B-Cell Responses Flashcards
The vast majority of vaccines induce protection because?
-they elicit the long-term generation of high-affinity neutralizing antibodies
B-cells bearing higher affinity receptors for antigen are more likely to become cross-linked, and more likely to remain cross-linked long enough to __________.
-induce an activation signal
What makes up the B-cell antigen receptor complex?
-Membrane IgM (and IgD) on the surface of mature B cells is associated with the invariant Ig-alpha and Ig-beta
What do the Iga and Igb molecules contain in their cytoplasmic tails that mediate signaling functions?
-ITAMs (Immunoreceptor tyrosine-based activation motif)
Signal transduction by BCR complex
- antigen-induced cross-linking of membrane Ig on B cells leads to clustering and activation of Src-family TKs and tyrosine phosphorylation of the ITAMs in the cytoplasmic of the Iga and Igb molecules
- eventually leading to the activation of several transcription factors
B-cell responses are amplified if …..
-antigen is coated by complement fragments
Role of complement in B cell activation
- B cells express a complex of the CR2 complement receptor, CD19, and CD81
- microbial antigens bound with C3d can simultaneously engage both the CR2 molecule and membrane Ig on surface of B-cell to get enhanced activation of signals compared to antigen alone
3 functional responses of B cells induced by antigen-mediated cross-linking of the BCR complex
- mitosis; increased proliferation and survival: allows cells to make large numbers of clonal daughter cells
- Increased expression of costimulators and cytokine receptors: mediate amplification and differentiation signals on activated B cells
- Altered expression of chemokine receptors:causes activated B cells to take on new migration properties
Antigen-induced T-cell-dependent B cell activation
- for many antigens, BCR engagement by antigen is not enough to generate a response
- instead, optimal B cell activation requires interactions between activated B cells and helper T (TH) cells
In broad terms, T cell help conists of a combination of ______________.
- cell surface receptor-ligand interactions
- TH-derived cytokines
Antigen-responsive B cells can generate 2 types of cells:
- antibody secreting plasma cells
2. memory cells
Role of memory cells
-they do not actively secrete antibodies, but they will quickly generate plasma cells when stimulated by antigen upon secondary infection
T-cell independent B-cell activation by antigen
- usually an antigen composed of highly repetitive epitopes, like carbohydrates
- they are very effective in crosslinking BCRs on specific B cells and may generate antibody secreting plasma cells, but do not induce T cell activation
- consequently they do not induce many of the hallwmarks of B cell memory responses
Would vaccines likely use carbohydrates or proteins as antigens?
- Proteins that generate a T-cell dependent response
- Carbs are T cell independent and thus lack the memory responses which result is low yield, shorter term immunity
T-cell independent antigens may fail to ________.
-induce effective memory responses
2 types of T-cell independent antigens
- Type 1: TLR ligands (Toll-like Receptor ligand)
2. Type 2: BCR ligands
Type 1 ligand
- bind toll-like R on B cells
- they are not antigen specific R, but still turn B cells into plasma cells
- polyclonal B cell differentiation can occur upon ligation of TLRs on the B cell surface
Classic example of type 1 ligands
- LPS which activates B cells by binding to TLR4
- bacterial DNA which activates TLR9
Type 2 ligand
-effectively crosslink the BCR on specific B cells
Type 1 and 2 ligands both do what?
-drive B cell activation and plasma cell differentiation without effectively inducing long-term protective immunity
Type 2 ligand example
-outer covering of encapsulated bacteria like Steptococci is made of polysaccharide
______ antigens effectively induce long-lived protective immunity, __________ antigens do not.
- Protein
- Polysaccharides
So, if polysaccharides do not effectively induce long-lived protective immunity, how would you design an effective vaccine against a pathogen whose outer coat is chiefly polysaccharide antigen?
-conjugate polysaccharide to a protein and use it as vaccine
Responses to protein antigens are ________ ddependent.
- Helper T cell
- Th provide antigen-stimulated B cells with additional second signals consisting of cytokines and cell-surface ligands/receptors
Polysaccharide antigens do not elicit T cell help, but can activate B cells through what 2 methods?
- optimal crosslinking of surface Ig molecules (BCR)
- activation of alternative B cell receptors (TLRs)
Switch class recombination
- heavy chain constant region isotypes change during the course of a T-cell dependent immune response
- starting with IgM but “switching” to IgG/A/E yet maintaining the specificity of the BCR
- switch regions upstream of each constant region exon are combined to splice out in order to generate cells with identical IgH V region but with different C region
-Isotype switching (SCR) is promoted by?
-Activation induced deaminase (AID)
Isotype switching is influenced by __________ derived signals.
- Helper T cell
- CD40L, cytokines
Affinity maturation
-affinity of antibodies increases over time after exposure
Somatic hypermutation
- occurs during T cell dependent B cell responses
- B cell clones are subject to this process whereby point mutations are introduced across the V(D)J region of the productively arranges allele
- ONLY MUTATE IN VARIABLE REGIONS
Induced somatic point mutations cluster within ________ over time.
-CDRs
Affinity maturation requires what 2 processes?
- somatic mutation
- competition for antigen binding
During somatic mutation, the more mutations the higher/lower the affinities of antibodies.
-higher
The expression of AID is limited to what cell type(s)?
-B cells
Somatic hypermutation is performed by what enzyme?
- AID: so this enzyme performs class switching and somatic hypermutation
- targets actively transcrived V regions
What syndrome can be caused by deficiencies of the AID enzyme?
-Hyper IgM syndrome
2 causes of hyper IgM syndrome
- AID deficiency
2. deficiency in CD40 ligand, emphasizing need for T cell help in AID function
What occurs in hyper IgM syndrome?
-patients present with high levels of unmutated and unswitched IgM antibodies
Two critical processes that are important to the memory or secondary response are :
- affinity maturation
- class (isotype) switching
The initiation of humoral immune responses to protein antigens in lymph nodes
- antigen-activated helper T cells and B cells move toward one another and make contact adjacent to the edge of primary follicles
- they communicate, allowing TH cells to provide antigen-activated B cells with critical signals that amplify antibody responses and induce class switching and affinity maturation
A critical outcome of helper T cell and Ag-activated B cell in lymph node interface is ___________.
-the induction of germinal centers
In T-cell driven responses, many B cells form germinal centers where?
-within B cell follicles
What are germinal centers?
-unique anatomical structures that form in lymphoid tissues and the spleen within B cell follicles in response to T cell dependent protein antigens
Germinal centers are _______-induced and depend on signals derived from _______. Therefore, germinal centers form after earlier communicated between Ag-reactive B cells and T cells.
- antigen-induced
- activated TH cells
T/F: Germinal centers are permanent.
-False; eventually dissolve
What processes occur in germinal centers?
- somatic hypermutation
- antigen-mediated positive selection
Germinal center B cells undergo ________ selection.
-BCR mediated selection
3 potential outcomes of somatic hypermutation that occurs in germinal centers
- lower affinity antibodies
- higher affinity antibodies
- autoreactive antibodies
Somatic hypermutation occurs mainly, and even perhaps exclusively, in _________.
-Germinal center B cells
Different zones of germinal centers and what occurs in them.
- Dark zone: consists of highly proliferative antigen-specific B cells (B-cell blasts aka centroblasts)
- Light zone: consists of activated B cells, sometimes called centrocytes, follicular helper T cells, and follicular dendritic cells (FDCs)
3 general events that occur in GCs
- B cell proliferation
- somatic hypermutation
- selection for antigen binding
Rapidly proliferating B cells in germinal centers are called ________ and they form the _______.
- Centroblasts
- Dark zone
As the activated B cells mature, they become small ________ and migrate out into the ________ where they make contact with FDC which express antigens from the original microbial infection.
- centrocytes
- light zone
FDCs express what 2 types of receptors. What does this allow?
- cell surface Fc receptors
- Complement receptors
- allow FDCs to collect and present antigen to GC B cells in the form of Ab-Ag complexes or complement coated antigen
- more effectively GC B cells bind Ag in GC, the more likely they will be selected to generate memory or long-lived plasma cells
Selection of high-affinity B cells in GCs
- some of the B cells are activated by antigen, with help from T cells
- they migrate into follicles to form GCs where they undergo rapid proliferation and accumulate mutations in their Ig V genes
- the mutations generate B cells with different affinities for the antigen
- FDCs display antigen and only B cells that recognize the antigen are selected to survive
Only activated _________ can help B cells make GC and plasma cells.
-CD4+ T “Helper” cells
Helper T cells express what ligand responsible for activating B cells?
- CD40L
- also secrete cytokines
Germinal center formation requires ___________ expressed by _______ cells.
-CD40L expression by Th cells
What is seen in mice who are administers CD40L blocking antibodies?
-severe and selective ablation of germinal center B cells
CD40 signaling in B cells is essential for _________.
-generation of high-affinity class switched antibodies
People with null mutations i the X-linked gene for CD40L experience recurrent bacterial and fungal infections due to inability to generate high affinity, class switch antibodies, but possess normal or elevated IgM serum antibodies. What is this called?
-Hyper IgM syndrome
What do prions target and what are the clinical issues associated with this?
- target FDCs because they require them to replicate before neuroinvasion
- over time these infections deplete FDCs, causing an inability to generate or sustain germinal centers
Ionizing radiation does not kill what cell type?
-Plasma cells
Results seen in immunized mouse receiving irradiation
- memory (secondary) responses are eliminated
- serum antibody titers are barely affected
- support notion of long-lived plasma cell
“Boost” responses are absent after irradiation, suggesting which cell types produce them?
-Memory cells
Long-lived humoral immunity is mediated by:
- antigen-induced memory B cells
2. long-lived plasma cells (in bone marrow)
