A

They both have variable and constant Ig domain structure portions.

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21
Q

What are the major differences between TcRs and BcRs?

A
  1. TcRs only have one copy each of both alpha and beta subunits
  2. TcRs have a single constant domain in both subunits as opposed to two
  3. TcRs are only present in the cell surface-bound forms
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22
Q

What do TcRs recognize?

A

Peptide antigen fragments bound to MHC molecules

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23
Q

Which portion of the antigenic peptide is recognized by the TcR?

A

The most variable loops of the variable (V) regions are the main contact of the peptide.

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24
Q

Where are the CDR loops in relation to the MHC?

A

Over both the peptide and polymorphic regions

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25
What are the functions of the CD4 and CD8 molecules on T cells with respect to the MHC? Where do they interact?
CD4 and CD8 co-receptors stabilize the TCR recognition of bound peptides by directly contacting the non-polymorphic regions of the MHC.
26
CD4 co-receptor contacts which portion of the MHC?
CD4 contacts the two beta subunits of the MHC class II
27
CD8 co-receptor contacts which portion of the MHC?
CD8 contacts the alpha 2 and 3 subunits on MHC class I
28
What are the differences between the BcR and TcR antigen binding sites?
BcR - made up of three CDRs in Vh and three CDRs in Vl | TcR - made up three CDRs in Valpha and three CDRs in Vbeta
29
What are the differences between the BcR and TcR structure of antigens bound?
BcR - can bind both linear and conformational determinants of both macro and micro molecules TcR - Can recognize only 1-3 AAs of a peptide and polymorphic residues of the MHC molecule
30
What are the differences between the BcR and TcR affinity of antigen binding?
BcR - Kd of 10-7 to 10-11 M which increases during immune responses TcR - Kd of 10-5 to 10-7 and does not change during immune responses
31
What are the differences between the BcR and TcR on and off rates?
BcR - rapid on rate, variable off-rate | TcR - slow on and off rates
32
What are the differences between the BcR and TcR accessory molecules involved in binding?
BcR - none | TcR - CD4 or CD8 simultaneously binds MHC molecule
33
Describe the steps undergone by a generation of unique V regions in different B cell clones through V(D)J recombination.
1. Germline DNA undergoes somatic recombination of D-J joining 2. Recombined DNA undergoes somatic recombination of V-DJ joining 3. The VDJ DNA recombination sequence undergoes transcription then RNA processing (splicing) 4. Messenger RNA (mRNA) undergoes translation 5. Ig u chains are now a part of B cell clones
34
Which parts of V, D, and J are a part of the light chain? Where are they located in the final product?
Only V and J | V is towards the outside, J is towards the inside next to the heavy chain.
35
Which parts of V, D, and J are a part of the heavy chain? | Where are they located in the final product?
V, D, and J | V is towards the outside of the Ig, J is towards the inside next to the heavy chain, and D is in the middle
36
How much diversity is possible in the B cell through VDJ recombination of heavy and light chains?
Heavy chain has 100 V, 27 D, and 6 J Light chain has 35 V, 0 D, and 5 J Total of approx 10^6 possible combinations
37
How much diversity is possible in the T cell through VDJ recombination of alpha and beta chains?
Alpha chain has 54 V, 0 D, and 61 J Light chain has 67 V, 2 D, and 4 J Total of approx 3x10^6 possible combinations
38
How much diversity is possible in the B cell through VDJ recombination of heavy and light chains after junctional diversity?
Approximately 10^11 possible combinations
39
How much diversity is possible in the T cell through VDJ recombination of heavy and light chains after junctional diversity?
Approximately 10^16 possible combinations
40
What is junctional diversity in B/T cell receptors?
When they are subject to the addition or the removal of nucleotides in the VDJ region changing their genetic makeup.
41
What is combinatorial diversity is B/T cell receptors?
The diversity that comes from the combining of the many different kinds of V, D, and J possibilities available in the germ line.
42
What are the problems caused by Burnet's VDJ recombination?
The system would generate non-functional receptors and generate receptors capable of binding to self antigen.
43
How could VDJ recombination generate non-functional receptors?
1. Reading frames of V and J aren't always aligned (only 1/3 chance that they are) 2. Incompatible pairing of 2 receptor chains 3. Protein insolubility or instability 4. Improper folding/transport to cell surface 5. **T cell receptors may not recognize MHC
44
How is the body able to overcome the potential issues with VDJ recombination?
Via positive and negative selection during lymphocyte development.
45
When does VDJ recombination take place in the life of a B/T cell?
ONLY during the pre-B and thymocyte phases right before the cells emerge as B/T cells.
46
Where does VDJ recombination happen and why?
In the Bone marrow and thymus where they have the expression of recombinase activating genes (RAGs).
47
What is the purpose of positive and negative selection?
The purpose is to remove lymphocytes expressing Ag receptors that are non-functional OR strongly self-reactive.
48
What happens to T cell precursors that have been rejected by the immune system as non-functional or self-reactive?
They undergo apopsosis in the thymus and are quickly engulfed by thymic macrophages.
49
How were we able to study increased negative selection in the thymus?
Tg mice were used by modifying their TcR. They had high affinity recognition of MHC antigens in the thymus.
50
How were we able to study increased positive selection in the thymus?
Tg mice were used by modifying their TcR. If only MHC I was presented then only CD8+ cells matured and if MHC II was presented then only CD4+ cells matured.
51
Why must the positive and negative T cell selection have different binding affinity/avidity?
If they were both the same then they would recognize much of the same things and would not be able to allow the maturation of peripheral T cells. Because they have different avidity/affinity, the negative selection is able to do its job properly and only select a few for deletion.
52
Which selection has higher binding affinity?
Negative selection
53
What kind of selection occurs in a T cell if it has weak recognition of the class II MHC + peptide?
Positive selection of a CD4+ T cell
54
What kind of selection occurs in a T cell if it has weak recognition of the class I MHC + peptide?
Positive selection of a CD8+ T cell
55
What kind of selection occurs in a T cell if it has no recognition of the MHC + peptide?
Failure of positive selection - death by neglect | Resulting in apoptosis
56
What kind of selection occurs in a T cell if it has strong recognition of the class I or II MHC + peptide?
Negative selection resulting in apoptosis
57
How do T cells get introduced to all bodily antigens if they are only in the thymus?
AIRE - a transcriptional regulator - is expressed in the thymic epithelial cells and promotes the expression of proteins normally expressing in non-lymphoid tissue.
58
What happens to an immature B cell in the bone marrow if it binds to a multivalent self molecule?
Clonal deletion or receptor editing resulting in apoptosis.
59
What happens to an immature B cell in the bone marrow if it binds to a soluble self molecule?
It migrates to the periphery and becomes anergic with IgD
60
What happens to an immature B cell in the bone marrow if it binds to a low affinity and noncross-linking self molecule?
It migrates to the periphery and becomes a clonally ignorant Mature B cell with IgM and IgD
61
What happens to an immature B cell in the bone marrow if it has no self reaction?
It migrates to the periphery and becomes a mature B cell with IgD and IgM
62
What does the activation of a B cell by antigen trigger?
Somatic hyper-mutation (SHM) and Ig class switch recombination (CSR)
63
What is somatic hypermutation?
The introduction of mutations into the V region of the BcR at a very high rate. THis can change the Ag binding ability positively or negatively.
64
What is class switch recombination?
The changing of the C region of an Ab from IgM to other isotype which provides functional diversification of the Ag receptor.
65
What is the purpose of class switching?
It provides the same Ag specificity but gives new effector functions for the immune system by being recognized by different receptors.
66
What are the common features of somatic hyper mutation and Ig class switching?
They only occur in B cells and they share some common enzymatic mechanisms.
67
Define affinity maturation.
The increase in average antibody affinity over time due to the V region mutations plus positive selection of B cell clones binding Ag with highest affinity.
68
How is SHM affected by immunization?
SHM leads to progressive accumulation of V region mutations among Ag specific B cells in both light and heavy chains.
69
List 6 somatic hypermutation facts:
1. 1 million times the normal error rate of DNA replication 2. Requires AID enzyme plus DNA mismatch repair enzymes 3. Restricted to brief period of B cell development during the T cell dependent B cell activation in germ center 4. Mutations begin just downstream of the Ig promotor and end about 1-2 kb further downstream 5. Most mutations decrease Ag binding or disrupt Ig fold stability but some mutations improve binding. Usually in CDRs. 6. Cellular positive selection mech in germ centers selectively expand the rare high affinity mutants via microevolution system
70
What is a microevolution system?
In B cell somatic hypermutation the germinal centers selectively expand only the B cells which have undergone changes to become higher affinity binding.
71
How is highly specific antigen recognition in the adaptive immune system achieved?
Clonal distribution of highly specific Ag receptors in B and T cells
72
Variable protein structures of AgRs are generated at which level by what kind of recombination?
Genetic | VDJ
73
Why bother learning about Ag recognition?
Adaptive immunity/immunological memory | Molecular probes/therapeutics

Immunology 7070 (15 decks)

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