Presentation on theme: "Chapter 11 B-cell Generation, Activation, and Differentiation"— Presentation transcript:
1Chapter 11 B-cell Generation, Activation, and Differentiation T cellInitial contact between B and T cellsDec 19, 2006
2你需要學習的課題： 人類及小鼠 B 細胞在骨髓中的成熟過程 B 細胞的 negative selection TD & TI 抗原 / B-1 & B-2 B 細胞 /BCR signaling / B 細胞的 coreceptor complexTH 細胞如何影響 B 細胞的活化及增值抗體反應 (humoral response)
3Bone-Marrow Stromal Cells Are Required for Maturation of Progenitor B Cells into Precursor B Cells VLA-4: very late antigen 4VCAM-1: vascular cell adhesionmolecule 1SCF: stem-cell factordirect contactis required.
4B-cell Maturation Depends on Rearrangement of the Ig DNA in the Lymphoid Stem Cells Naïve B CellRAG: recombination-activating genes (recombinases)TdT: terminal deoxynucleotidyl transferase
5Pre-B Cell Receptor Heavy chain: m Chain Surrogate (代理者) light chain: VpreB (V-like sequence)l5 (C-like sequence)Iga/Igb
6Sequential Expression of mIg and Surrogate L Chain During B-Cell DifferentiationB-cell development in l5-/- mice is blocked at the pre-B stage.
7Pre-TCR (pre-Ta / TCRb) Activates Signal Transduction Pathways
8Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone MarrowSequence of Events and Characteristics of the Stagesin B-cell Maturation in the Bone Marrowlymphoid pro-B pre-B immature maturestem cell cell cell B cell B cellmIgM+mIgD(IL-2R a)CD45R: a protein tyrosine phosphataseCD19: part of the B-cell coreceptorCD43: leukosialinCD24: heat-stable antigen (HAS)
9Negative Selection of Self-Reactive B Cells During Maturation in the Bone Marrow Ab against H-2Kktransgenes (H, L chain genes)↓H-2d/k or H-2d micenegativeselection !!
10Receptor Editing – secondary V(D)J recombination allows B lymphocytes to replace an inappropriatereceptor with a new receptor
11Overview of B-cell Development Sites of B-cell maturation –before birth: yolk sacfetal liverfetal bone marrowafter birth: bone marrowe.g., spleen,lymph nodes
12Negatively Selected in the Periphery Mature Self-ReactiveB Cells Can BeNegatively Selected inthe PeripheryHEL: hen egglysozymeHEL-binding B cells are present.
17Thymus-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 areable to activate B cells regardless of their antigenic specificity.
21Signal Transduction Pathways and the Activation of B Cells - Compartmentalization of function within receptor subunitsActivation by membrane-associated Src family proteintyrosine kinases (Lyn, Blk, and Fyn)Assembly of a large signaling complex with protein-tyrosine-kinase activity (Syk)Recruitment of other signal-transduction pathwaysChanges in gene expression
22Signal Transduction Pathways Activated by the BCR
27Role of TH Cells in B-cell Activation 1. Formation of T-B conjugates2. Contact-dependent help mediated by CD40/CD40L interactionCD40 signaling in B cells activation of Lyn and Syk PLC, IP3, DAG transcription factors, such as NF-kB3. Signals provided by TH-cell cytokinesredistribution of Golgi apparatus and the microtubular-organizingcenter toward the junction with the B cell Release of cytokines towardthe Ag-specific B cell(directional or polarizedrelease of cytokines)Initial contact betweena T cell and B cella T-B conjugate
32B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node
333 Important B-cell Differentiation Events Take Place in Germinal Centers1. Affinity maturation2. Class switch3. Formation of plasma cells and memory cells
34Cellular Events within Germinal Centers highly proliferative
35The Frequency of Somatic Hypermutation Decreases with the Distance from the Rearranged V(D)J Gene 0.5 kb kb
36AID (activation-induced cytidine deaminase) Mediates Somatic Mutation AID – an RNA editing enzyme, deaminatingselective cytidine in certain mRNAs,changing the cytosines into uracils– modifying DNA by the deaminationof cytosine, resulting in formation ofuracil