B Cell Immunity Flashcards
Describe the migration of mature naive B cells
Naive B cells enter the LNs across the HEV in the cortex
Slow down: L-selectin, CXCR5 (follicular chemokine receptor)
Stable arrest: LFA-1
Once in lymphoid tissue they migrate to primary follicles to sample Ags and receive survival signals from FDCs
What do mature naive B cells express on the surface?
BCR: IgM, IgD, Iga and b
Co-BCR: CD19, CD81 and CR2 (CD21)
HLA class II, CD40 and CD20
What are the two major divisions of B2 cells?
Follicular B cells which are re-circulating B cells and the majority
Marginal B cells which reside in the spleen and respond to blood borne polysaccharide Ags
Where are B1 cells located?
In the mucosa and they have limited Ag specificity
What happens if a B cell does not encounter a specific Ag in a LN?
It leaves the LN through the lymphatics and travels down the chain to the next LN
Characteristics of FDCs
Are not hematopoietic and do not process sAg or express MHC class II
They are not APCs
Express receptors for C3b (CR1) and IgG (FcyR)
Functions of FDCs
Ags are retained and concentrated in the follicles within LN by FDCs
Concentrate unprocessed opsonized Ags for naive B cells to sample for activation and activated B cells selecting of highest affinity Abs
Secrete cytokines for B cell recruitment, survival and differentiation
What are the three different mechanisms in which a first signal can be provided for B cell activation?
- Cross linking of several BCRs with signaling through Ig alpha beta ITAMs
- Cross linking of BCR with co-BCR with signaling through Ig alpha and beta ITAMs and with CR2 and CD19 signaling motifs
- Cross linking of BCR with TLRs with signaling through Ig alpha beta ITAMs and TLR signaling motifs
All three can be happening at the same time
What are the outcomes for the first signal of B cell activation?
Prepares the cell for interaction with second signal from Th cells
Receptor mediated endocytosis of BCR and Ag
Processing and presentation of Ag with MHC class II
Biochemical signaling
Increased expression of cytokine receptors
Secretion of levels of IgM
Migration of activated B cells
After activation B cells change their chemokine receptor expression and migrate to the edge of the follicular zone for interaction with activated Th cells for second signal
The newly activated T cells are also changing their chemokine receptors and moving towards the edge of the follicular zone
What changes occur in the activated B cell when it begins to migrate?
Downregulate CXCR5 and upregulates CCR7, migrates towards the paracortex, increases expression of MHC class II and B7 (CD80)
What changes occur in the T cells once they start to migrate along with the B cells that are also migrating?
Newly activated Th cells downregulate CCR7 and upregulate CXCR5, migrate towards follicles, increase expression of CD40L and cytokine secretion
What are the two ways a second signal can be provided for B cell activation?
T dependent and T independent
Explain the T dependent pathway of second signaling
Proteins
Activated CD4+ Th cell recognizes Ag displayed by B cell within MHC class II
B7 on B cell binds to CD28 on T cell
CD40L on T cell binds to CD40 on B cell
Cytokines bind to cytokine receptors on B cells
Induced expression of activation induced deaminase (AID) enzyme
Proliferation and expansion
Describe the T independent pathway of B cell activation
Everything other than proteins Mainly long repeating epitopes to be able to cross link several hundred BCRs to provide strong enough signal to bypass second signal from T cells Enough BCRs engaged to trigger enough Ig alpha and beta intracellular signaling to stimulate cell to secrete IgM No class switching, affinity maturation and little to no memory Can provide IgM Ab protection in a short amount of time
Why is B cell activation a two pronged approach (clonal selection)?
First signal: recognition of antigenic epitope by BCR
Second signal: maintains the specificity of the response to the specific epitope
This results in a large number of Ag specific plasma cells and Abs from rare Ag specific naive B cell
Describe the induction of anergy in B cells
B cells recognizing Ag without BCR cross linking, binding of co-stimulator ligands or cytokine support will not become activated
These cells become unresponsive to additional stimulus (anergic and tolerant)
Describe T follicular helper cells (Tfh)
CD4+/low levels of CD25 expression
Secrete IL-21, facilitates B cell survival, clonal expansion and differentiation into plasma cells
Secrete Th cytokines to influence isotype switching
Continued CD40L binding to B cell induction of AID
Cytokines released by Th and Tfh cells promote to general functions in B cells. What are these two functions?
- To induce heavy (H) chain class switching by opening switch regions in the heavy chain gene for somatic recombination
- To augment B cell differentiation and proliferation into plasma cells
What is the influence of IL-4 on isotype switching?
Induces IgG1 and IgE
What is the influence of IL-5 on isotype switching?
Augments production of IgA
What influence does IFN-gamma have on isotype switching?
Induces IgG3 and IgG2
What influence does TGF-beta have on isotype switching?
Induces IgG2b and IgA
Which process of B cells can only occur with T dependent Ags in which CD40/40L interaction is critical?
Heavy chain isotype switching and affinity maturation which often occur at the same time
What is the key enzyme in affinity maturation of B cells?
AID: converts Cs to Us
Describe the high affinity selection checkpoint by FDCs
Selective survival of the B cells producing the highest affinity Abs occurs in the GCs
FDCs provide intact Ag to the new BCR receptor specificity to sample
If binds with a higher affinity the B clone is selected for further differentiation to a plasma or memory cell
Interaction with which two cell types are necessary for survival of high affinity B cells?
FCDs and Tfh cells
Which cell makers do plasma cells express?
Decrease CD19 and CD20, HLA class II Increase D27 sIg class dependent — BCR is isotype switched to during process
What contributes to the long life span of memory B cells?
High levels of expression of the anti-apoptotic protein Bcl-2
Which surface markers do memory cells express?
CD27 and CD45R (O) and are sIg class dependent
What are survival niches for long lived plasma and memory cells?
Bone marrow and mucosal lymphoid tissue
Humoral immunity is the principle defense against what type of pathogen?
Extracellular
Effector functions of Abs are mediated by which region?
The Fc region but all functions are triggered by the binding of Ag to the Fab variable region
What are the two distinct functions of the Fc region of Abs?
Deliver Ab to inaccessible anatomical sites
Link bound Ag to molecules/cells that effect destruction (opsonin)
Immune complex binding via Fc receptor on phagocytes leads to
Receptor endocytosis and Ag processing
Binding of IC to FcR acts through signal transduction complexes to
Alter gene expression in cells (increases activation)
FcyRI (CD64)
Located on macrophages, neutrophils and eosinophils
Function: phagocytosis
FcyRIIA (CD32)
Macrophages, neutrophils, eosinophils and platelets
Function: phagocytosis and cell activation
FcyRIIB (CD32)
B cells, DCs, mast cells, neutrophils and macrophages
Function: feedback inhibition of B cells and attenuation of inflammation
FcyRIIIA (CD16)
NK cells
Function: ADCC
FceRI
Mast cells, basophils and eosinophils
Function: activation/degranulation of mast cells and basophils
Describe the FcRn receptor IgG
Transports maternal IgG from across the placental barrier into fetal circulation
Functions in recycling and transcytosis of IgG in a pH dependent manner
Important in maintaining IgG levels in the serum
Expressed on APCs, neutrophils, vascular endothelium, mucosal epithelial cells and podocytes
What are the effector functions of Abs?
Neutralization of microbes and toxins
Opsonization and phagocytosis of microbes
ADCC
Phagocytosis of microbes opsonized with complement fragments
Inflammation
Lysis of microbes
Complement activation
What is waste management?
Opsonization with IgG and C3b allows for clearance of immune complexes from circulation in a non-inflammatory manner
CR1 on RBCs binds circulating immune complexes with attached C3b
Organ resident phagocytes remove the ICs from the RBC surface and the RBCs continue to circulate
Phagocytes degrade the ICs
Describe ADCC in an antiviral state
IgG binds to surface bound Ags
NK cells bind to Ab coated cells by Fc receptors
Degranulation of NK cells perforin and granzyme granules
Induced apoptosis of target cell
What are natural Abs?
Naturally occurring Abs to blood group Ags we don’t have on our RBCs
Mainly IgG and IgM (some IgA)
Produced by B1 and marginal zone B cells in the MALT and spleen from exposure to intestinal bacteria, viral and/or food Ags
Group A blood Abs in plasma
Anti B
Group A blood Ags in RBCs
A antigen
Group B blood Abs in plasma
Anti A
Group B blood Ags in RBCs
B antigen
Group AB blood Abs in plasma
None
Group AB blood Ags in RBCs
A and B antigens
Group O blood Abs in plasma
Anti B and Anti A
Group O blood Ags in RBCs
None
When are babies the most vulnerable to infections?
Around 6-12 months of age when they are not completely immunocompetent
Describe passive immunization
The introduction of Ab or antiserum into a naive recipient
Immediate immunity but transient; no memory
Prevents disease after a known exposure, ameliorate sx of ongoing disease and protects immunosuppressed patients
Block action of bacterial toxins and prevent disease that they cause
Describe active immunization
The introduction of an Ag that provokes an adaptive immune response
Lag time
Memory
What are IVIG?
Replacement for Ab deficiencies
From pooled donor — lots of variation
Rapid protection after exposure
Serum is from immune individuals
Describe monoclonal Ab therapeutics
Highly specific recognition of epitope (high affinity)
Stimulate a variety of immune responses (side effects)
Can produce large quantities quickly (expensive)
Used in cancer and autoimmune diseases
What are some mechanisms of evasion?
Antigenic variation, inhibition of complement activation and blocking by hyaluronic acid capsule
