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B CELL DEVELOPMENT
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT
2. The stem cell develops into a mature IgM+ B cell.
1
2
GENERATIVE
LYMPHOID ORGANS
1. B Cells develop from pluripotent stem cells in the
bone marrow.
PERIPHERAL
LYMPHOID ORGANS
Asilmi 07- B CELLS AND ANTIBODIES
B Lymphocytes are predicted to generate
approximately 1 X 1011 distinct antigen
receptors.
However, the human genome only contains
about 35,000 distinct genes.
How does such a limited genome enable the
generation of an almost infinite number of
antigen receptors?
Asilmi 07- B CELLS AND ANTIBODIES
Answer: Diversity is generated through
somatic recombination of gene segments that
code for the variable regions of the receptors.
Asilmi 07- B CELLS AND ANTIBODIES
Going from DNA (gene) to protein:
the usual way.
Promoter
Exon 1
Exon 2
Genomic DNA
Transcription
Primary Transcript
Splicing
mRNA
Translation
Protein
Asilmi 07- B CELLS AND ANTIBODIES
THE GERMLINE ORGANIZATION OF ANTIGEN RECEPTOR GENE LOCI.
The Ig Heavy chain locus contains up to a few hundred variable (V) region
genes. The variable region gene segments are followed by diversity (D)
and joining (J) gene segments.
The Light chain loci displays a similar organization to the Heavy chain
locus, except that it lacks any D gene segments. There are two light chain
loci - k and l.
Asilmi 07- B CELLS AND ANTIBODIES
GENERATING DIVERSITY BY V(D)J SOMATIC RECOMBINATION
1. V, D and J gene segments are
arranged in tandem.
2. In a single lymphocyte clone,
one D gene segment randomly
recombines with one J gene
segment.
3. A V gene segment then
recombines with the D-J segment,
generating a recombined V-D-J
gene.
4. The new gene is then transcribed.
5. The V-D-J gene segment is
spliced to the first C region RNA (m
Chain)
6. The resulting mRNA is translated
to generate a unique IgM heavy
chain.
Asilmi 07- B CELLS AND ANTIBODIES
V
D
J
constant
V
VDJ recombination #1
variable
D
constant
VDJ recombination #2
variable
constant
J
constant
VARIABLE REGION
1. Each recombination generates a unique variable region - unique
antigen specificity.
2. In contrast, the constant region does not change - conserved effector
function.
Asilmi 07- B CELLS AND ANTIBODIES
SOURCES OF DIVERSITY
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT
2. The stem cell develops into a mature IgM+ B cell.
GENERATIVE
LYMPHOID ORGANS
1. B Cells develop from pluripotent stem cells in the
bone marrow.
1
2
3
PERIPHERAL
LYMPHOID ORGANS
3. The mature, naïve B cells circulates through the
peripheral lymphoid organs.
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT
2. The stem cell develops into a mature IgM+ B cell.
GENERATIVE
LYMPHOID ORGANS
1. B Cells develop from pluripotent stem cells in the
bone marrow.
1
2
3
4. B cells that fail to encounter antigen die through
apoptosis.
4
PERIPHERAL
LYMPHOID ORGANS
3. The mature, naïve B cells circulates through the
peripheral lymphoid organs.
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT
5
PERIPHERAL LYMPHOID ORGANS
5. B cells that encounter antigen are activated.
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL ACTIVATION
1. Naïve B cell encounters
antigen.
2. Helper T cells stimulate B
cells.
Asilmi 07- B CELLS AND ANTIBODIES
PRESENTATION OF ANTIGENS TO T HELPER CELLS BY B CELLS
1. The naïve B cell receptor binds its
cognate antigen.
2. The receptor triggers endocytosis of the
antigen.
3. Antigen is processed and presented on
a Class II MHC molecules. (B cell acts as
classical APC)
4. B cell stimulates T cell activation.
Asilmi 07- B CELLS AND ANTIBODIES
HELPER T CELL ACTIVATION OF B CELLS
1. B Cells process and present
antigens to helper T cells.
3. The combination of CD40
(physical contact) and cytokines
activates B cells.
2. T cells commence production of
molecules that activate B cells
(CD40, cytokines).
4. T helper cell signals induce B cell
activation (proliferation and
differentiation).
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL ACTIVATION
1. Naïve B cell encounters
antigen.
2. Helper T cells stimulate B
cells.
3. Activated B cells begin
clonal expansion.
Asilmi 07- B CELLS AND ANTIBODIES
CLONAL EXPANSION
Each B and T cell encodes a unique BCR or TCR
with a unique specificity.
When a BCR or TCR encounters its cognate antigen the B cell
or T cell is stimulated to undergo multiple rounds of cell
division, thereby expanding. Each daughter is identical to the
parent cell, i.e. a clone.
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL ACTIVATION
1. Naïve B cell encounters
antigen.
2. Helper T cells stimulate B
cells.
3. Activated B cells begin
clonal expansion.
4. Some B cells differentiate
into antibody secreting
plasma cells.
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL ACTIVATION
1. Naïve B cell encounters
antigen.
2. Helper T cells stimulate B
cells.
3. Activated B cells begin
clonal expansion.
4. Some B cells differentiate
into antibody secreting
plasma cells.
5. Others become memory cells.
Asilmi 07- B CELLS AND ANTIBODIES
MEMORY LYMPHOCYTES
Some active lymphocytes differentiate into memory
lymphocytes.
Active Lymphocyte
MEMORY LYMPHOCYTES: Produced from naïve
lymphocytes as a result of antigen exposure. Persist
for years in a quiescent state. Rapidly reactivated by
repeat exposure to antigen and mediate faster, more
potent immune responses.
Memory Lymphocyte
Asilmi 07- B CELLS AND ANTIBODIES
Secondary Versus Primary Antibody Responses.
THE SECONDARY
RESPONSE IS…….
FASTER
STRONGER
MORE SPECIFIC
Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL ACTIVATION
1. Naïve B cell encounters
antigen.
2. Helper T cells stimulate B
cells.
3. Activated B cells begin
clonal expansion.
4. Some B cells differentiate
into antibody secreting
plasma cells.
6. Others switch class to produce a new Ig Isotype.
5. Others become memory cells.
Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHING
A clone of B cells is not committed to make a single Ig isotype forever.
All mature B cells start out making IgM
m
d
V
g
a
e
IgM mRNA
IgM
Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHING
A clone of B cells is not committed to make a single Ig isotype forever.
m
V
d
g
a
e
B cell activation triggers rearrangements at the Ig locus
g
V
m
a
e
d
Exposed DNA ends are joined together
DNA encoding
some constant
regions is
deleted
IgG
End result: New class of Ig
Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHING - AFFINITY
A clone of B cells is not committed to make a single Ig isotype forever.
V
m
d
g
a
e
V
g
IgM mRNA
a
e
IgG mRNA
UNCHANGED
IgM
IgG
Class switching does not affect the variable region.
The Antibody retains Antigen specificity throughout.
Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHING
Class switching explains why IgM is not seen upon re-exposure to
antigen.
Ag
BCR
1. Mature B lymphocyte express IgM as BCR
Ag
2. Lymphocyte is activated by antigen and starts to
secrete IgM
BCR
IgM
Ag
IgG
BCR
3. Activation induces class switching, so that
repeat exposures induce IgG, IgA or IgE.
Asilmi 07- B CELLS AND ANTIBODIES