Bio 328 Immunology B-cell generation, activation, and differentiation.

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Presentation transcript:

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 Periarteriolar sheet Marginal follicle Immature B cell T1 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 cells by 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 T H cells: (a) Cross-linking CD40 – CD40L triggers signal transduction pathway. (b) B-cell activation with T H membranes (c) anti-CD40 antibodies

1 o immunization2 o immunization 2 o anti-Hapten Response Comment Hapten (DNP) --- Carrier 1 (BSA)Carrier 1 (BSA --- Hapten (DNP) + Carrier 1 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 Naïve T-cell + Secondary Response Memory B-cell Memory T-cell + Associative or linked recognition

Centroblasts CXCR5 Centrocytes CXCR4 FDC

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.

“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.