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Bio 328 Immunology
B-cell generation, activation, and differentiation
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B CELL DEVELOPMENT
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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.
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Early pro-B cell
Late pro-B cell
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Schooling of B-cells. Central schooling in the bone
marow. Clonal deletion
Nemazee and Burki (1989)Tieges et al. (1993)
In the periphery
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Bonemarrow
Spleen
Periarteriolarsheet
Marginal follicle
Immature B cell
T1 B cell
T1 B cell
T2 B cell
T2 B cell
Mature B cell
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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)
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The three major populations of mature B cells.
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Marginal zone B cells.
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B CELL ACTIVATION
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B cell activation: Competency signal (1) and (2) and Proliferation signal (3)
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Foxn1 deficiency
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Adaptive transfer experiments of Miller, Mitchell, and Mitchison (1960s).
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CD40L CD40
LFA-2
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Activation of B cellsby crosslinking the BCR
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B-cell Linker Protein
Bruton’s tyrosine kinase
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X-linked agammaglobulinemia
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Importance of co-receptor:
(1)# receptors needed to activate B cells(2)HEL-C3b construct(3)Anti-CD19 antibodies(4)CD19-/- mice
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X-linked hyperimmunoglobulinemia M
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CD40L CD40
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Importance of TH cells:
(a) Cross-linking CD40 – CD40L triggers signal transduction pathway.(b) B-cell activation with TH membranes(c) anti-CD40 antibodies
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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.
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Primary Response
NaïveB-cell
NaïveT-cell
+
Secondary Response
MemoryB-cell
MemoryT-cell
+
Associative or linked recognition
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Associative or linked recognition
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CentroblastsCXCR5
CentrocytesCXCR4
FDC
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CXCR5 CCR7
CXCL13(FDC)
CCL19CCL21
(Paracortex)
Movement into follicle
Movement into paracortex
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Activation-Induced Cytidine Deaminase
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AID is essential for somatic mutations.
Muramatsu M. et al. (2000). Cell 102 p560.
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AID is essential for class switching.
Muramatsu M. et al. (2000). Cell 102 p560.
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“Origininal Antigenic Sin”
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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.
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The End
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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.
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