Transcript Signal Transduction Pathways and the Activation of B Cells

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