Chapter 11 B-cell Generation, Activation, and Differentiation

Initial contact between B and T cells Dec 19, 2006

B cell

T cell

你需要學習的課題：

1.人類及小鼠 B 細胞在骨髓中的成熟過程

2. B 細胞的 negative selection

3. TD & TI 抗原 / B-1 & B-2 B 細胞 / BCR signaling / B 細胞的 coreceptor

complex

4. TH 細胞如何影響 B 細胞的活化及增值

5.抗體反應 (humoral response)

Bone-Marrow Stromal Cells Are Required for Maturation of Progenitor B Cells into Precursor B Cells

VLA-4: very late antigen 4

VCAM-1: vascular cell adhesion molecule 1SCF: stem-cell factor

direct contact is required.

B-cell Maturation Depends on Rearrangement of the Ig DNA in the Lymphoid Stem Cells

RAG: recombination-activating genes (recombinases)TdT: terminal deoxynucleotidyl transferase

Naïve B Cell

Pre-B Cell Receptor

Heavy chain: Chain

Surrogate ( 代理者 ) light chain: VpreB (V-like sequence) 5 (C-like sequence)

Ig/Ig

Sequential Expression of mIg and Surrogate L Chain During B-Cell Differentiation

B-cell development in 5-/- mice is blocked at the pre-B stage.

Pre-TCR (pre-T/ TCR) Activates Signal Transduction Pathways

Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone Marrow

Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone Marrow

lymphoid pro-B pre-B immature mature stem cell cell cell B cell B cell

mIgM +mIgD(IL-2R )

CD45R: a protein tyrosine phosphataseCD19: part of the B-cell coreceptorCD43: leukosialinCD24: heat-stable antigen (HAS)

Negative Selection of Self-Reactive B Cells During Maturation in the Bone Marrow

negative selection !!

Ab against H-2Kk transgenes (H, L chain genes)

↓

H-2d/k or H-2d mice

Receptor Editing – secondary V(D)J recombination allows B lymphocytes to replace an inappropriate receptor with a new receptor

Overview of B-cell Development

Sites of B-cell maturation – before birth: yolk sac fetal liver fetal bone marrow after birth: bone marrow

e.g., spleen, lymph nodes

Mature Self-Reactive B Cells Can Be Negatively Selected in the Periphery HEL: hen egg

lysozyme

HEL-binding B cells are present.

Clonal Anergy in Mature Peripheral B Cells

Production of Double-transgenic Mice Expressing the H-2Kb Molecule and Anti-Kb Ab

membrane form

Clonal Deletion of Self-reactive Mature Peripheral B Cells

Kb-binding B cells are deleted.

B-Cell Activation and Proliferation

Thymus-Dependent (TD) and Thymus-Independent (TI) Ag Have Different Requirements for Response

- The B cell response to TD Ags requires direct contact with TH cells. - Direct participation of TH cells is not required for TI Ags.

(unknown mechanism) (crosslinking the mIg receptor)

(helped by TH cytokines)

Most type 1 TI (TI-1) Ags are polyclonal B-cell activators (mitogens); that is, they are able to activate B cells regardless of their antigenic specificity.

Two Distinct Signals for B-Cell Activation

B-1 and B-2 B Lymphocytes

, class switching is not common

Bind Ag with lower affinityAbs are multispecific

, therefore, no affinity maturation

ITAM: immunoreceptor tyrosine-based activation motif ( 圖形 )

Signal Transduction Pathways and the Activation of B Cells

- Compartmentalization of function within receptor subunits

- Activation by membrane-associated Src family protein tyrosine kinases (Lyn, Blk, and Fyn)

- Assembly of a large signaling complex with protein- tyrosine-kinase activity (Syk)

- Recruitment of other signal-transduction pathways

- Changes in gene expression

Signal Transduction Pathways Activated by the BCR

The B-Cell-Coreceptor Complex Can Enhance B-Cell Responses : TAPA-1 (CD81), CR2 (CD21), and CD19

ITIM: immunoreceptor tyrosine inhibitory motif

Sequence of Events in B-Cell Activationby a Thymus-Dependent Ag

Role of TH Cells in B-cell Activation

1. Formation of T-B conjugates

2. Contact-dependent help mediated by CD40/CD40L interaction

CD40 signaling in B cells activation of Lyn and Syk PLC, IP3, DAG transcription factors, such as NF-B

3. Signals provided by TH-cell cytokines

redistribution of Golgi apparatus and the microtubular-organizing center toward the junction with the B cell

Release of cytokines toward the Ag-specific B cell (directional or polarized release of cytokines)

Initial contact between

a T cell and B cell a T-B conjugate

The Humoral Response

Primary (1° ) and Secondary (2 ° ) Responses

In Vivo Sites for Inductionof Humoral Response

B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node

3 Important B-cell Differentiation EventsTake Place in Germinal Centers

1. Affinity maturation

2. Class switch

3. Formation of plasma cells and memory cells

Cellular Events within Germinal Centers

highly proliferative

The Frequency of Somatic Hypermutation Decreases with the Distance from the Rearranged V(D)J Gene

0.5 kb 1.5 kb

AID (activation-induced cytidine deaminase) Mediates Somatic Mutation

AID – an RNA editing enzyme, deaminating selective cytidine in certain mRNAs, changing the cytosines into uracils

– modifying DNA by the deamination of cytosine, resulting in formation of uracil

Var

iab

ilit

y

Cytokines Affect Proliferation and Class Switching of B Cells During the Differentiation of B Cells into Plasma Cells