Lecture 4 - B cell response Flashcards
How does higher affinity for antigen receptors on B cells confer advantage?
- B cells with higher affinity receptors more likely to become cross-linked 2. B cells with higher affinity more likely to remain cross linked long enough to induce an activation signal
What constitutes the B cell antigen receptor complex?
IgM or IgD on surface associated with Iga and IgB which contain immunoreceptor tyrosin-based activation motifs (ITAMs)
How does the BCR deliver signals to activate the B cell?
Crosslinking of membrane Ig by antigen leads to clustering and activation of Src-family tyrosine kinaases aand tyrosine phosphorylation of the ITAMs in the cytoplasmic tails of the Iga and IgB which provides docking site for Syk which initiates a tyrosing phosphoyrlation cascade eventually activating transcription factors like NFAT, NF-kB and AP-1
How does complement amplify B cell repsonses?
Microbials antigens which bind the compliment fragment C3d can engage the CR2 molecule and the membrane Ig simultaneously leading to signaling cascades from both the BCR complex and the CR2 complex which includes CD19 and CD81
What effect do complement receptors have on signal threshold?
Lower the threshold since they amplify response.
What are the 3 general consequences of Ag induced B cell activation?
Mitosis/survival. Increased expression of costimulators and cytokine receptors (which mediate amplification and differentiation signals). Changes in chemokine receptors (change migratory route)
In broad terms how do helper T cells help?
Combo of cell surface receptor-ligand interactions and TH derived cytokines
What are the 3 catergories of antigens for B cell responses?
T cell independent type 1 are B cell mitogens like LPS, bind to TLRs, aren’t antigens because they don’t bind to antigen-specific receptors, B cell proliferation occurs with LPS regardless of specificit. T cell independent type II antigens can stimulate abody secretion w/o T cells, typically long, highly repetetive structures like polysaccharides. T cell dependent tend to be proteins to which B cells bind thorugh BCR but can’t effectively respond to without T cell help
What are the clinical ramifcations of type 1 TLR ligands?
Get polyclonal B cell differentiation. LPS on gram negative bacteria binds to TLR4. Bacterial DNA binds to TLR9.
What are the clinical ramifcations of type 2 BCR ligands?
Binds to outer covering of encapsulated bacteria if capsule made of polysaccharide eg streptococci species
Since polysaccharide antigens don’t effectively induce long-lived protective immunity, how can you design a vaccine against polysaccharide coated antigens?
Conjugate it to a protein
Why do induced antibodies alter their constant regions?
To allow the engagement of other effector activities without altering specificity
What changes and what stays the same during class switching?
Constant regions of heavy chains change. Variable light and heavy regions and constant light regions stay the same.
Where are the constant regions for the other isotypes located on a gene?
In exons downstream of the Cmu gene
How does activation induced deaminase promote isotype switching?
AID promotes enzyme activity between switch regions promoting excision of the DNA between switch regions and then DNA repair enzymes perform nonhomologous end joining
What directs isotype switching?
CD40L and cytokines from helper T cells
How does the B cell know which class to switch to?
Signals from the mmicroenvironemnt, pathogens and activated T cells dictate type
If activated T cells release IFN-y what class type does the B cell switch to?
IgGsubclasses. Effector: Fc receptor dependent phagocyte responses; complement activation; neonatal immunity
If activated T cells release IL-4 what class type does the B cell switch to?
IgE. Effector: against helminths; mast cell degranulation (immediate hypersensitivity)
If activated T cells release cytokines like TGF-B in mucosal tissue what class type does the B cell switch to?
IgA. Effector: mucosal immunity (transport of IgA through epithelia)
How do mutations in V genes differ with time after immunization and with repeated immunizations?
Increase
Where are induced somatic mutations clustered on B cell genes?
In the complimentarity-determining regions (CDRs) which attaches to the epitope/antigen
How do the affinities of the antibodies produced during hypermutation change?
Affinities increase with more mutations (lower Kd)
Which enzyme directs somatic hypermutation?
AID (activation induced cytidine deaminase)
During somatic mutation what does AID target?
Targets actively transcribed V regions
How does AID perform somatic hypermutation?
Converts C to U then error prone DNA repair substitutes an ATG or C at the site during repliication or the U is converted to adenosine (A)
What two types of deficiencies can lead to hyper IgM?
Deficiencies in AID or CD40L
What is hyper IgM syndrome?
Elevated unmutated and unswitched IgM antibodies due to lack of CD40L or AID. Recurrent bacterial and fungal infections
What happens during the initiation of humoral immune responses?
Ag-activated T cells and Ag-activated B cell s make contact at edge of primary follicles, Th cells provide the Ag activated B cells with critical signals that amplify abody responses and induce class switching, affinity maturation and the induction of germinal centers
What are germinal centers?
Ag induced mainly T cell dependent structures within B cell zones enriched for activated Ag-induced B cells undergoing somatic hypermutation and class switch recombination
What zones make up the germinal center and how are they different?
Dark and light. Dark has highly proliferative centroblast B cells where class switching and somatic hypermutation occur. Light is where centroblasts migrate to when they’re centrocytes and are tested by follicular dendritic cells (FDCs) which express antigens form the original microbial infection
How do follicular dendritic cells regulate germinal center response?
B cells with highest affinity survive. FDCs express cell surface Fc receptors and complement receptors and use these to preset either Ab-Ag complexes or complement coated Ag to germ. Center B cells. Those that bind continue to survive and selected to generate memory B or long-lived plasma cells, those that don’t bind/receive BCR signals while in GC apoptose
What kinds of T cells help B cells make germinal centers and plasma cells?
Activated CD4+ T cells
How do activated CD4+ T cells help B cells?
Express CD40L which is a B cell activation receptor and secrete cytokines like IL-4
How do prions that destroy FDCs disrupt humoral immunity?
Prions (agetns in scrapie and other transmissible spongiform encephalopathies) use FDCs to replicate depleting them causing an inability to generate or sustain germinal centers
What is the basis for long term maintenance of serum antibody titers?
Long living plasma cells which migrate from lymph to bone marrow and have expanded ER and Golgi to constantly secrete antibodies (even after ionizing radiation!)
