Bio 328 Immunology B-cell generation, activation, and differentiation.
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Transcript of Bio 328 Immunology B-cell generation, activation, and differentiation.
Bio 328 Immunology
B-cell generation, activation, and differentiation
B CELL DEVELOPMENT
Experimental tools to characterization of progenitors:
1. Surface antigens.2. In vitro culture.3. Stages of V(D)J rearrangement.4. KO transcription factors.5. 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
Bonemarrow
Spleen
Periarteriolarsheet
Marginal follicle
Immature B cell
T1 B cell
T1 B cell
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).
CD40L CD40
LFA-2
Activation of B cellsby crosslinking the BCR
B-cell Linker Protein
Bruton’s tyrosine kinase
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 immunization2o anti-Hapten
ResponseComment
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
NaïveB-cell
NaïveT-cell
+
Secondary Response
MemoryB-cell
MemoryT-cell
+
Associative or linked recognition
Associative or linked recognition
CentroblastsCXCR5
CentrocytesCXCR4
FDC
CXCR5 CCR7
CXCL13(FDC)
CCL19CCL21
(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.
“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.