IMMUNOGLOBULIN GENETICS

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IMMUNOGLOBULIN GENETICS
September 22, 2006
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IMMUNOGLOBULIN GENES ARE REARRANGED IN B CELLS
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V REGIONS ARE FORMED FROM MULTIPLE GENE SEGMENTS
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GENOMIC ORGANIZATION OF HUMAN Ig GENES
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DIVERSITY RESULTS FROM RANDOM RECOMBINATION
VH 65V x 27D x 6J 10.5 x 103 Vk 40V x 5J
200 Vl 30V x 4J 120 Total Diversity 4-5 x
106
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RECOMBINATION SIGNAL SEQUENCES
THE 12-23 RULE spacing determines ability to
recombine, namely a 12 can only pair with a 23.
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Figure 4-6
INTERVENING DNA IS DELETED DURING RECOMBINATION
Inversion Tx in opposite direction
Deletion Tx in same direction
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ENZYMATIC STEPS
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DIVERSITY IS INCREASED BY VARIABLE ADDITION OF
NUCLEOTIDES
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Single strand cleavage
Second strand cleavage and hairpin formation
Signal join formation
Hairpin is cleaved
N-nucleotide addition (H only)
Pairing
Coding joint formation
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SOMATIC MUTATION INCREASES DIVERSITY/AFFINITY
MATURATION
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MECHANISMS FOR GENERATION OF DIVERSITY

• MULTIPLE V GENES
• VJ AND VDJ RECOMBINATION
• IMPRECISE JOINING
• SOMATIC MUTATION
• COMBINATION OF H AND L CHAINS

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The Form of Immunoglobulin Changes During
Differentiation
The form of immunoglobulin on the membrane of a B
cell is different from secreted form of
immunoglobulin
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ALL HEAVY CHAIN GENES ARE ORGANIZED SIMILARLY
M1
M2
1
2
3
4
s
Cm
4
3
2
1
M2
M1
s
Ce
1
3
2
M1
M2
s
Cg
Ca
All isotypes have membrane and secreted forms
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GENERATION OF MEMBRANE AND SECRETED Ig
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EXPRESSION OF IgM AND IgD
VH is associated with Cd by differential RNA
processing
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ORGANIZATION OF HEAVY CHAIN GENES
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ISOTYPE OR HEAVY CHAIN CLASS SWITCHING
S-S Recombination leads to association of VH with
a new CH Recombination is between segments of
DNA Intervening DNA is deleted