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.