lecture 1- B cell activation Flashcards
describe the early events of B cell development
early pro-B cell –> heavy chain rearrangement –> 1st checkpoint (pre-B cell testing) –> light chain rearrangement –> 2nd checkpoint (tests light chain)–> immature B cell (negative selection, then positive selection)
what role does the pre-BCR play?
signals from a properly assembled pre-BCR induces allelic exclusion at other heavy chain locus
- surrogate light chain (VpreB and lambda5) takes place of rearranged light chain– allows testing of heavy chain
- fully formed BCR has both heavy and light chains
what does survival of the pro-B cell depend on?
first on productive rearrangement of the heavy chain:
early pro-B cell (D + J on both chromosomes) –> late pro-B cell (V + DJ) on first chromosome –> pre-B cell (light chain rearrangements- kappa, then lambda)
how many times can the kappa chain try and rearrange
5 successive attempts
describe the selection process in B cells
- immature B cell undergoes neg. selection in bone marrow
. receptor editing the light chain in bone marrow allows immature B cell more changes to make a non-autoreactive BCR - if no longer self-reactive, leave bone marrow to circulation and secondary lymphoid organs express both IgM and IgD, search for antigen
. to survive and mature, immature B cells must enter lymphoid follicles and interact with FDC’s for survival signals- positive selection - competition with other B cells is the limiting factor for space in the follicle
after proliferation and activation, a B cell will differentiate into…
1- plasma cell- become secreted as antibody (IgM forever)
2- isotype switch
3- undergo affinity maturation (changes in antigen binding site)
4- become a memory B cell on cell surface
how do FDC’s store antigens for B cell stimulation?
FDC’s express 2 different types of complement receptors (CR1 and CR2) that bind to intact antigens/pathogens coated with complement opsonins
name the 2 types of B cell activation (the 2 types of antigens that activate B cells)
1- T-dependent antigens
2- T-independent antigens
how do B cells become activated?
when BCR cross-links with antigens, leads to signals for gene expression in nucleus
- signaling at cell surface through Igalpha and Igbeta requires BTK –> signal cascade –> gene expression and clonal expansion
- BTK necessary for activation- signals for pre-BCR
BCR triggering is greatly enhanced by what two things?
1- B cell co-receptor
2- CD40 on B cell with CD40L on T cell
describe B cell co-receptor
- made of CD19/CR2/CD81
- increase BCR signal intensity by up to 10,000 fold
- work best with complement-labeled antigens, bringing together complement receptors and BCR
- any complement-labeled antigen can lead to enhances BCR signaling as long as its recognized by BCR and involves co-recruitment of B cell co-receptor
T-dependent antigens require ___ and are typically ___
require T cell help for production of antibodies
- are typically protein antigens
describe CD40/CD40ligand interaction
- essential for T cell help
- BCR binds to antigen, sends signal 1- BCR takes up antigen and processes and presents back on cell surface, recognized by MHC Class II –> TCR recognizes MHC-peptide complex (the degraded portion, CD4 positive helper T cells) –> this causes interaction of CD40 and CD40L (signal 2) –> necessary for later affinity maturation and isotype switching
- cytokines provided by T cells also help to instruct B cell on what type of antibody response to make (may influence isotype switching)
what are the 2 types of T-independent antigens
1- TI-1
2- TI-2
what antibody do T-independent antigens end up producing
only IgM
describe TI-1
- BCR binds to antigen and a toll-like receptor on B cell binds to same antigen
- these 2 signals together enhance activation
- needs activation of BCR and TLR
- only IgM produced because no AID from T cells
describe TI-2
- repeated antigens so close together, all about cross-linking
- repetitive carbohydrate antigens present at high density on a pathogen surface, leads to extensive BCR cross-linking
how do T and B cells work together?
- in the cell activation relay, T cells get activated first by the DC, then help to activate B cell – B cells activated, process and present peptide, class II MHC recognizes, CD40L of T cell reacts with CD40 on B cell, provides signal 2, signal 2 tells B cell to express AID –> affinity maturation and isotype switching and also provides cytokines (signal 3) for more proliferation of B cells
naive T cells interact with…
dendritic cells in T cell zone- activated and undergo clonal expansion…at same time, B cells interact with FDC’s
- T cells give B cells the signals they need to undergo somatic hypermutation and isotype switching
describe plasma cells
- do not undergo affinity maturation, have no cell surface immunoglobulin or MHC Class II, no further division, specialized for antibody secretion
- entirely devoted to antibody production
germinal centers
other activated B cells migrate to a nearby follicle which becomes a secondary follicle, containing a germinal center
- sites where somatic hypermutation, isotype switching, and affinity maturation occurs
- where B cells are constantly proliferating and receiving T cell help (T cells select the highest affinity B cells)
long-lived plasma cells migrate to ___ to make antibodies longterm
bone marrow
