chapter 11 b-cell generation, activation, and differentiation initial contact between b and t cells...
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Chapter 11 B-cell Generation, Activation, and Differentiation
Initial contact between B and T cells Dec 19, 2006
B cell
T cell
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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)
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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.
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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
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Pre-B Cell Receptor
Heavy chain: Chain
Surrogate ( 代理者 ) light chain: VpreB (V-like sequence) 5 (C-like sequence)
Ig/Ig
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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.
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Pre-TCR (pre-T/ TCR) Activates Signal Transduction Pathways
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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)
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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
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Receptor Editing – secondary V(D)J recombination allows B lymphocytes to replace an inappropriate receptor with a new receptor
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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
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Mature Self-Reactive B Cells Can Be Negatively Selected in the Periphery HEL: hen egg
lysozyme
HEL-binding B cells are present.
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Clonal Anergy in Mature Peripheral B Cells
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Production of Double-transgenic Mice Expressing the H-2Kb Molecule and Anti-Kb Ab
membrane form
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Clonal Deletion of Self-reactive Mature Peripheral B Cells
Kb-binding B cells are deleted.
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B-Cell Activation and Proliferation
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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.
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Two Distinct Signals for B-Cell Activation
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B-1 and B-2 B Lymphocytes
, class switching is not common
Bind Ag with lower affinityAbs are multispecific
, therefore, no affinity maturation
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ITAM: immunoreceptor tyrosine-based activation motif ( 圖形 )
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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
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Signal Transduction Pathways Activated by the BCR
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The B-Cell-Coreceptor Complex Can Enhance B-Cell Responses : TAPA-1 (CD81), CR2 (CD21), and CD19
ITIM: immunoreceptor tyrosine inhibitory motif
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Sequence of Events in B-Cell Activationby a Thymus-Dependent Ag
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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
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The Humoral Response
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Primary (1° ) and Secondary (2 ° ) Responses
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In Vivo Sites for Inductionof Humoral Response
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B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node
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3 Important B-cell Differentiation EventsTake Place in Germinal Centers
1. Affinity maturation
2. Class switch
3. Formation of plasma cells and memory cells
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Cellular Events within Germinal Centers
highly proliferative
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The Frequency of Somatic Hypermutation Decreases with the Distance from the Rearranged V(D)J Gene
0.5 kb 1.5 kb
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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
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Var
iab
ilit
y
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Cytokines Affect Proliferation and Class Switching of B Cells During the Differentiation of B Cells into Plasma Cells
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