1. Combination of gene segments results in a huge number of various variable regions of the heavy and light chains expressed by different B-cellsSOMATIC 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 co-dominantly, how could B cells shut down the genes on one of their chromosomes?

ALLELIC EXCLUSION

THE RESULT OF SOMATIC GENE REARRANGEMENTS

Evidence for allelic exclusion

Allotypes can be identified by staining B cell surface Ig with antibodies

a/a b/b a/b

YBb YBa YBb

Y

YB ab

YBa AND

ALLOTYPE- a polymorphism in the Heavy chain C region of Ig

Suppression of H chain rearrangement by pre-B cell receptor prevents expression of two

specificities of antibody per cell

Allelic exclusion is needed for efficient clonal selection

All daughter cells must express the same Ig specificityotherwise the efficiency of the response would be compromised

Suppression of H chain gene rearrangement helps to prevent the emergence ofnew daughter specificities during proliferation after clonal selection

S. typhi

Antibody

S. typhi

YY

Y Y

Suppression of H chain gene rearrangementensures only one specificty of Ab expressed per cell.

Allelic exclusion prevents unwanted responses

BSelf antigenexpressed bye.g. brain cells

S. aureusY Y

YYYB

S. aureus

YY

Y

YY

Y

Y

AntiS. aureus

Antibodies

Y

Y Y

Y Y

YAntibrainAbs

One Ag receptor per cell IF there were two Ag receptors per cell

Y

Y Y

Y

YY Y

AntiS. aureus

Antibodies

Prevents induction of unwanted responses by pathogens

ALLELIC EXCLUSION

Ig alleles are not differentially marked

Close (methylated) chromatin structure

Asynchronous -locus replication

Blastocyst

Pre-B cell Early replicating allele is chosen to undergo demethylation and

chromatin changesNucleosomes

Modified histones

The early replicating allele becomes accessible to rearrangement

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

RESULT OF SOMATIC GENE REARRANGEMENT AND ALLELIC EXCLUSION

INDEPENDENT ON ANTIGEN

OCCURS IN THE BONE MARROW

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

THE RESULT OF SOMATIC GENE REARRANGEMENTS

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

Exclusion of anti-brain B cells i.e. self tolerance

YYBB

One specificity of Agreceptor per cell

S. aureus

Anti-brain IgAND

anti-S. Aureus IgYYYBB

IF there were two specificitiesof Ag receptor per cell

Anti-brain Ig

BB

Deletion Anergy

OR

anti S.Aureus B cells will be excluded leaving a “hole in the repertoire”

BUT

YYYBB