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Even though we need diversity, what consistency do we need to maintain?
Consistency to recognize self HLA or use the constant regions of heavy chains
What are the two possible models for diversity?
Germ-line theory
Somatic variation
What is germ-line theory?
There is a different gene for each immunoglobulin/BCR (it is somehow encoded in our genome)
What is somatic variation?
The genome only has a few genes but they recombine to generate diversity (have all the parts but it is how you assemble them that makes the diversity) (encodes it in the genome but varies at the cellular level)
What is the concept behind VDJ recombination?
Assemble all the components in all the different combinations and release them to see if it can see that antigen. If it can’t then it will die
How does the immune system generate diversity?
With volume and by recombining gene fragments in many combinations
How is TCR and BCR diversity generated?
By permanent editing of genetic loci in individual cells
How do B cells generate diversity?
VDJ recombination/rearrangement
Romantic hypermutation/affinity maturation
Isotype switching
How do T cells generate diversity?
VDJ recombination/rearrangement
How are different isotypes generated?
Regions of the BCR locus can be put together in different combinations to have antibodies with different heavy chains (isotypes)
What is the variable region generated by?
VDJ recombination
Why might the B cell want to change its constant region?
This is because of what it might see in the environment
What can the same CH or CL region be connected to?
Millions of different VH or VL regions
What can the same VH region be connected to?
Different CH regions
Can B cells crop out pieces of their DNA?
Yes
What is the order for antibody production on the locus?
MADGE
If the B cell cuts out M from the locus will you ever get M again? Can you go from A to M?
No to both
Are there separate loci for each of the heavy chains in the genome?
Yes and they are selectively cut in B cells
Do separate genes encode the V and C regions in immunoglobulins?
Yes
What is the difference between individual and mature B cells?
Individual B cells had different sequences at the BCR locus and mature B cells were often missing parts of the constant locus
Why are B cells cutting pieces of DNA out of the locus?
To sequence the same locus over and over again
What os BCR diversity generated by?
Shuffling the constant and variable regions
What does the immune system encode for TCR and BCR?
Alternates for the gene loci
What does the random combination of the loci generate?
Extensive diversity while only taking up a bit of space in the genome (don’t have to keep replicating DNA because you keep certain segments)
What does a mature B cell encode? What is this process called?
A BCR locus where one of each of VDJ or VJ is retained then joined to a constant region (Heavy and light chain rearrangement)
Is the locus further edited and activated after VDJ or VJ is joined to the constant region?
Yes
Is VDJ the light or heavy chain?
Heavy chain
Is VJ the light or heavy chain?
Light chain
Will the B cell die if it can’t undergo heavy and light chain rearrangement?
Yes
Do B cells have two chromosomes (two loci)?
Yes
What is allelic exclusion? Does this occur in B cells?
It is when one locus is silenced in each B cell and one locus is kept one. This is to ensure the B cell only has specificity for one antigen. It is now able to make a BCR for that specific antigen
What is the end product of BCR gene recombination?
A B cell capable of making only one type of BCR
Is TCR recombination the same as BCR recombination? Does it include allelic exclusion
Yes for both
What is something different between TCR and BCR gene recombination?
TCR can not further mature beyond this stage so all the diversity is generated during VDJ rearrangement