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Chapter 11 B-cell Generation, Activation, and Differentiation B cell T cell Initial contact between B and T cells Dec 19, 2006 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 1 SCF: stem-cell factor direct contact is required. B-cell Maturation Depends on Rearrangement of the Ig DNA in the Lymphoid Stem Cells Naïve B Cell RAG: recombination-activating genes (recombinases) TdT: terminal deoxynucleotidyl transferase Pre-B Cell Receptor Heavy chain: m Chain Surrogate (代理者) light chain: VpreB (V-like sequence) l5 (C-like sequence) Iga/Igb Sequential Expression of mIg and Surrogate L Chain During B-Cell Differentiation B-cell development in l5-/- mice is blocked at the pre-B stage. Pre-TCR (pre-Ta / TCRb) Activates Signal Transduction Pathways Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone Marrow lymphoid stem cell pro-B cell pre-B cell (IL-2R a) CD45R: a protein tyrosine phosphatase CD19: part of the B-cell coreceptor CD43: leukosialin CD24: heat-stable antigen (HAS) immature B cell mature B cell mIgM + mIgD Negative Selection of Self-Reactive B Cells During Maturation in the Bone Marrow Ab against H-2Kk transgenes (H, L chain genes) ↓ H-2d/k or H-2d mice negative selection !! 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 , therefore, no affinity maturation , class switching is not common Bind Ag with lower affinity Abs are multispecific 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 proteintyrosine-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 Activation by 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-kB 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 Initial contact between a T-B conjugate a T cell and B cell the Ag-specific B cell (directional or polarized release of cytokines) The Humoral Response Primary (1° ) and Secondary (2 ° ) Responses In Vivo Sites for Induction of Humoral Response B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node 3 Important B-cell Differentiation Events Take 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 Variability Cytokines Affect Proliferation and Class Switching of B Cells During the Differentiation of B Cells into Plasma Cells