Download 15 B cell development BA

ANTIGEN-INDEPENDENT DEVELOPMENT
OF B-LYMPHOCYTES
The development of B cells can be divided into six
functionally distinct phases
bone marrow
secondary lymphoid tissues
B cells develop in bone marrow and then migrate to
secondary lymphoid tissues
Pro-B cells develop from the pluripotent hematopoietic
stem cell
IL7-Rα
The early stages of B-cell development are
dependent on bone marrow stromal cells
60 billion B cells/day
Various cell adhesion molecules cytokines and
transcription factors regulate B cell development
PU.1
Ikaros
EBF, E2A
Pax5
VLA-4
CLP
(Integrin)
c-Kit
Receptor
Stem cell
factor (SCF)
VCAM-1
(Ig superfamily)
adhesion
molecules
early
pro-B
Cell membrane
bound
Stroma cell
Cytokines and cell adhesion molecules change with
successive steps of development
Interleukin-7
receptor
Interleukin-7
Growth factor
Early
pro-B
Late
pro-B
VLA-4
(Integrin)
VCAM-1
(Ig superfamily)
Stromal cell
Pre-B
Immunoglobulin heavy-chain gene rearrangement in
pro-B cells gives rise to productive and nonproductive
rearrangements
The pre B-cell receptor monitors the quality of heavy chain
rearrangement
FIRST checkpoint!
Mutation in λ5– arrest at Pro-B cell
stage
SEVERE IMMUNODEFICIENCY
Productive µ-chain rearrangement
- Assembly of pre-BCR
- Switch off RAG genes, enzymes
No further µ-chain rearrangement
ALLELIC EXCLUSION
Only one specificity
. ALLELIC EXCLUSION
Successful somatic rearrangement in one chromosome
inhibits gene rearrangement in the other chromosome
Allelic exclusion at the immunoglobulin loci gives rise
to B cells having antigen receptors of a single specificity
A genetic model provides evidence
for allelic exclusion
ALLOTYPE- a polymorphism in the Heavy chain C region of Ig
Allotypes can be identified by staining B cell surface Ig with antibodies
B
a
B
Y
b
AND b
b
B
B
Y
Y
B
Y
a
a/b
b/b
Y
Y
a/a
a
Allelic exclusion is needed for efficient clonal selection
Antibody
S. typhi
S. typhi
All daughter cells must express the same Ig specificity
otherwise the efficiency of the response would be compromised
Suppression of H chain gene rearrangement helps to prevent the emergence of
new daughter specificities during proliferation after clonal selection
Allelic exclusion prevents unwanted responses
One Ag receptor per cell
IF there were two Ag receptors per cell
Y
Self antigen
B
Y Y
Y Y
S. aureus
Y
Y
Y
Y
Anti
S. aureus
Antibodies
S. aureus
Anti
self
Abs
Y
Y
Y
Y
B
Anti
S. aureus
Antibodies
Suppression of H chain gene rearrangement
ensures only one specificty of Ab expressed per cell.
Prevents induction of unwanted responses by pathogens
Allelic exclusion is needed to prevent holes in the repertoire
One specificity of Ag
receptor per cell
IF there were two specificities
of Ag receptor per cell
Anti-brain Ig
Anti-self Ig
AND
anti-S. Aureus Ig
B
B
Exclusion of anti-brain B cells
i.e. self tolerance
B
Deletion
OR
B
BUT anti S.Aureus B cells will
be excluded leaving a
“hole in the repertoire”
Anergy
B
S. aureus
Assembly of the pre-B cell receptor induces cell proliferation
Large
pre-B
Proliferation
Large
Pre-B
Large
Large
Pre-B
Large
Pre-B
Large
Pre-B
Pre-B
Large
Pre-B
Large
Large
Pre-B
Large
Pre-B
Large
Pre-B
Pre-B
About 100 large preB cells
RAG off
small
Large
pre-B
proliferation
stops
Pre-B
receptor
disappears
IgM
Intracellular VDJCH chain
VL-JL rearrangement
Y
RAG on
Immature
B cell
L chain expressed
Membrane-bound IgM
Nonproductive light-chain gene rearrangements can be
superseded by further gene rearrangement
Rearrangement of the immunoglobulin light-chain genes
in pre-B cells leads to the expression of cell-surface IgM
One B cell produces only one type of heavy and one type
of light chains
COMMITMENT TO ONE TYPE OF ANTIGEN BINDING SITE
B cells that are not able to express functional BCR
die by apoptosis
There are two fate-determining checkpoints during
B-cell development in the bone marrow
Comparison of the properties of B-1 cells and B-2 cells
B lymphocyte subsets
NEGATIVE SELECTION I.
Immature B cells specific for soluble, monovalent
self antigens develop a state of anergy
Anergic B cells have a half
life of 4-5 days
(10% that of regular B cells)
NEGATIVE SELECTION II
Immature B cells with specificity for multivalent self
antigens are retained in the bone marrow
By changing their antigen specificities receptor editing
rescues many self-reactive B cells
The B cell pool consists of B cells with differently
rearranged immunoglobulin genes
Co-Expression of cell surface IgM and IgD
on mature B-cells is controlled by alternative
RNA processing
Immature B cells express IgM and IgD surface Ig
with the same variable domains
B-cell circulation through a lymphoid tissue
POSITIVE SELECTION
Immature B cells must pass through a primary follicle
in a secondary lymphoid tissue to become mature B cells
Result of somatic gene rearrangement and
allelic exclusion
1. Somatic rearrangement of Ig gene segments occurs in a highly
controlled manner
2. Single B-cells become committed to the synthesis of one unique Hchain and one unique L-chain variable domain, which determine their
specificities
3. In one individual a large B-cell repertoire is generated consisting of Bcell clones with different H- and L-chain variable domains
4. This potential B-cell repertoire is able to recognize a wide array of
various antigens
Summary of the main stages in B-cell development