Lecture 14 (pt 2) Flashcards
where do antigen-specific T and B cells meet?
in secondary lymphoid organs
where do naive B cells search for antigen?
in primary follicle
describe naive B cells searching for antigen
naive B cells in the primary follicle capture antigen displayed on follicular DC that displays a lot of antigens
how do B cells enter the secondary lymphoid organs?
via HEV
how do naive B cells capture antigen that directly enter the secondary lymphoid organs?
ex. viruses
pathogen enters in capsule and are captured by macrophages to be presented to B cells
what happens once B cells meet their antigen in the follicles?
B cells express CCR7 which lets them migrate to boundary region
what happens at the boundary region?
B cells meet T cells which have been activated by the same antigen –> B cells activate and make the FIRST WAVE of B cells that produce Ab
which B cells go thru the germinal center?
the FIRST WAVE of Ab-producing B cells don’t go thru the germinal center
then other cells go thru germinal center to make higher affinity Ab
where do T cells meet their antigen in the secondary lymphoid organ?
T cell zone
where are Tfh cells located?
in LN, spleen
what are Tfh required for?
Tfh are required for the germinal center reaction
what causes T cells to differentiate into Tfh?
lineage-determining TF called BCL6
Describe the activity of Tfh
- T cell meets antigen from DC
- T cell has BCL6 to make Tfh
- Tfh meets B cell
2 outcomes of Tfh interacting with B cell
- B cells that receive help from T cell and become Ab-producing cell
- B cells that migrate to germinal center
what ligand is important in the interaction btwn Tfh and B cell?
ICOS
What are 2 cytokines that are important for activating B cells?
- IL21
- IL4
What are the 2 waves of B cells?
- B cells that are short-lived and rapidly producing Ab
- B cells that migrate to germinal center with higher affinity and memory
what is the germinal center?
aggregation of T and B cells
where is the germinal center?
B cell follicle
2 zones of germinal center?
LIGHT
DARK
what happens in the light zone of the germinal center?
B cells capture antigen and interact with Tfh
what happens in the dark zone of the germinal center?
B cells leave the light zone and go to the dark zone –> B cells proliferate and increase Ig affinity
why is the dark zone called the dark zone?
very cell dense since B cells are proliferating
how does Ig increase its affinity
affinity maturation
in addition to affinity maturation, what happens to Ig?
also undergo class-switching
key role of germinal center
memory
why is it important that we increase Ig affinity?
so Ab can respond to any antigen with sufficient affinity
where and how do B cells first increase diversity?
in BM
there is random VDJ recombination in pre/pro/immature B cells before antigen is seen –> creates primary repertoire
where and how (2) do B cells increase diversity after BM?
in secondary lymphoid organs
1) SOMATIC HYPERMUTATION - mutations in variable region of Ig to increase binding affinity
2) CLASS SWITCH RECOMBINATION - diff genes for diff isotypes with switch regions to allow certain constant region
what enzyme allows for affinity maturation in secondary lymphoid organs
Activation Induced Cytidine Deaminase (ACID)
Why is there B cell negative selection?
B cells always re-testing ability of Ig to recognize antigen
what happens if the affinity of Ig to antigen is NOT strong enough?
B cells will be deleted
what happens if the affinity of Ig to antigen IS strong enough?
T cells will activate B cells and instruct them to enter germinal cell for further maturation
what happens if there is a defect or deficiency in genes involved in B cell development and function?
can lead to severe primay immunodeficiency and inability to mount proper response
what happens if a gene deficiency makes you unable to class switch?
cannot make specific Ab and only make IgM –> develop hyper-IgM syndrome and cannot fight infection
does the gut have T-independent or T-dependent pathways
both
why does the gut have immune response?
requires epithelium to prevent microbes from entering and must regulate microbiota
what is the most important mechanism of immune defense in the gut?
IgA
How does IgA allow for immune defense in the gut?
IgA forms dimer that can cross epithelium barrier and trigger immune exclusion
what is immune exclusion?
IgA binds microbes and prevents them from penetrating and entering lamina propria
what determines whether there is a T-dependent or T-independent response in the gut?
location!
where does the T-dependent response occur in the gut?
in Peyer’s Patch
what is a Peyer’s Patch?
secondary lymphoid organ located right below epithelium
what occurs in Peyer’s Patch?
has germinal center and generation of Ab in T-dependent manner
where does the T-independent response in the gut occur?
in lamina propria
describe the T-independent response in the gut
DCs produce mediators like BAFF and APRIL that are recognized by the TACI receptor on B cell
this signal is sufficient to promote differentiation of IgA-producing plasma cells in the gut
what is a good way of determining whether a pathogen triggers T-dependent or T-independent response?
give pathogen to control mice and mice without T cells –> compare the production of Ab in absence and presence of T cells
which 2 pathogens allowed for production of Ab only when T cells are present?
- Mucispirillum
- SFB
How can you determine if there are germinal center reactions occuring?
Day 0 - cells have fluorescence of 1 colour
Day 7 - lots of colours with differentiation
Day 14 - just 1 colour proliferates via clonal expansion
what determines the B cell response in COVID?
the severity of the infection
describe the production of B cells with SEVERE COVID
Impaired germinal center reaction –> plasma and memory B cells are made outside of the germinal center in the extra-follicular space
describe the Ab with SEVERE COVID
Since B cells not produced in germinal center, they are lower affinity Ab
describe the production of B cells with MILD COVID
Make germinal and non-germinal center plasma and memory cells
when are B cells APC?
In germinal center to present antigen to Tfh
3 main functions of B cells
- Ab production
- Ag presentation
- Cytokine production
2 treatments for MS
- Anti-CD20
- TACI-Ig
what does anti-CD20 do?
deplete B cells to prevent them from reaching the brain and creating inflammatory lesions –> helps disease!
what does TACI-Ig do?
acts on plasma cells to reduce serum Ab titers (only affects circulating B cells) –> does NOT help disease!
in general, why do anti-CD20 and TACI-Ig have different effects on disease severity
B cells have diff roles in diff contexts
why does anti-CD20 treatment work?
Anti-CD20 removes B cells that make pro-inflammatory cytokine IL6 –> treatment prevents inflammation via blocking this cytokine
why does TACI-Ig not work?
plasma cells produce inflammatory cytokines that are actually beneficial –> treatments prevents this benefit
