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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. How B cells express one light chain species and one heavy chain species even
though every B cell possesses a maternal and paternal locus of both genes.
Since all other genes known at the time appeared to be expressed codominantly, how could B cells shut down the genes on one of their
chromosomes?
ALLELIC EXCLUSION
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
AND b
b
B
B
Y
Suppression of H chain rearrangement by
pre-B cell receptor prevents expression of two
specificities of antibody per cell
Y
b
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
YY
S. aureus
Y
Y
Y
Y
Anti
S. aureus
Antibodies
B
S. aureus
Anti
brain
Abs
Y
Y
Y
Y
Self antigen
expressed by
e.g. brain cells
YY
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
Ig alleles are not differentially marked
Blastocyst
Close (methylated) chromatin
structure
Asynchronous -locus replication
Pre-B cell
Early replicating allele is chosen
to undergo demethylation and
chromatin changes
Nucleosomes
Modified histones
The early replicating allele becomes
accessible to rearrangement
RESULT OF SOMATIC GENE REARRANGEMENT AND
ALLELIC EXCLUSION
1. Somatic rearrangement of Ig gene segments 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 huge 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
INDEPENDENT ON ANTIGEN
OCCURS IN THE BONE MARROW
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
Allelic exclusion helps diagnose and monitor
lymphoma:
Due to clonal expansion of a single cell that contains a unique
rearrangement the amount of cancer cells in blood or in bone
marrow can be determined
Can be used to monitor residual tumor cells upon treatment
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-brain 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