CSIM 1.18 Humoral Immunity Flashcards
What is the ‘unit’ of humoral immunity?
What is humoral immunity?
Antibodies produced by B cells
The molecular aspect of the adaptive immune response
What are the markers for B cells?
Proteins: CD19 and CD20
What is a terminally differentiated B cell called?
A plasma cell
What are B cell receptors?
B cell receptors are actually just antibodies
recall CGP book
Describe the structure of antibodies
- 2 heavy chains
- 2 light chains
- Hinge regions
- Constant region at C terminus
- Variable region at N terminus
- Disulphide links
IMG 45
What is the role of the constant region and the variable region? How many different forms does each have?
Constant region: (5 forms)
• Effector region that has a function depending on the antibody
Variable region: (10^18)
• Binds to pathogen
What are the 5 classes/isotypes of antibodies? What do these depend on?
The identity of the heavy chain of the constant region • IgG (γ-chain) • IgM (μ-chain) • IgD (δ-chain) • IgA1 (α-chain) • IgE (ε-chain)
What is the first antibody class produced?
What happens after this?
How can this be used clinically?
IgM
After antigen stimulation, some antibodies undergo isotype class switching, and substitute the μ heavy chain for α, ε or γ (NOT δ)
If the identity of the most prevalent antibody for a particular infection (e.g. measles) is IgM, the infection was recent, whereas if it is mostly IgG the infection is less recent
What are the types of heavy and light chain in the constant region?
Heavy:
• α, μ, δ, ε, γ
• All can be transmembrane OR secretory
Light:
• κ, λ (no real functional difference)
Describe how antibodies undergo isotype class switching
By ‘looping out’ heavy chain genes between ‘switch regions’ until the variable region is spliced next to the desired heavy chain gene
(example of alternative DNA splicing)
IMG 46
Which antibody isotype has the correct chain to be:
1) transferred through the placenta?
2) Classical pathway of complement activation?
3) Binding to mast cells
4) Secreted in the breast milk
1) IgG ONLY
2) IgG and IgM
3) IgE
4) IgA ONLY
Which antibody is found in gut, lung and eye secretions? Why this antibody?
IgA, because it’s constant region is designed for the transport across epithelia
Why are specific antibodies not coded for by genes?
What process is used instead to make a functional gene for all different antibody variable regions?
Because there are 10^18 variable region combinations and only 30,000 genes. B cells for ANY pathogen must be available at all times (just not activated yet).
V(D)J somatic recombination
Describe V(D)J somatic recombination
Instead of having separate genes for all possible variations of antibodies, the genetic information for ALL is stored in one super gene
There are three genes coding for variable region segments: • Variable (all possible versions) • Diversity (all possible versions) • Joining (all possible versions) One version for each variable region segment is randomly picked every time a progenitor differentiates into a B cell, e.g: • V1D1J1 • V1D2J1 • V5D4J4
Heavy chains need one V, one D and one J. Light chains need only one V and one J
Junctional diversity is then added, to give an overall vast number of possible variable regions
Which VDJ gene segments are found in the heavy chain portion of the variable region, and the light chain portion of the variable region?
Heavy chain portion of variable region has:
• One Variable
• One Diversity
• One Joining
Light chain portion of variable region has:
• One Variable
• One Joining
Describe what is meant by junctional diversity
When joining the V, D and J segments, the joining is done imprecisely, so that there are minor differences in position of V-D and D-J join
Furthermore N regions are added at random (nucleotides at V-D and D-J junction)
Which enzyme adds N regions during junctional diversification?
Terminal transferase
How are V, D and J versions selected at random?
Each version lies adjacent to recombination signal sequences, which are randomly sought out by complimentary Rag-1 and Rag-2 proteins, which ‘bring together’ whichever versions of each gene they happen to bind adjacent to
This ‘loops out’ the DNA in the middle, forming what is called a signal joint (a ring of useless DNA with no function) which floats away
The loose ends are then joined together, closing the DNA and placing the desired versions together
What is the name of an antigen that a B cell is specific for?
What is the name of a B cell which has not encountered this antigen yet?
What is the name of a B cell which has encountered this antigen?
Cognate antigen
Naive B cells
Experienced activated B cells
What are the two types of B cell activation?
Thymus dependent
Thymus independent
What are the Igα and Igβ proteins?
Transmembrane proteins found next to B cell receptors (transmembrane antibodies) which are closely associated with the heavy chain of the antibody and assist in signalling
NB: has no role in specificity
IMG 47
Describe the process of thymus dependent B cell activation
- Naive B cell receptor (BCR) finds complimentary antigen
- Multiple B cell receptors bind to the same antigen
- This causes clustering of BCRs, and thus clustering of their associated Igα and Igβ proteins
- These Igα and Igβ proteins can then dimerise, triggering intracellular signalling
What is the difference between a primary and secondary follicle in a lymph node?
Secondary follicles have an active germinal centre inside
IMG 48
Once B cells are activated by their complimentary antigen-specific T cell counterparts, what are the possible fates for this cell?
- Some become plasma cells and secrete immunoglobulin (IgM)
- Some become memory B cells
- Some proliferate in ‘clonal expansion’ with antigen-specific T cells to form a germinal centre (IgG, IgA, IgE)
By which process does affinity maturation occur in germinal centres?
What does this result in?
Somatic hypermutation
• As the B cells proliferate, single amino acids in the V region mutate (with enzyme help)
The change may or may not make a change (due to codon degeneracy) through synonymous change. Alternatively there may be a change in shape of the variable region, and thus a change in affinity for the antigen
During clonal expansion, If somatic hypermutation generates an antibody with a higher affinity for the antigen than the original antibody, what occurs?
What is this process called?
The new B cell binds to a complimentary T cell, which sends the B cell a survival signal, causing it to proliferate aggressively. The B cell then undergoes more somatic hypermutation to try and find an even higher affinity antibody
Affinity maturation
In which sections of the V region are most affinity maturation changes found and why?
- CDR1 (complimentary determining region)
- CDR2
- CDR3
These are the areas of the variable region that typically bind to the antigen
If a somatic hypermutation change leads to an antibody with lower affinity for the antigen, what happens?
The new BCR cannot bind to the T cell, and thus cannot receive its survival signal, and so undergoes apoptosis.
What do memory B cells allow?
Secondary humoral immune response:
• The process of presentation, T cell presentation, B cell activation, clonal expansion, somatic hypermutation and affinity maturation can be bypassed as they have already been performed
• Instead the memory cell simply becomes activated and proliferates, neutralising the microbe before symptoms can arise
What are the actions of antibodies on pathogens?
Neutralisation
• Binds to bacterial toxins
Opsonisation
• Covers pathogen, leaving the constant region exposed as a receptor target for macrophage ingestion
Complement activation
• The antibody activates complement which helps by coating the pathogen by complement opsonisation
Name the 3 ways antibodies vary
Isotypic differences
• Different isotypes (differing heavy chain)
Allotypic differences
• Slight changes due to genes (e.g. one amino acid difference from person to person)
• No functional difference
Idiotypic differences
• Different specificities (even if on same isotype)
IMG 49
What are the names given to the portion of an antigen recognised by a given antibody or antigen receptor?
Antigenic determinant or epitope
What does the heave chain switched to in isotype class switching depend on?
SPECIFIC CYTOKINES BEING EXPRESSED IN THE B CELL ENVIRONMENT
