Lecture 15 Flashcards
Where are membrane-bound antibodies found?
Where are secreted antibodies found? What can these become and eventually develop into?
Membrane-bound found in LN and spleen
Secreted is found in the bloodstream
- Become short-lived plasma cell
- Can become memory cells
What are the membrane-bound Ig?
IgM/IgD only membrane-bound BCRs
Can IgM be secreted? If so, how?
IgM can also have secreted form
-Loses its tail piece and TM segment
What is the membrane-bound or secreted form dependent on? What type of secreted protein do activated B cells increase?
Form is dependent on alternative processing of primary RNA
-Activated B cells increase the amount of secreted µ protein
What 3 structures are found on secreted antibodies? Describe the 2 regions secreted Ig contain.
Heavy and light chains
Fc region
-Effector region (determines activity)
Fab region
- Ag binding fragment
- Comprised of both heavy and light chain
- Contains CDR which are varied mutations to give specificity
Where does class switching occur on the Ig? Which region is actually being changed?
Occurs with the Heavy chain
-Changes of the constant region
Where does class switching occur? What does it require? Is there a change in Ab specificity?
Occurs in germinal centers of the LN
Requires T follicular helper cells
NO CHANGE IN AB SPECIFICITY
Which Ig does IFNy stimulate? What 2 things is this Ig used for?
INF-y - -> IgG
Used for opsonization of phagocytes, complement activation
Which immunoglobulin does IL4 stimulate? For immunity from what? What does this Ig contribute to?
IL-4 - -> IgE
Immunity from helminths
Allergies
Which immunoglobulin do TGF-Beta and BAFF stimulate? For what kind of immunity?
Where does TGF-Beta come from?
Where does BAFF come from?
TGF-Beta, BAFF - -> IgA
-Mucosal immunity
Note* TGF-Beta comes from Treg cells and Macrophages
Note* BAFF comes from DCs and Macrophages
Interactions between what induces Activation Induced Deaminase (AID)? Note what cell each receptor is found on. What is process AID required for?
CD40 on APCs (ex. B cells)
CD40L on T cells
Interactions induces AID (THIS IS REQUIRED FOR CLASS SWITCHING)
What cell activates Class Switching Recombinase? To which region (variable or constant) does this work in? What specific genes does it change?
Where is the switch (S) sequence found?
What 3 molecules work together to splice and loop out DNA at the S sequence?
In cells activated by Tfh cells
Changes Cµ/∂ gene to other C-heavy gene
Switching (s) sequence in front of each heavy chain gene
AID, UNG, APE1 work to splice and loop out DNA at the S sequence - -> piece of DNA is excised to specific new heavy chain gene
Describe the mechanism of action for Class Switching.
Tfh -> CD40: CD40L -> AID -> (Cytosine -> Uracil) -> UNG -> APE1
For class switching, describe the functions for each of the following molecules:
Tfh CD40:CD40L AID Cytosine -> Uracil UNG APE1
Tfh cell presented to by B cell -> Induces CD40L expression
CD40 on B cells binds to CD40L on T cell
CD40:CD40L interaction induces the production of AID
AID deaminates cytosines
UNG removes Uracils
APE1 endonucleases make nicks to cause looping out of the DNA and remove part of the sequence
In what type of activation does B cell affinity maturation occur?
Only occurs in B cells activated by T-cell dependent Ags
For affinity maturation of B cells, where does the mutation occur in? How many mutations per cell division?
Causes mutations in the variable region that allow the Ab to bind stronger
- One mutation/cell division
- Occur in V (variable) region* typically in Ag-binding
In what zone does affinity maturation occur in?
Light zone
Describe affinity maturation in terms of availability of Ag. What kind of B cells will bind to Ag first?
What 2 mechanisms protect B cells from apoptosis?
As Ag is eliminated, less available in GC -> B cells with high affinity to Ag will bind first
- Other weaker B cells will undergo apoptosis via Fas:FasL
- High affinity activated CD40:CD40L signaling and Fas inhibitors (protects from apoptosis)
What occurs in the dark zones and the light zones of the germinal center?
Dark Zones- Somatic Hypermutation and Proliferation
Light Zones- Affinity Maturation via FDC and Class Switching via Tfh cells
-Where apoptosis of many B cells occurs due to the lack of affinity for Ag
Where do lymphomas (B cell tumors) develop? Why?
Lymphomas ( B cell tumors) develop in GC
Higher risk of this here because somatic hypermutation and isotype switching
What can somatic mutation also cause within the dark zone of the germinal center?
Autoimmunity
-Somatic mutation defect can produce self-reactive B cells
What are plasma cells and what are the two types?
Terminally differentiated B cells -> LOTS of Ab
Short lived
Long lived
Describe short lived plasma cells. Where are they generated/do they require T cells? Where are found after they are generated?
Generated in extrafollicular compartments in T-INDEPENDENT response
Found in the secondary lymph nodes
Describe long live plasma cells. Do they require T cells? What kind of Ag do they respond to? What 2 signals are required to generate long lived plasma cells. What signal maintains them? how long can they live? How long does it take to mature after immunized at the doctors office?
Generated in T-DEPENDENT repsonse
- To protein Ag - Generated by signals from BCR and IL-21 - Maintained by BAFF - Lives months to years - Occurs 2-3 weeks post immunizations
Long lived plasma cells constitute about how many of the Abs found in healthy adults?
Describe the pathway for differentiation of long lived plasma cells? **Make sure to note where they reside for good when they are fully mature
-Constitutes 50% of Abs in healthy adults
In GC (plasmablasts) -> enter circulation -> bone marrow -> differentiate
Where are memory B cells generated and in response to what?
Generated in GC in response to T-dependent Ags
What protein does memory cells express high amounts of?
What other 2 structures do memory B cells express high levels of?
Express HIGH Bcl-2
-Anti-apoptotic protein
Express high affinity BCR and switched isotypes
For memory cells, compare primary and secondary response to Ab production in terms of speed? Do memory B cells require helper T cells?
Allows faster Ab production in secondary exposure to Ag cells
-Still require Th cell mediated regulation just works faster than in naïve B cells
Where are memory B cells located?
Some remain in LN, others circulate
What do T-Independent B cells react to? What do they activate? How are these B cells activated? (think of the previous question)
Any non-protein Ag (MAJOR MECHANISM FOR IMMUNITY TO ENCAPSULATED BACTERIA)
Often activate complement (alternative) -> C3b to C3d which binds CR2 on B cells
What kind of Abs do T-Independent B cells produce? What kind of affinity maturation do they have?
What kind of Ig do they produce? Describe the diversity of this Ig’s isotype switching.
Most ags that activate the T-independent B cells are multivalent. What does this allow for B cells?
Abs produced here are low affinity (little affinity maturation)
Mostly IgM
-Limited isotype switching
Most are multivalent
-Allows cross linking which gives strong enough response to forego T cell interaction
Where are T-Independent B cells activated? What can they differentiate into?
Occur in marginal zone in B1 cells
Can persist to short lived plasma cells (IgM only)
Effective vaccines require ____ __ cell formation.
This only occurs if the vaccines can activate what?
Effective vaccines require memory B cell formation
Only occurs if vaccine can activate T helper cells
If vaccines can only work if they can activate helper T cells, what about vaccines that work on TI Ags? What are the polysacchrides linked to? What does this induce? Give an example of a vaccine that does this.
Polysaccharides are linked to foreign PROTEIN -> Hapten carrier conjugate
Induce high affinity Abs and memory cells for capsular polysaccharides
Ex. Pneumococcal Vaccine
Describe FcyRIIB. What portion of the Ab can it bind to?
When FcyRIIB binds, that signal does it initiate? What doe this lead to?
Receptor that can bind the Fc portions of Ab
-Allows Ag-Ab complexes to bind
Binding initiates signal -> production of phosphatases that inhibits B cell activation
What does FcyRIIB tell B cells to inhibit B cell activation? What kind of Abs dose this occur in? *What are the effects of the Complement Activation while this is going on?
Inhibition of B cell activation
- Tells B cells that enough Ab has been produced and to stop producing the Ab
- Self regulation
- This only occurs in secreted Ab
Note* Complement activation still activates an Ab response
