Lectures 12 + 13: B cells Flashcards
Effector B cells are ___
Antibody secreting plasma cells
What are the two subclasses of B cells
B1- primarily mature in fetal liver and can self renew
B2- follicular- mature in bone marrow
What does the transmembrane region of BCR interact with for signaling
CD79 (Ig-alpha and Ig-beta)
What is the BCR complex
BCR, Ig-alpha, Ig-beta
Expressed by all B cells and is important during signal transduction during antigen induced B cell activation
Where does B cell development occur
Bone marrow
What directs the development of B cells
Stromal cells in bone marrow
How are the gene segments of BCR made
Random somatic recombination
What is the early pro B cell stage
Rearrangement of D-J on heavy chain mediated by RAG 1 and RAG2
What is late pro B cell
Rearrangement of V-DJ on heavy chain
First start with V-DJ rearrangement on first chromosome- if successful signaled to survive
If not make V-DJ rearrangement on 2nd chromosome- if successful then survive if not apoptosis
What is the first checkpoint in B cell development
Large Pre-B cell to check functional HC with VpreB lambda5
What is Large Pre-B cell step
Checks for functional heavy chain and compatibility with surrogate light chain-VpreB lambda 5
If comparable will express and proliferate line
What is allelic exclusion and why is it important
Ensures B cells express only one receptor type, if expressed more would hinder response especially T-independent B cell activation that requires crosslinking
What is X-linked agammaglobulinemia
Mutation in BTK-serine kinase important for signal transduction in pre-B cell
Disease is characterized by lack of B cells and low serum antibodies
What is small Pre-B cell stage
V-J rearrangement on LC
Start with kappa and then move to lambda
V-J rearrangement on kappa gene on first chromosome, if successful=survive and make kappa,mu IgM if not try V-J rearrangement on kappa gene on 2nd chromosome if works=survive and kappa, mu on IgM
If rearrangement on kappa doesn’t work move to lambda gene, V-J rearrangement on lambda gene on first chromsome if works=survive and lambda mu IgM, if not try V-J rearrangement on 2nd chromosome if works=lambda mu IgM, if doesn’t=apoptosis
What is combinatorial diversity
What V, D, J rearrangements are used and how do heavy and light chains interct
What is junctional diversity
During splicing what nucleotides are added or removed
What happens after completing small pre B cell process
Result is immature B cell that enters negative selection
What is negative selection
Assess self-recognition and reactivity to self, if reacts to self either will undergo clonal deletion, receptor editing on V-J on LC, anergy or immunological ignorance
What is clonal deletion
Removal of cells of a specific antigen specificity
What is receptor editing
Further genetic rearrangement to replace BCR with one that doesn’t self react
What is anergy
Permanent state of unresponsiveness, eventuality leading to death
What is immunological ignorance
Cells have affinity for self antigens but do not response
What occurs after negative selection of B cells
Alternative RNA splicing to make a VDJ region with either a mu or delta constant region
What does the mu constant region express
IgM
What does the delta constant region express
IgD
What does alternative splicing allow B-2 B cells to have
Synthesize both IgM and IgD and can now be released from bone marrow
Is B cell maturation antigen dependent or independent
Independent
What do B-2 cells make
Effector and memory B cells
What do B1 cells make
Effector Cells
T-dependent B cell activation
Protein antigens that lead to B cell activation with helper T cells
T-independent B cell activation
Non-protein antigens that lead to B cell activation without helper T cells
Where do B2 cells reside and what do they respond to
Reside in follicle and respond to TD antigens
Where are B1 cells located and what do they respond to
Located in mucosal tissue and pleural/peritoneal cavities and respond to TI antigens
What attracts follicular B cells
Attracted to follicles by chemokines secreted by follicular dendritic cells
If B cells are inactivated what happens
Exit the follicle following the S1P gradient
What happens when a B cell recognizes a protein antigen
Becomes activated resulting in proliferation and differentiation into memory and effector B cells
What are some things follicular B cells can undergo once activated
Class switching, affinity maturation and development of memory cells
What is the first signal in B cell activation
1a. Aggregation of BCR’s to crosslink when antigen binds
1b. Antigen crosslink BCR with CR19/21 instead of needing two BCR’s
What happens after B cells are activated by first signal
Migrate to outer edge of follicle into T cell zone and interact with Th cells and present antigen to T cell
What is the second signal for B cell activation
Interaction with B cell and T cell with CD40L and CD40 and Th cytokine release (IL-4 causes proliferation)
After activation and proliferation of B cells what happens
Rapidly differentiate into antibody producing plasma cells and migrate to extract follicular area, short lived plasma cells producing low affinity IgM
After B cells migrate to extrafollicular space what happens
Undifferentiated B cells migrate back to follicle with extrafollicular T cells (TfH)- site of germinal reaction
What is the germinal center reaction
Follicle B cells interact with FDC’s and TfH cells to undergo isotope switching and affinity maturation (somatic hypermutation)
What directs class switching
TfH interaction via CD40-CD40L and cytokines
What cytokine induces isotope switching to IgG
IFN-y
What cytokine induces class switching to IgE
TNF-alpha
What cytokine induces class switching to IgA
TNF-Beta
What are the steps in class switching
Requires recombining of V region with different constant region
What enzyme is responsible for class switching
Activation-induced cytidine deaminase (AIDs)
How does the enzyme AIDs work
Intentionally introduces mutations
What are the results of a deficiency in enzyme AIDS
Produces a normal or high concentrations of IgM with low IgA, IgG, IgE and patients have recurrent bacterial, respiratory and GI infections
How does affinity maturation occur
AID induced somatic hypermutation within gene segments encoding the variable domains of heavy and light chains
Exposure to antigen leads to new round of affinity maturation (ex: why we do booster vaccines to re-up memory cells and induce somatic hyper mutation)
What occurs after affinity maturation
Mutation in proliferating B cells in follicle so they now express a BCR with either higher or lower binding affinity for original antigen and must be tested, those that have the highest binding affinity to antigen survive, those that don’t undergo apoptosis
High affinity follicular B cells differentiate into
Effector B (plasma) or memory cells
What is the role of plasma cells
Make antibodies, no longer express MHC II or co-stimulatory molecules so can’t present antigen
What does the activation of memory B cells result in
Secondary immune response
What cells are activated in primary immune response
Naive B cells
what Ig is synthesized in primary immune response
IgM then go through affinity maturation, class switching to IgE, IgG, IgA and produce memory cells
What Ig is synthesized during secondary immune response
IgG no IgM
Affinity maturation occurs, creating higher affinity antibodies and more memory cells produced
B1 cells serve as _____ against pathogens at mucosal tissues, pleural and peritoneal cavities
First line of defense
How are B1 cells activated
Multivalent binding and cross-linking of BCR’s
