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SMP - MIM Part 1 > Lecture 3 - Antigens and Immunogenicity > Flashcards

Lecture 3 - Antigens and Immunogenicity Flashcards

1
Q

What molecules are the model immunogens/antigens used in immunology research? Why?

A

Proteins because most is known about the immune response to this class of molecule

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2
Q

What animals are the model immunogens/antigens used in immunology research?

A

Mice

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3
Q

What is the difference between antigens and immunogens? What to note?

A
  1. Antigens: molecules that can be recognized (bound) by antigen receptors of B cells (BCR) and T cells (TCR), but do not necessarily induce them
  2. Immunogens: molecules that can induce an immune response de novo and contain Pathogen-Associated Molecular Patterns (PAMPS) or DAMPS

Note: all immunogens are antigens, but not all antigens are immunogens

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4
Q

How can TCRs recognize antigens? Is this true for BCRs?

A

Antigens must be presented bound to (in the context of) a Major HistoCompatibility (MHC) molecule

NOPE - BCRs can bind antigens directly

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5
Q

What is immunogenicity?

A

Measure of how effective a substance is at provoking an immune response against it

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6
Q

Are all vaccines immunogens?

A

Not all, but some:

  1. Whole bacteria and viruses vaccines are
  2. Sub-unit vaccines (i.e. purified components) may not be (e.g. tetanus)
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7
Q

What is the immunoglobulin super-gene family? What does this mean?

A

Gene family including:

  1. BCR
  2. TCR
  3. MHC

Means they have structural similarities:

  1. Domain-like structure
  2. Form a 3D structure that is complimentary to the ligand at the N-terminus = paratope that binds the epitope/antigenic determinant
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8
Q

What does signaling through BCRs and TCRs require?

A

Requires the co-operation of additional molecules to transduce the signal to the interior of the cell:

  1. BCRs: Igβ and Igα with cytoplasmic tails (ITAMs)
  2. TCR: CD3 and ζ chain with cytoplasmic tails (ITAMs)
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9
Q

What is a BCR exactly?

A

Cell membrane form of an antibody

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10
Q

8 differences between BCRs and TCRs?

A
  1. BCR is membrane-bound and secreted/TCR is only membrane-bound
  2. TCR has the same structure as one of the arms of BCR
  3. BCR recognizes epitopes on the solvent exposed surface of a protein/TCR binds to epitopes presented by MHC molecules
  4. BCR can recognize conformational and linear epitopes/TCR can recognize linear epitopes
  5. BCR involves binary complex of membrane Ig and antigen/TCR involves ternary complex of TCR, antigen, and MHC molecule
  6. BCR binds soluble antigen/TCR binds particulate antigen
  7. BCR recognizes proteins, polysaccharides, lipids, glycolipids, glycoproteins, etc./TCR recognizes mostly proteins, but also some lipids, oligosaccharides, and glycolopids presented on MHC like molecules
  8. No somatic mutations possible for TCRs
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11
Q

Do BCRs and TCRs have a cytoplasmic component/tail? What does this mean?

A

NOPE

They cannot transduce signals to the inside of the cell

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12
Q

What are ITAMs?

A

Immunoreceptor tyrosine-based activation motifs

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13
Q

Form of CD3?

A

Heterodimer

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14
Q

Other name for paratope of antibody?

A

Variable domain

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15
Q

Structure of BCR?

A
  1. Two long chains = heavy chains

2. Two short chains = light chains

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16
Q

Form of TCR?

A

Heterodimer

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17
Q

Form of MHC molecules?

A

Heterodimers

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18
Q

Structure of MHC Class I molecules?

A
  1. α chain with 3 α domains: 1, 2, and 3, with 1 and 2 forming a cleft together to bind a peptide
  2. β2-microgobulin domain non-covalently bound
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19
Q

Other name of peptide binding cleft of MCH?

A

Peptide binding groove

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20
Q

What do MHC I bind?

A

Peptides generated in the cytoplasm of the cell, which may derive from:

  1. Aging self protein molecules that are replaced as a normal housekeeping function of the cell
  2. Pathogens in the cytosol
  3. As a result of the cell undergoing malignant transformation
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21
Q

What do MHC II bind?

A

Peptides derived from pathogens that have been taken up from outside the cell by the process of phagocytosis and been broken down inside the phagolysosome of professional APCs

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22
Q

Where does loading of MHC I occur?

A

In the ER

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23
Q

Where does loading of MHC II occur?

A

Late endosome/phagolysome

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24
Q

Structure of MHC Class II molecules?

A
  1. α chain with 2 α domains: 1 and 2
  2. β chain with 2 β domains: 1 and 2

β1 and α1 form a cleft together to bind a peptide

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25
Q

2 types of antigens/immunogens?

A
  1. Foreign: dangerous or innocuous

2. Self

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26
Q

What are the 9 properties of antigens i.e. the factors that influence their immunogenecity?

A
  1. Foreignness
  2. Molecular Size
  3. Chemical nature and composition
  4. Physical form
  5. Genetic factors
  6. Age
  7. Degradability
  8. Dose of the antigen
  9. Route of administration
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27
Q

How does foreignness of an antigen affect its immunogenicity?

A

The greater the phylogenetic distance the more immunogenic

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28
Q

How does molecular size of an antigen affect its immunogenicity?

A
  • Antigens are generally 14 kDa to 600 kDa
  • Molecules < 5-10 kDa are poor immunogens
  • Small molecules below about 1 kD are not antigenic
  • Some polysaccharides must be > 1,000 kD to be antigenic because they lack structural complexity
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29
Q

How do chemical nature and composition of an antigen affect its immunogenicity?

A

Generally, the more chemically complex the more immunogenic (e.g. with disulfide bonds, with 3D folded structure)

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30
Q

How does physical form of an antigen affect its immunogenicity? Why?

A
  1. Particulate antigens are more immunogenic than soluble ones because dendritic cells have an easier time taking up particulate antigens
  2. Denatured antigens are more immunogenic than the native form
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31
Q

How do genetic factors of individuals affect the immunogenicity of an antigen? Why?

A

Some substances are immunogenic in one species but not in another and some substances are immunogenic in one individual but not in another

Reason: the MHCs’ affinity to peptides is genetically determined

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32
Q

How does age of individual affect the immunogenicity of an antigen? Why?

A

Usually the very young and the very old have reduced ability to elicit an immune response to an immunogen

Reason: immune system is suboptimal

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33
Q

How does degradability of an antigen affect its immunogenicity? Why?

A

Antigens that are easily phagocytosed and degraded are generally more immunogenic

Reason: if it cannot be degraded it cannot be loaded onto an MHC

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34
Q

How does dose of an antigen affect its immunogenicity? Why?

A

There is a dose of antigen above or below which the immune response will be suboptimal

Reason: not enough antigen to trigger the dendritic cell or too much and saturates it/paralyzes it

35
Q

How does route of administration of an antigen affect its immunogenicity? Why?

A

It can alter the nature of the response

Reason: given later in the course

36
Q

Which APC is designed to take up soluble antigens? Why?

A

B cells because they have cell-associated Igs

37
Q

What are adjuvants?

A

Any substance that enhances immunogenicity => molecules that contain pathogen-associated molecular patterns (PAMPS) or DAMPS (danger-associated molecular patterns)

Some convert soluble antigens to particulate antigens

38
Q

4 effects of PAMPS binding to PPRs?

A
  1. Signal transduction
  2. Cytokine release
  3. Chemokine release
  4. Upregulation of various other molecules
39
Q

What is an example of an antigen that requires an adjuvant to be immunogenic?

A

Tetanus toxoid vaccine

40
Q

Do adjuvants form stable linkages with the immunogen?

A

NOPE

41
Q

What is an example of a human adjuvant that convert soluble antigens to particulate antigens?

A

Al(OH)3

42
Q

Modes of action of Al(OH)3 adjuvant?

A
  1. Delayed release of antigen

2. Enhanced uptake of antigen by APCs by converting soluble antigens to particulate antigens

43
Q

Mode of action of complete Freund’s adjuvant?

A

Activates Th1 cells through TLR2 and TLR4

44
Q

Composition of complete Freund’s adjuvant?

A

Oil-in-water emulsion with dead mycobacteria

45
Q

Toxicity of complete Freund’s adjuvant?

A

High

46
Q

Toxicity of Al(OH)3 adjuvant?

A

Very low

47
Q

What are immune stimulatory complexes (ISCOMs)?

A

Adjuvants

48
Q

Composition ISCOM adjuvant?

A

Matrix of Quil A (saponin = amphiphatic glycoside) containing viral proteins

49
Q

Toxicity of ISCOM adjuvant?

A

Low

50
Q

Mode of action of ISCOM adjuvant?

A
  1. Delivers antigens to cytosol

2. Allows induction of cytotoxic T cells

51
Q

Do BCRs and TCRs recognize the entire antigen?

A

NOPE

52
Q

Length of B cell epitope? What is this comparable to?

A

15-22 AAs

Length of peptides bound by MHC II

53
Q

How many H bonds between epitope and paratope?

A

75-120 H bonds

54
Q

Which are longer: peptides bound by MHC I or MHC II?

A

MHC II

18-20 vs 9-12 AAs

55
Q

How can the number of epitopes affect the immune response? What do we call these antigens?

A

The immune response is more likely to be successful if the antigen contains a large number of different epitopes =

  1. Multivalant antigens with multiple epitopes that are identical or different
  2. Multideterminant antigens with multiple structurally different epitopes
56
Q

3 types of epitopes? Which is most potent?

A
  1. ***Immunodominant
  2. Subdominant
  3. Cryptic
57
Q

Differences between BCR and TCR epitopes?

A
  1. B-cell epitopes are generally accessible, mobile, hydrophilic and can be derived from native or denatured proteins
  2. T-cell epitopes are generally hydrophobic and are derived from the interior of the folded protein
58
Q

What is a cryptic epitope? Example?

A

Epitope exposed by conformational change of the antigen

Example: HIV binding on receptor on CD4 T cell changes its conformation prior to entry into the cell

59
Q

Other name for conformational epitope?

A

Discontinous epitope

60
Q

What is a neoantigenic epitope?

A

Epitope created by proteolysis

61
Q

What is a hapten? Example?

A

Small organic molecule of simple structure that does not provoke antibodies when injected by themselves

Example: urushiol = skin-sensitizing agent in poisoin ivy

62
Q

How can antibodies against haptens be raised? What is this called? What to note?

A

If haptens are covalently attached to a protein carrier (does not need to be an immunogen) that is used in priming and challenge => carrier effect

Note: anti-carrier protein and anti-protein-hapten complex (neoepitope) antibodies will also be formed (minor though)

63
Q

Why are anti-hapten antibodies important medically?

A

They mediate allergic reactions to penicillin and other compounds that elicit antibody responses when they attach to self-proteins in the blood

64
Q

Other name for linear epitope?

A

Sequential epitope

65
Q

What is the paratope formed by?

A

3D structure of the variable domain of the heavy and light chains

66
Q

What does the strength of the binding between the epitope and the paratope depend on? What is this called?

A

Depends on the goodness of fit (complementarity) between paratope and epitope = hand in glove concept

67
Q

What are the 4 different types of binding between an epitope and a paratope? Provide an example for each.

A
  1. Pocket: ferrocene (small hapten) with the complementaritydetermining regions (CDRs) of a Fab fragment
  2. Groove: HIV peptide
  3. Extended surface: hen egg-white lysozyme and the Fab fragment of its corresponding antibody (HyHel5) (all six CDRs of the antigen-binding site are involved in the binding)
  4. Protruding surface: antibody against HIV gp120 antigen has an elongated CDR3 loop that protrudes into a recess on the side of the antigen
68
Q

Describe the binding between MHC I and peptides.

A

Peptide is bound in an elongated conformation with both ends tightly bound at either end of the cleft

69
Q

Describe the binding between MHC II and peptides.

A

Peptide is also bound in an elongated conformation but the ends of the peptide are not tightly bound and the peptide extends beyond the cleft

70
Q

What exactly is recognized by T cells?

A

The upper surface of the peptide:MHC complex composed of residues of the MHC molecule and the peptide

71
Q

Why do MHC II bind longer peptides than MHC I?

A

Because with MHC II the ends of the peptide are not tightly bound and the peptide extends beyond the cleft

72
Q

Can one paratope bind multiple epitopes?

A

YUP

73
Q

What is a cross-reacting paratope?

A

Paratope that can bind multiple epitopes

74
Q

What forces bind paratope to epitope? What does it mean?

A

Noncovalent forces:

  1. Electrostatic forces between opposite charges
  2. Hydrogen bonds
  3. Van der Waals forces
  4. Hydrophobic forces

=> REVERSIBLE binding

75
Q

Do covalent bonds occur between antigens and naturally produced antibodies?

A

NOPE

76
Q

What is intrinsic affinity between paratope and epitope?

A

The goodness of fit between a single epitope and paratope aka the degree of complementarity

77
Q

What is functional affinity between paratope and epitope?

A

The increase of affinity resulting from valency, i.e., 2 or more epitope-paratope interactions

78
Q

What is avidity between paratope and epitope?

A

The average function affinity of a population of antibodies recognizing epitopes on an antigen

This is what happens in a normal polyclonal humoral immune response

79
Q

By how much is affinity increasing by bivalency?

A

x10,000 increase

80
Q

What is a multivalant antibody?

A

Antibody molecules that have either two, four or ten paratopes

81
Q

What are mitogens? Which cells can they activate?

A

Antigens that trigger signal transduction pathways in which mitogen-activated protein kinase (MAPK) is involved, leading to mitosis

They have the capacity to activate ALL B cells or ALL T cells and some can activate both B and T cells

82
Q

What are superantigens? Which cells can they activate?

A

Antigens from some bacteria and viruses that can bind independently to MHC class II molecules outside the peptide-binding site and to TCRs (Vβ domain = variable domain) away from the complementarity determining regions, regardless of their specificity

They can activate any CD4 T cell that has the appropriate binding site on the Vβ domain.

83
Q

What are T-independent antigens? What are they important for? What to note? Which cells can they activate?

A

Antigens with repeating epitopes that can activate B cells without the need for T cell help

This ability is important early in the adaptive immune response to generate IgM antibodies

Note: however, without T cell help, B cells cannot make other types of antibody such as IgG or IgA

84
Q

Difference between particulate and soluble antigens?

A
  1. Soluble antigens: molecules that dissolve in a solvent in the human body, the solvent being tissue fluid, lymph, blood, etc.
  2. Particulate antigens: microorganisms (bacteria, fungi, virus particles, etc.)

The importance difference between the two is the ease with which antigen-presenting cells (APCs) take them up. Only the B-cell takes up soluble antigens efficiently. The DC and macrophage (MO) use pinocytosis which is less efficient.

SMP - MIM Part 1 (14 decks)

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