Download 11-LECTURE-B cell dev

Development of B lymphocytes in the bone marrow
The development of B cells can be divided into
six functionally distinct phases.
Pro-B cells develop from the pluripotent
hematopoietic stem cell.
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
EBF, E2A
Pax5
VLA-4
CLP
(Integrin)
c-Kit
Receptor
Tyrosine
kináz
Stem cell
factor (SCF)
VCAM-1
(Ig superfamily)
addhsion
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
Korai
pro-B
Késői
pro-B
VLA-4
(Integrin)
VCAM-1
(Ig superfamily)
Stramal cell
Pre-B
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
---assembles pre-BCR
Switches off RAG genes, enzymes
No further µ-chain rearrangement
ALLELIC EXCLUSION
Only one specificity
Assembly of the pre-B cell receptor
induces cell proliferation
Kb. 100 utódsejt
Nagy
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
Éretlen
B sejt
L chain expressed
Membrane-bound IgM
Nonproductive lightchain gene rearrangements can
be superseded by further gene rearrangement.
Steps of allelic exclusion during development
(And backups)
Two main checkpoints during B cell development:
(PreBCR µ, and az L chain)
Immature B cells with specificity for multivalent
self antigens are retained in the bone marrow.
Receptor Editing of Immature B cells with
self-reactive BCR (Bone Marrow)
Immature B cells specific for 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)
THE RESULT OF SOMATIC GENE REARRANGEMENTS
1. Combination of gene segments results in a huge number of various variable regions of
the heavy and light chains expressed by different B-cells
SOMATIC GENE REARRANGEMENT
2. Successful somatic rearrangement in one chromosome inhibits gene rearrangement in
the other chromosome
ALLELIC EXCLUSION
3. One B-cell produces only one type of heavy and one type of light chain
COMMITMENT TO ONE TYPE OF ANTIGEN BINDING SITE
4. The B-cell pool consist of B-cells with differently rearranged immunoglobulin genes
INDEPENDENT OF ANTIGEN
OCCURS DURING B-CELL DEVELOPMENT IN THE BONE
MARROW
How can mature B-cells express
surface IgM and IgD
Co-Expression of cell surface IgM and IgD
On Mature B-cells is controlled by alternative
RNA processing
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
H-chain and one unique L-chain variable domain, which
determine their specificities
3. In one individual a large B-cell repertoire is generated consisting
of B-cell 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
5. Immature B-cells express IgM and IgD surface Ig with the
same variable domains
B – CELL ACTIVATION
Where and how do all these things
take place?
B-cell recycling in the absence of antigen
(lymph node)
T cell area
B cells
in blood
B cell
area
Efferens
lymph
Recirculating B cells are trapped by foreign
antigens in lymphoid organs
Antigen enters
node in afferent
lymphatic
YY
Y
B cells
proliferate
rapidly
B cells leave blood &
enter lymph node via
high endothelial venules
Y
YY
Y
Y
Y
GERMINAL CENTRE
Transient structure of
Intense proliferation
YY
Y
Germinal centre
releases B cells
that differentiate
into plasma cells
Germinal Center Reaction
„Dating” in the peripheral lymphoid organs
The structure of the germinal centre
Somatic hypermutation
LZ
FDC
DZ
Somatic hypermutation
LZ: light zone
DZ: dark zone
FDC: follicular dendritic cell
Antigen is bound on the surface of follicular dendritic cells (FDC)
FDC
 FDC-s bind immune complexes (Ag-Ab )
 Ag detectable for 12 months following immunization
 A single cell binds various antigens
B cells recognize Ag on the surface of FDC
Fig. 9.15. On the surface of FDC-s immune
complexes form the so-called iccosomes,that can be
released and taken up later by the surrounding
germinal center B cells
T CELL DEPENDENT B CELL ACTIVATION IN LYMPHOID ORGANS
IgM
IgG
IgA
IgE