Download B cell - Catalyst

IMMUN 441
AC Quiz Section Week 7
B Cell Immunity
Mucosal immunity
Exam #1
Exam #2
Final Exam
Negative Selection
MHCa
IR
Review: Skin Graft Experiment
MHCb
MHCa/b
IR
MHCa
MHCa
Skin Graft
Graft Rejected
Graft Tolerated
B cell Immunity
B cell antigens differ in their requirement for T cell help
T-cell dependent (TD)
T-independent (TI)
'activation' signal
but not mitogenic
BcR signal
Mitogensis
Mitogenesis
Differentiation
Class switch
Recombination
somatic
Hypermutation
•
Protein antigens
•
Non-proteins/highly repetitive structure
antigens
Different classes of TI antigens
TI-1
TI-2
• Highly repetitive structures
• Typically occurs in marginal zone B cells
• Mainly TLR ligands
• Can occur in all types of B cells
T-dependent responses
Antigen
DC
T cell
Dendritic Cell (DC)
internalizes antigen (Ag),
processes into peptides,
presents peptides
together with MHC
molecules to T cells
T cell
B cell
B cell binds Ag via surface
Ig, transmits BCR signals
and presents peptides to T
cells, receives
T cell help (growth and
differentiation factors)
plasma cells
Secretes
Antibody (Ab)
441 Lecture #17 Slide 7 of 35
Savan
11/07/2016
T cell-dependent antigens: Linked antigen
recognition
•
B cells that capture linked antigen
are the ones that can get T cell help
•
Only T cells that recognize epitopes that are
physically linked to the BCR epitope can
provide costimulation signal
Internalized
B cell
B cell
B cell
CD40
cytokines
CD40L
Activated
B cell
Antigenprimed
T cell
Epitope BCR recognizes is not necessarily the same peptide the TCR recognizes
Linked antigen recognition
T cell
B cell
B cell
A way to increase this rare
encounter is for the T cell to be able
to recognize any processed epitope
from same complex that was
originally recognized by the B cell.
T cell
T cell
Chemokine-mediated migration facilitates T:B
interactions and germinal center formation
Germinal center & follicular DCs
Each germinal center is an isolated event based on what the B cell encountered i.e.
bacterial, viral, or parasite protein
FO DC
Migrate to the dark
zone where affinity
maturation can occur
(SHM and CSR)
CXCR5
B cell
B cell
B cell
Y
CXCL13
T FH
Follicular DC (light zone)
Can trap antigen complexes at
cell surface and holds all
antigens
Present to T cell for
survival/differentiation signal
Destination:
1) Back to dark zone
2) Memory B cell or a longlived plasma cell
Germinal center & follicular DCs
Each germinal center is an isolated event based on what the B cell encountered i.e.
bacterial, viral, or parasite protein
FDCs GC B cells Naive B cells
After appropriate activation the B cell
differentiates into an antibody secreting cell, also
known as a Plasma Cell
Plasma Cell
B cell
membrane Ig
Master
Transcription
Factors:
secretory Ig
Blimp1
XBP1
441 Lecture #17 Slide 14 of 35
Savan
11/07/2016
B cell antibody response - clonal replication enters
into a higher order upon plasma cell differentation
3 days
12 divisions
naive
B cell
1
1 day
differentiation
activated B cells
212 =
4,096
1 day
103 Ab/cell/sec
plasma cells
antibodies
4,096
>1012
441 Lecture #17 Slide 15 of 35
Savan
11/07/2016
Antibody Affinity Maturation
Germinal Center
Low affinity B cell
High affinity B cell
mutation
Ag
VH VL
VH VL
VH VL
selection
Ag
VH VL
VH VL
VH VL
441 Lecture #17 Slide 16 of 35
Savan
11/07/2016
Affinity Maturation Selection Model
441 Lecture #17 Slide 17 of 35
Savan
11/07/2016
B cell activation leads to production of antibodies with
diverse functions
Antibody isotypes facilitate diverse types of immunity
Monomer: IgD,
Dimer: IgA
IgG, IgE, IgA
Pentamer: IgM
Neutralizing antibodies can block
viral/bacterial entry
Memory B cells
• Generated during the primary response
– best characterized for T-dependent responses involving GC but some
evidence exists for memory to TI antigens
•
•
•
•
Small, recirculating cells
Typically isotype switched (e.g. IgG+ or IgA+)
Typically have higher affinity for the inducing Ag
Longer lived than naïve B cells
– Persistence of memory B cells after an immune response ensures that
we have increased numbers of B cells specific for the antigen and
ready to respond on re-encounter
• May have intrinsic differences that promote greater clonal
expansion and more rapid differentiation to plasma cells
– differences in cytoplasmic domains of IgG vs IgM/D
– upregulation of TLRs
441 Lecture #17 Slide 21 of 35
Savan
11/07/2016
Mucosal Immunity
The mucosal immune system: overview
Small
Intestine:
104-107
bacteria per
ml
Large Intestine:
1011-1012
bacteria per ml
441 Lecture #18 Slide 23 of 28
Savan
11/09/2016
Organization of the mucosal immune system
M Cells
441 Lecture #18 Slide 24 of 28
Savan
11/09/2016
T cell priming and redistribution in the MALT
Naïve T cells enter
PP the same way they
enter LN: through HEV
T cells activated in the MALT
are imprinted with adhesion
molecules that mediate
distribution throughout the MALT
441 Lecture #18 Slide 26 of 28
Savan
11/09/2016
Mucosal IgA
neutralizes antigens
IELs live in between epithelial cells
Lamina propria
lymphocytes
Direct contact with epithelial cells allows for close communication and rapid
effector responses
441 Lecture #18 Slide 29 of 28
Savan
11/09/2016
Two types of IELs kill infected epithelial cells
Commensals directly compete with pathogens
Niche-filling function prevents overgrowth of pathogenic bacteria
Another reason why antibiotics should be used sparingly!
441 Lecture #18 Slide 31 of 28
Savan
11/09/2016
Epithelial cells express key PRRs to detect invasion
DCs that reach into lumen also contribute to innate immune detection in the gut
1
2
Commensals stimulate 1
Pathogens breach the barriers and stimulate 1, 2, 3
3
441 Lecture #18 Slide 32 of 28
Savan
11/09/2016
Questions?
441 Lecture #18 Slide 33 of 28
Savan
11/09/2016
Acronyms
BALT-bronchial associated lymphoid tissue
GALT-gut associated lymphoid tissue
NALT-nasal associated lymphoid tissue
MALT- mucosa associated lymphoid tissue (all)
IEL-intra epithelial lymphocytes
M cells- microfold cells
PIGR- poly-Ig receptor
PP- Peyer’s Patch