Bio 328 Immunology
B-cell generation,
activation, and
differentiation
B CELL DEVELOPMENT
Experimental tools to characterization of
progenitors:
1.
2.
3.
4.
5.
Surface antigens.
In vitro culture.
Stages of V(D)J rearrangement.
KO transcription factors.
Expression of TF-driven GFP.
Early pro-B cell
Late pro-B cell
Schooling of B-cells.
 Central schooling in the bone
marow.
 Clonal deletion
Nemazee and Burki (1989)
Tieges et al. (1993)
 In the periphery
Spleen
Bonemarrow
Immature B
cell
T1 B cell
Periarteriolar
sheet
T1 B cell
Marginal
follicle
T2 B cell
T2 B cell
Mature B cell
Schooling of B-cells.
 Central schooling in bone marrow
 Clonal deletion (Nemazee and
Burki, Tieges et al.)
 Peripheral schooling in spleen
 Clonal anergy (Goodnow et al.)
 T3 B cells
 Clonal deletion (Nemazee and
Burki)
The three major populations of mature B cells.
Marginal zone B cells.
B CELL ACTIVATION
B cell activation: Competency signal (1) and (2) and
Proliferation signal (3)
Foxn1 deficiency
Adaptive transfer experiments of Miller,
Mitchell, and Mitchison (1960s).
LFA-2
CD40L
CD40
Activation of B cells
by crosslinking the BCR
Bruton’s tyrosine
kinase
B-cell Linker
Protein
X-linked agammaglobulinemia
Importance of co-receptor:
(1)# receptors needed to activate B cells
(2)HEL-C3b construct
(3)Anti-CD19 antibodies
(4)CD19-/- mice
X-linked
hyperimmunoglobulinemia M
CD40L
CD40
Importance of TH cells:
(a) Cross-linking CD40 – CD40L triggers
signal transduction pathway.
(b) B-cell activation with TH membranes
(c) anti-CD40 antibodies
1o
immunization
2o
immunization
2o anti-Hapten
Response
Comment
-----
Hapten (DNP)
Hapten (DNP)
Carrier 1 (BSA)
Carrier 1 (BSA
Hapten (DNP)
+ Carrier 1 BSA)
Hapten (DNP)
+ Carrier 1 BSA)
---
Hapten-Carrier 1
conjugate
(DNP-BSA)
Hapten-Carrier 1
conjugate
(DNP-BSA)
+++
Hapten-Carrier 1
conjugate
(DNP-BSA)
Hapten-Carrier 2
conjugate
(DNP-BGG)
---
Carrier effect
Hapten-Carrier 1
conjugate
(DNP-BSA)
+ Carrier 2 (BGG)
Hapten-Carrier 2
conjugate
(DNP-BGG)
+++
Circumvention
of carrier
effect.
Primary Response
Naïve
B-cell
Secondary Response
Memory
B-cell
+
Naïve
T-cell
+
Memory
T-cell
Associative or linked recognition
Associative or linked recognition
FDC
Centrocytes
CXCR4
Centroblasts
CXCR5
CXCR5
CCR7
CXCL13
(FDC)
CCL19
CCL21
(Paracortex)
Movement into
follicle
Movement into
paracortex
Activation-Induced Cytidine Deaminase
AID is essential for somatic mutations.
Muramatsu M. et al. (2000). Cell 102 p560.
AID is essential for class switching.
Muramatsu M. et al. (2000). Cell 102 p560.
Class-switch recombination can occur in two orientations, on
of which results in a productive rearrangement whereas the
other prevents antibody production.
“Origininal Antigenic Sin”
Regulation of Immune Responsiveness
1. Effect of prior antigen exposure (anamnestic
response or tolerance).
2. Antigen-mediated regulation (antigenic competition,
antigen concentration).
3. Antibody-mediated suppression.
4. Immune complexes as regulators.
5. Cytokine-mediated regulation: Th1 and Th2 cells.
6. Idiotype network regulation
7. T-cell -mediated suppression.
8. Neuroendocrine regulation.
The End
Regulation of Immune Responsiveness
1. Effect of prior antigen exposure (anamnestic
response or tolerance).
2. Antigen-mediated regulation (antigenic competition,
antigen concentration).
3. Antibody-mediated suppression.
4. Immune complexes as regulators.
5. Cytokine-mediated regulation: Th1 and Th2 cells.
6. Idiotype network regulation
7. T-cell -mediated suppression.
8. Neuroendocrine regulation.