germinal center response
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What are the secondary lymphoid organs?
spleen, lymph nodes, tonsil
How does a T cell become trapped in the T cell zone of the secondary lymphoid organ?
circulating naiive CD4+ T cell first recognizes APC in an antigen non-specific fashion via adhesion molecules; interactions stabilized by recognition of processed antigen on surface of APC by T cell
How must a T cell become active?
recognize peptide antigen bound to MHC-2 on APC and receive co-stim signal from same cell
What is the co-stimulatory signal?
CD28 on T cell interacting w/ B7 on APC; co-stim signal makes IL-2 which is needed for T cell proliferation
When can active T cells differentiate?
once interacted w/ IL-2 can become TH cells via IL-4
How do follicular B cells get to the T zone?
follicular B cells must recognize antigen to move to T zone of secondary lymphoid organ; directed by CCL19 and CCL21
Where are CCL19 and CCL21 produced?
T cell zone of secondary lymphoid organ
What interacts with the Ag-MHC-2 complex on B cells in the T zone?
TCR on TH2 cells; CD4 stabilize adhesion
TH cells and B cell must recognize epitopes of same molecular complex to interact
How is the B cell activated?
- signal 1: Ag/Ab interaction
- signal 2: co-stimulatory signals provided by IL-4 (from TH2 cell) and interaction between CD40 ligand (TH2 cell) and CD40 on B cell
*TH2 already activated by this point
What is hyper IgM syndrome?
CD40 ligand deficiency (from TH2 cell)
What are two pathways for activated B cells in the T zone to take?
- 1. differentiate/proliferate into plasma cells that secrete IgM
- 2. activated B cells and TH2 migrate into follicle; B cells (aka centroblasts) divide rapidly and form a dark zone in the germinal center
What composes the dark zone of the germinal center?
rapidly dividing centroblasts and TH2 cells
What composes the light zone of the germinal center?
centrocytes (non dividing); FDCs
What happens in the dark zone of the germinal center?
isotype switching, somatic hypermutation
What do centrocytes do?
centrocyte Ag receptors interact w/ Ag on surface of FDC in light zone of germinal center; facilitates high affinity Ag-specific B cells
What are the 2 possible pathways for activated follicular B cells?
- 1. differentiate into plasma cells
- 2. return to resting state to become memory cells
What can induce B cell responses in the absence of T cells?
bacterial polysaccharides, polymeric prot, lipopolysaccharides
B cell mitogen
substance w/ an intrinsic activity that can activate B cells indep of interaction w/ Ag receptor
can activate B cells through heavy BCR crosslinking of Ab on surface of B cell; this delivers both signal 1 and 2
over immune response, strength of Ab produced are changing and getting stronger
mech by which additional diversification of entire variable region of Ab occurs after the mature follicular B cell encounters Ag
req Ag, T cell help, in germinal center, AID protein
used in somatic hypermutation; converts C to U in DNA of V region and initiates mutation process
What does AID create?
mismatch (transition mutation)
OR UNG prot removes U to make abasic site (which can be knicked out and converted further into a transversion mutation
same set of antigenic determinants in the Fc of the heavy chains of the same class are the same
Heavy chain isotype switching
activated B cells in dk zone of germinal center of secondary lymphoid organ can switch from expression of IgM and IgD to expression of other heavy chain classes by asoc w/ rearranged VH gene segment w/ other heavy chain constant region (CH) genes
What is the significance of CH genes encoding Fc region of the Ab in isotype switching?
isotype switching allows B cells to produce Ab w/ other effector functions while maintaining specificity for immunizing Ag
second type of somatic recombination event in activated mature B cell; brings assembled VDJ exon into close proximity w/ another CH gene
Where does switch recombination occur?
btw switch regions (highly repetitive DNA) in heavy chain gene
What is another name for switch recombination?
deletional somatic recombination
How does switch recombination work?
signal induces two switch regions to come together and become ligated; intervening DNA is looped out and cut away; switch regions are in introns so reading frame is not messed up
How does AID work in switch recombination?
still converts C to U in switch region to create a base mismatch and initiate recombination process
What is the recombination process?
AID---(C to U)---> UNG---- (U to abasic)---> APE 1---ss knicks ---> DNA-Pk---staggered DS breaks ---> ---> DSBR machinery ---> class switch recombination
How does IL-4 play a role in isotype switching?
How does IFN-gamma play a role in isotype switching?
How does TGF-beta play a role in isotype switching?
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