3. Humoral Immune Responses Flashcards
What broad class of antigens is T Dependent for B Cell antibody production?
Protein antigens
What class of antibody is produced in greater numbers during the secondary antibody response?
IgG
Which complement system is often activated by the presence of polysaccharides?
Alternative pathway
What is the function of CD81?
Ensures normal CD19 expression, and forms a complex with CD19 as well.
What is required for T Follicular Helper Cell (Tfh) activation?
Sequential activation by dendritic cells, then by activated B Cells
What disease has been linked to a polymorphism in FcγRIIb?
Systemic lupus erythematosus
What is the function of the CD19 B Cell co-receptor
Acts as the dominant signaling component of B Cells.
Works with CD21 to lower the antigen threshold for B Cell activation (positively regulates B Cell activation)
Where would you find high affinity B Cells?
In the light zone of the germinal center with the follicular dendritic cells.
What class of antibody is produced in greater numbers during the primary antibody response?
IgM
How does somatic hypermutation lead to more specific antibodies?
Mutations occur in the V region while the B Cells are in the germinal center. Antigens contact the B Cells, and if they can internalize and present the antigen to Tfh cells, they are rescued from apoptosis. The B Cells with more specific antibodies are more likely to survive, ala Darwinian Evolution.
How does the activation of Helper T Cells by B Cells promote B Cell proliferation and differentiation?
Helper T Cells that are activated by B Cells begin to produce CD40L, which binds to CD40 on the B Cell and triggers differentiation.
What are two examples given for tyrosine phosphatases recruited by phosphorylated ITIMs?
SHP and SHIP
What is C3d?
A fragment of C3b, that is left on the antigen when C3b is degraded.
What do you find in the dark zone of the germinal center?
Proliferating B Cells
How to marginal zone B Cells shuttle antigens to the follicular region?
They bind immune complexes coated in compliment fragments with their compliment receptors (CRs) “in a manner independent of B Cell receptor specificity.”
Follicular dendritic cells then compete for binding and present to the follicular B Cells. The marginal zone B Cells then go back to the marginal zone.
Why are the germinal centers a location for “tremendous apoptosis?”
Because most B Cells are out competed by higher affinity B Cells
What are the three receptors involved in the B Cell co-receptor complex?
CD19, CD21, CD32
What is the function of Syk?
Phosphorylates BLNK, and recruits BTK and PLC-γ, which continue the B Cell receptor signal
What chemokine attracts naive B Cells to the lymphoid follicles?
What cell produces these chemokines?
CXCL13
Dendritic cells
How do phosphorylated ITIMs continue their inhibitory signal?
They recruit an SH2 domain-containing tyrosine phosphatase, which attenuates immune receptor signaling.
What is the function of IL-21?
Generates B-cell responses in germinal centers
Results in isotype switching, affinity maturation, and antibody production.
Which antibody response, primary or secondary, releases antibodies with a higher average affinity?
Secondary
What are the characteristics of a secondary antibody response, relative to the initial response?
Faster response (1-3 days instead of 5-10)
Peak response is higher (more antibodies)
More heavy chain isotype switching
Higer average affinity
pg 150
Where might memory B Cells be found?
Some may remain in the lymphoid organ in which they were produced.
Others recirculate between the blood and lymphoid organs
What causes activation of the B Cell receptor?
Cross Linking
The B Cell must have multiple receptors activated at one time
What cytokine promotes expression of IgA?
TGF-β
What is the function of the CD21 B Cell co-receptor?
It is a compliment receptor (aka CR2)
Works with CD19 to lower the antigen threshold for B Cells
By what mechanism is CD40 essential for B Cell isotype switching?
CD40 induces Activation-Induced Deaminase (AID) which is necessary for isotype switching.
What kind of antigen can be presented to marginal zone B Cells by marginal zone macrophages?
Polysaccharide antigens
How might one create a vaccine against a polysaccharide, since TI B Cells don’t create memory cells?
Create a hapten-carrier conjugate vaccine by linking a foreign protein to the polysaccharide.
What happens to the B Cells after B-T interaction?
The B Cells become short lived plasma cells, mainly producing IgM, and head to the germinal centers for affinity maturation, isotype switching, and memory B Cell / long lived plasma cell generation.
Which subset of B Cell antigens is typically multivalent?
Why does this matter?
T Independent (TI) antigens
(eg. polysaccharides)
Multivalency leads to additional cross linking, which helps amplify the B Cell’s intracellular signaling since it doesn’t have T Cell help.
What is the function of follicular dendritic cells?
They retain immune antigen-antibody complexes on their surface for long periods so they can contact B Cells.
Drives antibody affinity maturation.
What cell causes a B Cell to undergo isotype switching?
Tfh cells
What three receptors are used by follicular dendritic cells to retain antigens?
FcγRIIb (Fc receptor)
CR1 and CR2 (aka CD21 - compliment receptors)
Where does B Cell isotype switching typically occur?
Inside the germinal centers
What mechanism makes TLR signaling in B Cells an interesting topic for vaccine design?
TLR stimulation can cause proliferation of B Cells and differentiation into plasma cells, which means TLR signaling has an adjuvant effect in immunization.
What isotype of antibody is promoted by IFN-γ?
IgG (involved in intracellular pathogen blocking)
What kinase is responsible for phosphorylating ITIMs to inhibit B Cell responses?
Src kinases
How might a Tfh cell induce apoptosis in a B Cell not presenting an antigen?
Some Tfh cells produce FasL to recognize Fas on a B Cell and induce Fas mediated apoptosis.
When B Cells are activated, what receptor induces migration toward the T Cell zone?
CCR7
What are “natural antibodies” and what produces them?
Antibodies that are produced without prior exposure to the antigen
Produced by T Independent B Cells
Are Follicular B Cells T Dependent or Independent?
What about Marginal Zone B Cells and B1 Cells?
Follicular B Cells are T Dependent
Marginal Zone and B1 B Cells are T Independent
What subset of T Cells primarily responds to protein antigens?
Follicular T Cells
What do marginal zone B Cells primarily respond to?
Polysaccharides
How do larger antigens get presented to follicular B Cells?
They are consumed by APCs and carried there.
Why might a B Cell lymphoma be likely to occur?
Because the DNA breaks associated with somatic hypermutation and isotype switching facilitate incorporation of oncogenes.
What do you find in the light zone of the germinal center?
Follicular Dendritic cells
Where are the B-1 cells produced, and when?
They are produced in the fetal liver, by the eighth gestational week.
How does activation of CD21 (CR2) lead to phosphorylation cascades inside the cell?
By bringing CD19 in proximity to BCR associated kinases, causing CD19 to become phosphorylated, and recruiting Lyn kinase to phosphorylate ITAMs.
What anti-apoptotic protein is produced by memory B Cells that allows them to survive for so long?
BCL-2
What part of the B Cell receptor complex contains ITAMs?
Igα and Igβ
What are the functions of SHP and SHIP?
They remove phosphates from PIP3 and thus inhibit PI3-kinase activity in lymphocytes NK cells and innate immune cells
What process might randomly create a self-reactive B Cell after it’s already been activated by a non-self antigen?
Somatic hypermutation
What is the funciton of Tfh cells?
Secretion of IL-21 to assist in the germinal reaction (production of plasma cells)
Secretion of IFN-γ and IL-4 to control isotype Th1/Th2 switching
What might cause a microbial antigen that has been opsonized by C3d to have a greatly enhanced B Cell activation?
The antigen-C3d complex can activate the B Cell receptor and CD21 (CR2) simultaneously.
What is the relationship between PAMPs and B Cell activation?
B Cells produce TLRs to recognize PAMPs, and simultaneous PAMP recognition by BCR and TLRs may contribute to B Cell activation.
How do small antigens get delivered to B Cells in follicles?
They are washed directly into the follicles by the subcapsular sinus, where they meet B Cells without an APC.
What might induce T Independent B Cells to switch isotypes (even though this doesn’t happen very often)?
Specific antigens (Eg: Pneumococcal capsular polysaccharide induces IgG2)
TGF-β (induces IgA at mucosal sites)
BAFF produced by DC and Macrophages can induce AID synthesis
What is the function of the CD32 (FcγRIIB) B Cell co-receptor?
Contains an ITIM and negatively regulates BCR signaling
What class of antigen is more likely to elicit a secondary immune response?
Protein antigens
What is the function of fyn, lck, and blk?
Activate Syk kinase
What motif will you typically find on inhibitory receptors?
ITIMs
What part of the genome controls the Class-Switch Recombination (CSR)?
The “Switch” (S) Sequence
What happens when an antigen binds to a BCR, but an already secreted antibody bound to that antigen binds to FcγRIIb?
The phosphatases associated with FcγRIIb prevent the B Cell from being activated, despite the association with the BCR.
What is the main mechanism of defense against encapsulated bacteria?
Humoral immunity (antibodies)
How does affinity maturation occur?
Over time, in the germinal center, less and less antibody is available for binding. As a result, only the B Cells with the highest affinity / specificity for their antigen are able to survive.
What sort of pathogen is likely to be captured by plasmacytoid dendritic cells and delivered to marginal zone B Cells in the spleen?
Blood borne pathogens
When high affinity Ig - containing B Cells are selected for and become long lasting plasma cells, where do they go?
The bone marrow.
