Lec 16: B cell DADM Flashcards
VDJ recombhination
process by which T cells and B cells randomly assemble different gene segements
variable V, diversity D, and joining J regions
generates unqiue receptors (known as antigen receptors) that can collectively recognize many different types of molecuels
requries the activity of RAG1/2 compelx
consider VDJ recombination of light and heavy chains
bruh idk
multiple gene segements
VDJ segment recombination provides extensive combinatoral diveristy
P nucleotide addition
adds a short palindromic sequence at the join
allows for the coding of more peptides
Exonuclease trimming
loss of nucleotides at the joints
loss of aa = end up with a different sequence
non-tempalte N nucleotide additon
facilitated by TdT enzyme, up to 20 extra nuclotides can be added at the joints of heavby chain genes
combinatoral diversity
same heavy chain can combine with different light chains and vise versa
somatic hyper mutation
through the activity of an enzyme called activation induced (cytidine) deaminse (AID) and DNA repair process, the variable regions of IG-BcR locus ar emutated
lots leads to frameshift mutations, and thus the loss of a functional BcR
However can lead to new affinity/ a higher affinity for something you otherwise couldn’t code for
Class-switch recombination
CSR
process by which immunoglobulin heaavy chain locus contant region is changed, but the variable region remains the same (this is also called isotype swithing)
- > does not alter antigen specificity
- > central to the maturation of the antibody resposne
- > crucially requires cyidine deaminase AID
- > is an irreverible process
B cell development and clonal selection
clonal selection hypthesis:
each B cell bears a singal type fo BcR
*Upon stimulation, each cell will create a clone of cells bearing the same Ag receptor as the original
activated B cells can become antibody secreting plasma cells or memoty B cells
memory cells retain thier BcR, howver plasma lose them and secrete them instead
B cell antigen recognition
bcr clustering induces internalization and antigen presentation by b cell
Inital interactions induce a clustering of bcr and ther cognate antigens
- > antigen binding induces conformational change in cu4domain -> oligomerization of antigen-bound igM moleucles
- > antigen ahbound bcr moved into lipid rafts of the membrane -> allows for association of bcr signalling molecules -acitvation signal
bcell membrane rapidly spreads over the target membrane before contracting back
-> the entire process takes only minutes to comples
bcr causes smac formaiton
coordinated cell signalling and antigen extraction
b cells can capture membrane bound antigens from other APCs
T cell-depended B cell responses
classical Bcell activaion
B-cell bind antigen via bcr
within secondary lymphoid organs, inteaction with Th cells provides co-stimulation and cytokines for differentiation and memory cell production
T cell-depended B cell responses
B-cell bind antigen via bcr
antigen recognition by mature B cells provides a survival signal
if B cell doesn’t encounter its cogante Ag, it will die by apoptosis within moths after emerging from the bone marrow. ( tonic Bcr singlalling generaties a survival response)
inital activationa nd proliferation events
some antigen is internalised, processed and presented on MHCII
-> exogenous antigen (needs to be internalized and processes)***
T cell-depended B cell responses
within secondary lymphoid organs, inteaction with Th cells provides co-stimulation and cytokines for differentiation and memory cell production
B celles express CCR7 after antigen processing
B cells move into T cell rich zone until they encounter and interact with theri counterpart antigen-specific T cell
Bcells then down-regulate CCR7, leave Tcell areas and enter follicles
->innitial for mation of a GC
-> internalization and prossecing of antigen
=many different peptides
=many Th cells could activate the Bcells
=many novel peptides processed and presented on MHCII
-> many different T cells could recognize
BcR and TcR dont recognize the same thing
B cell differentation and memory
plasma cells are Ig producting machines
- > found within the first 5-6 days of immune responses in lymph
- > some stay in GCs and lymph nodes, others home back to the bonemarrow
Class-switched memory B cells have primarily a plasma cell fate
Other activated B cells (IgM+IdG+) move into the follicles and initatite a GC response
activated B cells (IgM+IdG+) move into the follicles and initatite a GC response
CD40/CD40L costimulation between B/T cells and cytokines form FDCs and Tfh cells stimulate proliferation further
follidle dark zone = densly pakced with proligerating B cells
Follicle light zone = B cells intersparesed within the FDC network
Collapse of antigen-specific B cell population
most B cells are lost at the ends of the primary immune response
-> lack of antigen means reduciton in survival signals-> apoptosis mechanism via Fas-FasL
Remaing memory cells
- > respond to lower concentration of antigens
- > faster response to antigen stimulation
- > higher-affinity ig receptors
- > class switched IgD-
- > longer lived cells
T-depended responses require help from T cells
TD
TD-1: Recognition of protein Ag+ Tfh helo
TD-2: Tecognition of lipid Ag+ NKTfh helo
convential T cell dependent B cell responses are optimal for producing memory plasma cells
-> long term immunity
T-independent responses do not require T-cell help
TI
TI-1: Ag binds B cells via PRRs and BcR
TI-2: Elicited by distinct Ag types whihc cross-link large numbers of BcRs
TI-3: B cells receive help from bone-marrow derived myeloid cells
Two subclasses of B cells mediate the response to T-independent antigens
B-1 and marginal zone B cells
B-1 cells
Polyspecific antibodies (broad and low affinity)= innate and adaptive
- > often recognize polysaccharides antigens
- > clustering of antigen (in large immune complexes) facillitaes antigen internalizationa and prevention of microbial disseminaiton
CD5+, and 5% of Bcell population, primarily produce IgM
self-renewing in the periphery, moslty in the peritoneal and pleural cavities
do not develop into memory cells
like gd T cells, functional niche bridges innate and adaptive immunity
Marginal zone B cells
Must receive low-level signals through bcR for Survival
self-renewing in the periphery
specilized to respond to blood-borne antigen entering the spleen
High-affinity requires T cells
Dual BcR and TLR engagement also generates high-affinity and class-swithced B cells
class switch recombination can occur independent of T cell help however, somatic hypermutation requires T cell help
What is the function of RAG1/2
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What is the funciton of TdT
Terminal deoxynucleotidyl transferase (TdT), also known as DNA nucleotidylexotransferase (DNTT) or terminal transferase, is a specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells. TdT adds N-nucleotides to the V, D, and J exons of the TCR and BCR genes during antibody gene recombination,
What is the function of AID
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What is VDJ recombination and how doe sit impact formation of the bcr
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What is class switch recombination and how does it impact antbody production
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List the steps of GC formation
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Compare and contrast T cell dependent and T cell independent B cell activation
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