32 - B cells: Germinal Center Flashcards
2 zones in Germinal center
Dark zone & light zone
what happens in & what is found in light zone
Follicular helper T cells found in light zone
-To receive signal again
Follicular DCs (FDCs) retain Ag in light zone
What happens in germinal center:
B cells that first enter germinal center
-Have already encountered Ag (Signal 1 ) &
-activated by a T cell at T-B border (signal 2) & proliferated
–Have ability to produce IgM (mostly) /IgD of baseline affinity
—Transmembrane
In the germinal center:
o Somatic hypermutation
-Affinity for antigen improves
o Class switching
-From IgM/IgD to IgG or IgA or IgE
-Ag specificity of BCR is same – but lock & key better
Light zone thought to be…
primary site of plasma & memory cell differentiation
Dark zone thought to be…
site of somatic hypermutation
Role of FDCs & TFH cells in germinal center
Follicular DC (FDCs) -retain Ag
-FDCs serve as Ag concentration site for future selection & differentiation
TFH - provide signal 2 again - tell B cell to differentiate into plasma cell or memory B cell & which class of Ab to produce
-Interaction of B cells with follicular helper T cells provides conditions for:
–Differentiation
–memory cell production
–class switching
step by step: Secondary diversification in germinal center
- B cells in dark zone undergo somatic hypermutation = cells with same specificity but different affinity
- Resulting B cells migrate to light zone where they compete to bind Ag trapped on FDCs
- Higher affinity B cells will bind Ags= signal 1 (will internalize Ag:BCR & process it to present on MHC II) –affinity maturation
-Affinity maturation: select for survival of mutated B cell with high affinity for Ag - Lower affinity BCR fail to bind Ag = don’t receive signal 1 & die by apoptosis
- B cells that process Ag & present it on MHC II can interact with TFH (linked recognition)
- Signal received via CD40
-Part of signal 2 - B cells receive cytokines from TFH–class witching
-Informs type of Ab the B cells is going to produce - Theres a possibility that B cells can then re-enter dark zone & undergo additional somatic hypermutation
Outcomes of processes that occur in GC: Plasma cells
-They stop expressing high levels of BCR
-Secrete Ig of same specificity as BCR of their progenitor B cell
-Should bind Ag with higher affinity
-Secrete Ig can be IgG, IgA, IgE
Outcomes of processes that occur in GC: Memory B cells
-Express high levels of BCR
-BCR has same specificity as progenitor B cell
-BCR should have higher affinity
Which of the following describes the pathway used to process antigen
and the MHC class used to present antigen in B cells?
Exogenous pathway and MHC class II
Which of the following is false?
a) Allelic exclusion is the process used to ensure that each B cell synthesizes only one heavy and one light chain
b) Both IgM and IgD have 4 constant regions in their heavy chain
c) RSS are gene segments that are recognized by recombinase enzymes
d) TdT can add up to 20 nucleotides to cleaved strands (primarily in the D-J
junction of the heavy chain)
e) Plasmablasts still can proliferate
Both IgM and IgD have 4 constant regions in their heavy chain
Somatic hypermutation: what is protein responsible & what happens?
AID (Activation-induced cytidine deaminase)
- Protein responsible for somatic mutations=deaminate cytidine residues in ssDNA
- Cytidine to uridine, then removed
- Mismatch repair pathways + error-prone polymerase activity = shove any nucleotide into the nick
-Random = make affinity better/worse/same depend on affinity maturation - Produces individual point mutations in Ig heavy & light chain invariable regions
- Some of these changes = nonproductive
Ag-induced selection of B cells with higher affinity
Somatic hypermutation mainly occur in CDR loops of V regions
-CDR = more variable
B cells that can bind, process, present more Ag to T cells for cytokine assistance survive = affinity maturation
Increased Ab affinity with increased exposure
Every re-exposure with same Ag= Increase Ab affinity
-Bc theres more somatic hypermutation happening
Somatic hypermutation and affinity maturation leads to antibodies that
Have higher affinity and the same specificity
Class switching :
Class switching recombination (CSR)
CSR occurs within germinal center after Ag contact (signal 2 a 2nd time)
-Signals from class switch recombination
-B cells must receive costimulatory signals from CD40 to engage in CSR
-Which cytokine signal is received determines which isotype will be produced
Class switching=
which heavy chain constant region is going to be selected
- TH2 cytokines induce IgE
- Recombination (AID nicks) occurs between switch regions (pink)
o On after VDJ region
o One upstream of constant region to be recombined
what is switch regions, what happens here and where is it? (2)
Recombination (AID nicks) occurs between switch regions
o On after VDJ region
o One upstream of constant region to be recombined
Class switching recombination
- When B cell receives cytokine signal, transcription is active upstream of constant region -
- DNA now accessible to AID
-Activation-induced cytidine deaminase on ssDNA ( C to U and removed) - Nicks made on both strands of DNA
-Irreversible - Double stranded breaks in DNA upstream of constant regions -recombined
- DS break repair machinery repair break by cutting out the intervening DNA
- Selected region now adjacent to VDJ region
The light zone of the germinal center _____ whereas the dark zone of the germinal center____
is occupied by FDCs and follicular helper T cells; has mainly B cells
Memory:
Protective Immunity- exposure by 3 times
- Initial immune response:
-1st infection
-7-14 days: Ab & effector T cells increase - Protective immunity ( less than a week later)
-Inapparent reinfection
-Early reinfection handled by preformed Abs/effector Y cells from primary the previous response - Immunological memory (a year later)
-Mild/inapparent reinfection
-Late reinfection handled by immune memory B/T cells
-Respond faster better, more effective
memory response:
Ability of immune system to response more rapidly & more effectively on a 2nd encounter with an Ag
-Dependent on adaptive immunity mechanisms
–Ag-specific
–Memory responses occur after primary response (Secondary, tertiary) by lymphocytes initially generated late in primary response
–Long lived
memory leads to
resistance to a particular infectious disease upon re-exposure only AFTER having had that disease once before
o Or after being vaccinated
Differences between primary & memory responses:
o More Abs, more cells
o Different Abs (higher affinity), different lymphocyte features
-memory cells have different features
