Humoral Immunity I - Activation of B cells Flashcards
classes of Ab
MAGED
mechanisms of antibodies
- neutralization
- opsonization
- antibody dependent cell cytotoxicity
how do Ag flow into lymph node?
afferent lymphatics
what do follicular DC do? (FDC)
capture, concentrate and slowly release Ag (in follicles of lymph node) so B cells have a better chance of seeing Ag
what is a BCR crosslink
when a cluster of BCR engage with Ag which have repeats of epitope
what are the signaling molecules of BCR
Ig-alpha and Ig-beta
what occurs when BCR are activated?
Ig-alpha and beta ITAMs are phosphorylated by Src kinases
what occurs once ITAMs are phosphorlyated
Syk binds to ITAMs (acts like ZAP70 inT cells)
what does Syk binding do?
PLC and Ras pathways are activated and TF are bound to B cell DNA
what does Syk in B cells correspond to in T cells?
ZAP70 = Syk
what are components of B cell co-receptors?
- CR2 aka CD21
- CD19
- CD81
what does CR2/CD21 do
recognizes iC3b and C3d derivatives of C3b fragments
what is CD19
signaling chain of co-receptor
benefit of co-receptor activation in B cells?
increases BCR signaling events by 1,000-10,000
what occurs if patient lacks functional B cell co-receptor CD19 or 81?
- low levels of serum Ab
- limited isotype switching
- poor response to infections and vaccinations
unique characteristics of FDC
- extensive surface for large quanitities of Ag
- lack phagocytic activity
- Ag capture are preserved for months/years
how do FDC tether Ag
on CR1 and CR2 to be screened by naive B cells
what occurs first in B cell activation
- proliferation of B cell army
2. increased antiapoptotic factors like BCL
what occurs 2nd in B cell activation
- upregulated MHC I and II expression
2. increased B7 (CD80/CD86) which allows engagement with T cells
what occurs 3rd in B cell activation
increased cytokine receptors IL-2R, IL-4R, IL-5R, IL-21R
what occurs 4th in B cell activation
- CCR7 is upregulated (move to paracortex)
2. decreased CXCR5
what T helper cells reside near follicles
TFH (t follicular helper cells)
what do TFH do
promote Ab production
where do pre-TFH live
interfollicular zone, so they have CCR7 and CXCR5 (localizes to paracortex)
how are pre-TFH activated
DC engagement by presenting CD40, which makes secrete IL-2,IL-4,IL-5
what does binding of DC to pre-TFH do?
- proliferation
- anti-apoptotic factors
- IL2,4,5
- other cytokines by signal 3
what do activated pre-TFH cells do ?
engage activated B cells in the interfollicular zone to induce B cell proliferation and AID
what does CD40 ligation between pre-TFH and B cell do
induces AID and makes pre-TFH fully differentiate into TFH
which cytokines produced by TFH promote differentiation of B lymphoblasts into PC
IL-5
IL-6
IL-10
describe B cell clonal expansion (primary focus)
B cells turn into B lymphoblasts which turn into plasma cells secreting IgM
primary focus of B cell clonal expansion
turn into PC: in medulla, B and TFH cells divide and B cells become PC
secondary focus of B cell clonal expansion
make a secondary follicle:
some B lymphoblasts leave medulla attached to TFH and go to primary follicle. the proliferation of these in primary make a secondary follicle
what are centroblasts
rapidly dividing B cells with downregulated BCR (lost surface Ig)
secondary focus of B cell clonal expansion again
make a germinal center:
TFH cells undergoing slower differentiation, so centroblasts push them and naive B cells out to form germinal center
what does germinal center represent
B cell responses to specific Ag
what TFH cytokines initiate proliferation
IL-2
IL-4
IL-5
what sustains proliferation??
FDC cytokines
what promotes somatic hypermutations
AID
what induces more AID?
interactions of centroblasts with TFH cells in germinal center
where do mutations occur on light and heavy chain
variable region
benefit of somatic hypermutation
Igs with varying affinities for Ag, improves
what are centrocytes
aka germinal center B cells, centroblasts that have completed a somatic hypermutation and now express a BCR
what is affinity maturation
centrocytes engage FDC via BCR and CR2/CD21, and the centrocytes with the highest affinity BCR for Ag survive
what occurs once centrocytes (GC B cells) win affinity maturation?
they engage TFH cells and differentiate into PC and also undergo isotype switching
what signaling promotes proliferation and differentiation of GC B cells into PC
IL-10
IL-21
what occurs if GC B cells and TFH don’t interact?
phagocytosed by tingible body macrophages
what occurs if centrocyte and FDC don’t interact
phagocytosed by tingible body macrophages
what plasma cells are generated first?
short lived to produce IgM, and undergo apoptosis as the long lived Pc are generated
where are long lived PC localized?
- inflamed/infected tissues
2. bone marrow
what do long lived PC do at inflamed tissue
secrete high levels Ig – long term, but undergo apoptosis once Ag levels go down
what do long lived PC do in bone marrow?
is a memory plasma cell, don’t migrate, but they constantly secrete low levels of Ig *** this is what we want vaccines to do
what are memory B cells?
non Ab producing B cells, serve as a reservoir for memory B cell responses and have a BCR.
where are memory B cells?
remain in blood circulation or reside in lymphoid organs
what induces memory B cell formation?
IL-4
switch of TFH cytokine production from IL-10 and IL-21 to IL-4 and IL-21
what induces plasma cell formation
IL-10
IL-21
what are immune complexes
secreted Ig that bind Ag
how is Ig production regulated
Immune complexes form and bind to B cells on their Fc receptor. this activates phosphatase which removes phosphate from BCR signaling proteins to shut down Ab production in plasma cell
