B cell activation and antibody production (part II) Flashcards
B cells must etner ____ to become mature
spleen
precursor B cells – ________ –> immature B cell
VDJ recombination
membrane BCR vs Soluble BCR:
difference are in ____ region due to ____ ____
tail alternative splicing
____ and ____ are co-expressed on naive B cells through the mechanism of alternative splicing of the primary mRNA transcript of the Ig heavy chain locus
IgM and IgD
expression of AID (activation-induced [cytosine] deaminiase) requires ____ - ____interaction
CD40 - CD40L
CD40L is on T helper cells, so AID is only present in ____ responses (protein Ag only)
thymus (T-cell) dependent
in the GCs, B cells express activation induced deaminase (AID) which initiates somatic ____ and affinity ____
hypermutation
affinity
affinity maturation is observed only in Ab responses to ____ Ags
thymus-dependent (TD)
affinity maturation occurs within the ____ , where somatically mutated BCRs undergo selection on antigen retained on ____
GCs
FDCs (follicular dendritic cells)
Ag retained on FDCs are retained in the form of ____ complexes and involves the interaction of both ____ receptors and FcgammaRIIB with these immune complexes on FDCs
immune
complement
mechanism of affinity maturation:
- Dark Zone:
- AID creates ____ mutations in ____ regions (also called somatic hypermutation)
- light zone processes:
- changed BCR is exposed to Ag on ____
- increased affinity receptors receive stimulus to ____ , decreased affinity receptors do not
- process repeats so further ____ increases can occurs
- Dark Zone:
- point V
- light zone processes:
- FDC
- live
- affinity
B cell proliferation takes places in the ____ zone of the GC
dark
dark zone:
- cognate contact between TFH cell recognizing the Ag presented by B cells ____ B cell
- the T cell-derived cytokines stimulate proliferation and ____ of B cell clone
- the ____-____ interaction activates somatic hypermutation in proliferating B cells leading to diversification of BCR
- T cell-derived cytokines also stimulate ____ switch of Abs produced by activated B cell
- activates
- expansion
- CD40-CD40L
- class
affinity maturation results from repeated ____
mutations
light zone:
- B cell with mutated BCR performs ____ scanning and if BCR affinity is increased then B cell proceeds to start proliferation process over again
- if the mutated BCR has low affinity then this B cell undergoes ____
- FDC
- apoptosis
how increased affinity is determined:
- mutations correlate with increasing ____ of the Abs for the Ag that induced the response
- Ag recognition promotes expression of ____
- Ag recognition stimulates production of ____ inhibitor
- affinities
- anti-apoptotic Bcl-2
- Fas
stronger ____ → more stimulation → more Bcl-2 → stronger T cell interations (CD40-CD40L) → more Fas inhibitor
affinity
many tumors of B cells, B cell lymphomas develop from B cells in ____
its caused by chromsomal ____ of various oncogenes into Ig gene loci
the DNA breaks associated with somatic hypermutation and isotype switching facilitate incorporation of ____
GCs
translocations
oncogenes
____ can contribute to the pathogenesis of autoimmunity
GCs
Ig isotype switching:
- isotype switching primarily occurs in the ____ and is driven by ____ cells
- some isotype switching may occur in B cells in ____ foci and driven by extrafollicular Th cells
- class-switching occurs in resonse to changing the ____ regions of the heavy chain
- Abs specificity which is determined by the ____ regions in the class-switched Abs remains unaltered
- GCs TFH
- extrafollicular
- constant
- variable
intracellular pathogens → increased ____ differentiation → increases ____ → ____ isotype switching
Th1
IFN-gamma
IgG
helminth infections → increased ____ differentiation → increased ____ → ____ isotype switching
Th2
IL-4
IgE
mucosal tissues produce ____ and ____ → increased IgA isotype switching
TFG-beta and BAFF
B cells in different anatomic sites switch to different Ab isotypes, this is controlled by local cytokine ____
milieu
both isotype switching and affintiy maturation depend on ____
AID (activation-induced deaminase
CD40 engagesment induces ____
AID
somatic mutation of ____ genes genreates Abs with different affinities for Ag
Variable
binding of the B cells to Ag displayed on ____ is necessary to rescue the B cells from apoptosis
FDCs
B cells that have undergone somatic mutation migrate into the FDC-rich ____ zone of the GC
light
survival of B cells with high-affinity BCRs
- Ag recognition (presented by FDC) induces expression of anti-apoptotic proteins of the ____ family
- high affinity B cells will preferentially endocytose and present the Ag for ____ cells in the GC which signal via CD40L to promote the survival of the B cells
- expression of engogenous inhibitors of ____ in high-affinity B cells may be activatd when their BCRs recognize Ag and thus be protected from death
- Bcl-2
- TFH
- Fas
long-lived plasma cells:
- generated in T-____ responses to protein Ag in GC
- ____ cytokine from TFH cells stimulate differentiation
- ____ provides survival signals
- T-dependent
- IL-21
- BAFF
short-lived plasma cells:
are generated in ____ compartments during T-____ responses
extrafollicular T-independent
plasmablasts are generated in GC and enter the circulation and home to the ____ ____ wher they differentiate into long-lived plasma cells
bone marrow
long-lived plasma cells are maintained by ____ allowing the cells to survive for long periods often as long as the life span of the host
BAFF
memory B cells:
- memory cells are generated mainly in the GCs for T-____ protein Ags
- acquire the ability to survice for long periods of time without continuing ____ stimulation
- typically are higher ____ and isotyped switched
- constitutively express ____ resulting in their long survival
- can be found both in ____ and in ____
- dependent
- Ag
- affinity
- Bcl-2
- secondary lymphoid organs and in circulation
TI Ab responses:
- typically respond to ____, ____ Ags; these are not presented on ____ and don’t activate T cells
- typically no isotype switching, ____ predominants
- multivalent , nonprotein MHC
- IgM
most TI Ags are multivalent:
- the majority of TI Ags are multivalent, being composed of ____ identical Ag ____
- such multivalent Ags may induce maximal ____of the BCR complex on specific B cells leading to activation ____ a requirement for cognate T cell help
- repeated epitopes
- cross-linking without
MZ B cells are a distinct population of B cells in the spleen that mainly respond to
polysaccharides
what B cells respond primarily to TI Ags
MZ B cells
B-1 cells
the most important TI Ags are
polysaccharides, glycolipids, and nucleic acids
many polysaccharides activate the complement system by the ____ pathway, generating C3b which first binds to teh Ag and then processed into C3d recgonzied by CR2 on B cell
alternative
memory occurs only if the vaccines are able to activate ____ , therefor effective vaccines must induce both affinty maturation and memory B cell formation
T helper cells
conjugate vaccines:
- TI Ags cannot produce memory because they are ____ Ags
- to resolve this, non-protein Ag (e.g. polysaccharide) is covalently linked to a foreign protein to form the equivalent of a ____ ____
- non-protein
- hapten-carrier conjugate
how are vaccines produced for TI Ags
- attach the TI Ag to a ____ (called a carrier).
- the protein is loaded onto MHC of APCs and the TI Ag is what’s recognized by the ____
- this allows for presentation of non-protein Ags to T cells so ____ interaction can occur and generate long lived plasma cells and memory
- protein
- TCR
- CD40-CD40L
Ab production feedback inhibition
- ____ (CD32) is a low affinity receptor for IgG found on B cells
- because it is low affinity, IgG will tend to form a complex with ____ first and then that complex sill bind with BCRs bringint IgG into proximity with FcgammaRIIB
- when IgG binds FcgammaRIIB it inhibits signals generated by BCR complex recognition of ____
- this results in feedback ____ for production of IgG
- FcgammaRIIB
- Ag
- Ag
- inhibition
