Chapter 11 B-cell Generation, Activation,

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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
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• ????????
• ????? B ???????????
• B ??? negative selection
• TD TI ?? / B-1 B-2 B ?? /
• BCR signaling / B ??? coreceptor complex
• TH ?????? B ????????
• ???? (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 1 SCF
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
Naïve B Cell
RAG recombination-activating genes
(recombinases) TdT terminal deoxynucleotidyl
transferase
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• Pre-B Cell Receptor
• Heavy chain m Chain
• Surrogate (???) light chain VpreB (V-like
  sequence)
• 
  l5 (C-like sequence)
• Iga/Igb

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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.
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Pre-TCR (pre-Ta / TCRb) 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 a)
CD45R a protein tyrosine phosphatase CD19 part
of the B-cell coreceptor CD43 leukosialin CD24
heat-stable antigen (HAS)
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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 !!
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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
, therefore, no affinity maturation
, class switching is not common
Bind Ag with lower affinity Abs are multispecific
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ITAM immunoreceptor tyrosine-based
activation motif (??)
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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 Activation by 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-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 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 Induction of 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 Events Take
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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Variability
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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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