asilmi 07- b cells and antibodies today b cell development
TRANSCRIPT
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Asilmi 07- B CELLS AND ANTIBODIES
TODAY
B CELL DEVELOPMENT
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Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT GE
NE
RA
TIV
E
LY
MP
HO
ID O
RG
AN
S1. B Cells develop from pluripotent stem cells in the bone marrow.
1
22. The stem cell develops into a mature IgM+ B cell.
PE
RIP
HE
RA
LL
YM
PH
OID
OR
GA
NS
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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?
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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.
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Asilmi 07- B CELLS AND ANTIBODIES
Going from DNA (gene) to protein:the usual way.
Genomic DNA
Promoter Exon 1 Exon 2
Primary Transcript
Transcription
mRNA
Splicing
Protein
Translation
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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 - and .
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Asilmi 07- B CELLS AND ANTIBODIES
GENERATING DIVERSITY BY V(D)J SOMATIC RECOMBINATION
6. The resulting mRNA is translated to generate a unique IgM heavy chain.
5. The V-D-J gene segment is spliced to the first C region RNA ( Chain)
4. The new gene is then transcribed.
3. A V gene segment then recombines with the D-J segment, generating a recombined V-D-J gene.
2. In a single lymphocyte clone, one D gene segment randomly recombines with one J gene segment.
1. V, D and J gene segments are arranged in tandem.
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Asilmi 07- B CELLS AND ANTIBODIES
V D J constant V D J constant
VDJ recombination #1
variable constant
VDJ recombination #2
variable constant
1. Each recombination generates a unique variable region - unique antigen specificity.
VARIABLE REGION
2. In contrast, the constant region does not change - conserved effector function.
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Asilmi 07- B CELLS AND ANTIBODIES
SOURCES OF DIVERSITY
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Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT GE
NE
RA
TIV
E
LY
MP
HO
ID O
RG
AN
S1. B Cells develop from pluripotent stem cells in the bone marrow.
1
22. The stem cell develops into a mature IgM+ B cell.
PE
RIP
HE
RA
LL
YM
PH
OID
OR
GA
NS
3
3. The mature, naïve B cells circulates through the peripheral lymphoid organs.
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Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT GE
NE
RA
TIV
E
LY
MP
HO
ID O
RG
AN
S1. B Cells develop from pluripotent stem cells in the bone marrow.
1
22. The stem cell develops into a mature IgM+ B cell.
PE
RIP
HE
RA
LL
YM
PH
OID
OR
GA
NS
3
3. The mature, naïve B cells circulates through the peripheral lymphoid organs.
4. B cells that fail to encounter antigen die through apoptosis.
4
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Asilmi 07- B CELLS AND ANTIBODIES
STAGES OF B CELL DEVELOPMENT
5. B cells that encounter antigen are activated. PE
RIP
HE
RA
L L
YM
PH
OID
OR
GA
NS
5
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Asilmi 07- B CELLS AND ANTIBODIES
1. Naïve B cell encounters antigen.
STAGES OF B CELL ACTIVATION
2. Helper T cells stimulate B cells.
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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.
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Asilmi 07- B CELLS AND ANTIBODIES
HELPER T CELL ACTIVATION OF B CELLS
1. B Cells process and present antigens to helper T cells.
2. T cells commence production of molecules that activate B cells (CD40, cytokines).
3. The combination of CD40 (physical contact) and cytokines activates B cells.
4. T helper cell signals induce B cell activation (proliferation and differentiation).
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Asilmi 07- B CELLS AND ANTIBODIES
1. Naïve B cell encounters antigen.
STAGES OF B CELL ACTIVATION
2. Helper T cells stimulate B cells.
3. Activated B cells begin clonal expansion.
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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.
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Asilmi 07- B CELLS AND ANTIBODIES
1. Naïve B cell encounters antigen.
STAGES OF B CELL ACTIVATION
2. Helper T cells stimulate B cells.
3. Activated B cells begin clonal expansion.
4. Some B cells differentiate into antibody secreting plasma cells.
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Asilmi 07- B CELLS AND ANTIBODIES
1. Naïve B cell encounters antigen.
STAGES OF B CELL ACTIVATION
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.
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Asilmi 07- B CELLS AND ANTIBODIES
MEMORY LYMPHOCYTES
Active Lymphocyte
Memory Lymphocyte
Some active lymphocytes differentiate into memory lymphocytes.
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.
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Asilmi 07- B CELLS AND ANTIBODIES
Secondary Versus Primary Antibody Responses.
THE SECONDARY RESPONSE IS…….
FASTER
STRONGER
MORE SPECIFIC
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Asilmi 07- B CELLS AND ANTIBODIES
1. Naïve B cell encounters antigen.
STAGES OF B CELL ACTIVATION
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.
6. Others switch class to produce a new Ig Isotype.
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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
V
IgM mRNA
IgM
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Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHING
A clone of B cells is not committed to make a single Ig isotype forever.
V
B cell activation triggers rearrangements at the Ig locus
DNA encoding some constant regions is deleted
V
Exposed DNA ends are joined together
End result: New class of Ig
IgG
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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
IgM mRNA
IgM
V
IgG
IgG mRNA
The Antibody retains Antigen specificity throughout.
Class switching does not affect the variable region.
UNCHANGED
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Asilmi 07- B CELLS AND ANTIBODIES
CLASS SWITCHINGClass switching explains why IgM is not seen upon re-exposure to antigen.
2. Lymphocyte is activated by antigen and starts to secrete IgM
1. Mature B lymphocyte express IgM as BCRBCR
Ag
IgM
BCR
Ag
3. Activation induces class switching, so that repeat exposures induce IgG, IgA or IgE.
IgG BCR
Ag