Humoral Immune Responses Flashcards
Primary immune response
Naive B cells are stimulated by Ag, become activated and differentiate into plasma cellsthat produce Abs (IgM>IgG).
Secondary immune response
Response elicited when the same Ag stimulates memory cells leading to the production of Abs (IgG>IgM).
Follicular B cells
Respond to protein Ags and initiate T cell dependent Ab responses.
MZ B cells
Respond to multivalent Ags and are T cell independent.
B-1 cells
In mucosal sites. Respond to multivalent Ags and are T cell independent.
B-2 cells overview
Widely distributed.
Continually replaced by bone marrow..
Require interaction with T cells for activation and proliferation.
B-1 cells overview
Arise from fetal liver.
May represent bridge between innate and adaptive immune system.
B-1 Abs are often directed against conserved microbial Ags.
CXCL13 function
Secreted by FDCs and guides the movement of B cells into the follicle of the LN.
Most Ags from the tissues are transported to LNs via:
Afferent lymphatic vessels that drain into the subscapular sinus of the LNs.
Soluble Ags:
May reach the B cell zone of the follicle and interact directly w/ specific B cells.
Large Ags:
May be captured by resident FDCs and transported into follicles where they activate B cells.
Microbes and Ag-Ab complexes:
Are captured by subscapular sinus Mo which deliver Ags to follicles.
Unique function of FDCs:
Can retain Ag-Ab complexes on their surface for weeks to months.
Ag retention by FDCs is mediated by:
FC receptors, CR 1 or CR 2 complement receptors.
FDCs do not:
Express MHC II OR phagocytose and process exogenous Ags for MHC I.
Cells in the marginal zone (2):
MZ Mo.
MZ B cells.
MZ B cells in the spleen can:
Bind immune complexes containing Ag and are coated in complement using complement receptors in a manner that is independent of BCR specificity.
MZ B cells can now shuttle to follicular region.
In the follicular region, FDCs can compete to bind to the Ag.
MZ B cells then migrate back to the marginal zone.
Ag capture in the spleen:
Ags usually presented to MZ B cells in native conformation.
Ags in immune complexes may bind to CR2 on MZ B cells.
MZ B cells can transfer the complex to FDCs.
What captures blood-borne pathogens?
pDCs in the blood and transport them to spleen and deliver to MZ B cells.
What captures polysaccharide Ags in the spleen?
MZ Mo and displayed for MZ B cells.
BCR anatomy
Transmembrane molecule that expressed IgM/D in naive form.
Signaling is via Ig-alpha and Ig-beta, which are connected by disulfide linkage and contain ITAMs.
B cell coreceptors
Associate with BCR complex and enhance or inhibit signal.
CD19
Dominant signaling component of B cells
CD21
AKA CR2. When combined with CD19, positively regulates B cell activation and lowers threshold for B cell activation.
CD32
Contains ITIM nad negatively regulates BCR signaling.
Signaling mechanism of BCR complex (4)
- Ag binding causes conformational change in ITAMs, making them accessable to Src kinases (Lyn, Fyn, Blk).
- Src kinases phosphorylate ITAMs of Ig-alpha/Ig-beta.
- Phosphorylated ITAMs allow space for Syk tyrosine kinase, which phosphorylates a Tyr residue on BLNK.
- Follows with recruitment of enzymes which actiavte Ras and Rac, PLCy2 and Btk.
CD81
Complexes with CD21 and CD19 and is necessary for normal CD19 expression.
C3d
Fragment of C3b that remains on the microbial surface after C3b is degraded. Binds to CD21/CR2.
The complex of C3d and Ag interacts with the B cell how?
The Ag binds to the BCR and CR2/CD21 recognizes C3d.
B cell coreceptor components
CR2/CD21-CD19-CD81
How does CD19 enhance the amplification of BCR signaling?
Tail of CD19 becomes phosphorylated and recruits Lyn kinases which can phsophorylate ITAMs in Ig-alpha and Ig-beta..
Mechanism of T cell mediated activation of B cell
When Th cells become activated by binding Ags presented on B cells, they express CD40L.
CD40L binds to CD40 on B cells and stimulates B cell proliferation.
Upon B-T cell inteaction:
B cells produce short-lived plasma cells mainly producing IgM.
B cells then migrate to GC and undergo somatic mutation, affinity maturation, isotype switching and generation of memory B cells and long lived plasma cells.
Generation of Tfh requires:
Sequential activation of T cells, first by DCs ad then activated B cells. Tfh migate into GCs where they activate B cells.
IL-21 is secreted by Tfh cells because:
It is required for GC development and generation of plasma cells.
Tfh secrete IFN-y or IL-4 because:
It controls isotype Th1 or Th2 switching.
Tfh express (4):
ICOS
PD-1
IL-21
Bcl-6
IL-21 and B cells
IL-21 is important for generation of B cell responses in GCs.
Dark zone of GC
Formed by activated B cells migrating back into the follicle and proliferating. These cells undergo extensive isotype switching and somatic hypermutation,
Light zone of GC
Formed by the area that B cells encounter with FDCs.
Where do plasma cells and memory cells live?
Plasma cells live in BM and memory B cells return to the recirculating lymphocyte pool.
Isotype switching occurs in:
The GCs and is driven by Tfh cells.
The variable chains is unaltered, but the constant regions of the heavy chains are altered.
IFN-y (Th1) induces what kind of switching?
IgG swithcing
IL-4 (Th2) induces what kind of switching?
IgE swithcing
Switching sequence
Precedes C gene and controls rearrangement process.
Affinity maturation is only found in:
Ab responses to T cell dependent Ags.
There are more mutations in IgG than:
IgM
Class-switch recombination
Occurs in activated B cells and changes Cm gene to another CH gene.
Takes place between 2 switch regions (S) and results in a looped out deletion of DNA.
Causes a switch from IgM/IgD to IgA/G/E, etc.
Affinity maturation leads to:
Increased affinity of Abs for an Ag.
What is required for somatic hypermutation of Ig V genes?
Tfh cells and CD40:CD40L interactions.
How are B cells “chosen” in the in the GC?
In dark zone, Ag specific B cells are produced. The cells with the most affinity for an antigen presenting FDC proliferates, and the others undergo apoptosis.
Where are mutations from affinity maturation clustered?
In the V regions, mostly in the Ag-binding complementary-determining regions.
Why is the GC considered the B cells’ graveyard?
Because of somatic hypermutation and affinity maturation that occur there causing an increase in apoptosis.
Mechanism of B cell survival:
Cells that have undergone somatic hypermutation enter the light zone of the GC to interact w/ FDCs.
- Ag recognition induces expression of Bcl-2, an anti-apoptotic protein.
- High-affinity B cells will endocytose and present for Tfh cells in the GC which signals CD40L to promote B cell survival.
- High-affinity B cells may also activate inhibitors of Fas once they recognize Ag.
B cell lymphomas develop in:
Germinal centers.
DNA breaks in somatic hypermutation and isotype switching can facilitate incorporation of oncogenes.
Memory B cells express high levels of what?
Bcl-2 (anti apoptotic)
T independent
Some non-protein Ags can elicit Ab production without access to Th cells. They are T independent.
The Abs produced are usually low affinity, consist mainly of IgM and have limited isotype switching.
MZ B cells are mainly involved.
Most TI Ags are:
Multivalent. Usually bind to IgM.
Induce maximal cross-linking of the BCR and lead to activation without a Th.
TI Ags cannot be recognized by:
MHC molecules and are not recognized by CD4+.
Some TI Ags can induce:
Isotype switching, which can be enhanced by release of cytokines from non T cells.
In humans the dominant Ab class induced by pneumococcal capsular polysaccharide is:
IgG2
IGF-beta can help mediate what?
Switch to IgA. It is secreted by non-lymphoid cells at mucosal sites.
Memory from vaccines occurs only if:
The vaccine can activate Th cells.
Vaccines for capsular polysaccharides do not stimulate memory because:
How do we get around this?
They don’t stimulate Th cells.
The polysaccharide is linked to a foreign protein to forma hapten-carrier conjugate (conjugate vaccine).
Inhibitor signaling in lymphocytes
Ligand binding of ITIM causes its phosphorylation by Src kinase.
The phosphorylated ITIMs recruit tyrosine phosphatases which attenuate immune signaling.
How does FcyRIIB (CD31) affect signaling?
The Ag-Ab complex can bind to both the BCR and FcyRIIB via the Fc portion of the Ab. The FcyRIIB can activate phosphatases which inhibit the signaling.
SHP and SHIP are:
Phosphatases recruited by ITIMs.
