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Immunoglobulin Genetics

Immunoglobulin Genetics. Immunoglobulin Genetics History. Same C region could associate with many V regions IgG Ab with different specificities Same V region could associate with many C regions Same idiotype on IgG and IgM Ab V and C regions coded for by separate genes. V λ n. V κ 2.

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Immunoglobulin Genetics

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  1. Immunoglobulin Genetics

  2. Immunoglobulin GeneticsHistory • Same C region could associate with many V regions • IgG Ab with different specificities • Same V region could associate with many C regions • Same idiotype on IgG and IgM Ab • V and C regions coded for by separate genes

  3. Vλn V κ2 V κ1 Vλ2 V κn Vλ1 L L L L L L Jλ1 Jλ2 Jλ3 Jλ4 Cλ2 Cλ1 Cλ4 Cλ3 P P P P P P E E E E Lambda light chain genes; n=30 Jκ1 Jκ2 Jκ4 Jκ3 Jκ5 Cκ E Kappa light chain genes; n=300 Light Chain Gene FamiliesGerm line gene organization

  4. Vκ1 Vκ2 Vκn Jκ1 Jκ2 Jκ3 J4 Jκ5 Cκ L L L DNA P P P P E DNA Rearrangement Vκ2 Jκ4 Vκ1 Jκ5 Cκ L L DNA P E Transcription V J C L Primary transcript RNA E RNA Processing V L J C mRNA RNA Translation V L J C Protein Transport to ER J V C Protein C V Light Chain Gene FamiliesGene rearrangement and expression

  5. Heavy chain genes; Vn=1000, Dn=15 D1 D2 Dn V1 V2 Vn J1 J2 J3 J4 J5 D3 L L L P P P E Cµ Cδ Cγ3 Cγ1 Cγ2 Cγ4 Cε Cα1 Cα2 CH1 CH2 CH3 CH4 H Introns separate exons coding for H chain domains Heavy Chain Gene FamilyGerm line gene organization

  6. V1 V2 Vn L L L P P P Dn J1 J2 J3 J4 J5 Cµ Cδ D1 D2 D3 DJ rearrangement E E E D2 J4 D1 V1 V2 Vn J5 Cµ Cδ L L L DNA P P P E VDJ rearrangement V2 L V2 D2 J4 V1 J5 Cµ Cδ L L DNA P P Transcription D2 J4 J5 Cµ Cδ RNA Primary transcript Heavy Chain Gene FamilyGene rearrangement and expression

  7. V2 D2 J4 J5 V2 L Cµ Cδ D2 J4 J5 L Cµ Cδ Primary transcript E E RNA Processing V D J Cδ L V D J Cµ L An An mRNA for Cδ mRNA for Cµ Translation V D J Cµ V D J Cδ L L Cµ heavy chain Cδ heavy chain Transport to ER V D J Cµ V D J Cδ V V C C Cµ heavy chain Cδ heavy chain Heavy Chain Gene FamilyGene rearrangement and expression

  8. J C V L 1 Nonamer ACAAAAACC TGTTTTTGG Heptamer CACTGTG GTGACAC Heptamer CACAGTG GTGTCAC Nonamer GGTTTTTGT CCAAAAACA 23 bp 23 bp 12 bp 12 bp One turn RSS Two turn RSS 2 1 Kappa light chains 2 Lambda light chains V J L C Heavy chains 2 1 V J C L D 2 2 1 1 Mechanism of DNA Rearrangements • Recombination signal sequences (RSS) • Nonmer • Heptamer • 1 or 2 turn signals • Rag-1 and Rag-2

  9. Progenitor B cell 1st Heavy chain gene - + VDJ recombination 2nd No Productive rearrangement ? Apoptosis Yes Transcribe/translate µ (δ) Heavy chain µ µ Maternal Paternal or Pre B cell Order of Ig Gene Expression

  10. µ µ or Pre B cell Light chain gene 1st - κ 2nd -κ 3rd λ 4th - λ - + VJ recombination 4 th µ No Productive rearrangement ? Apoptosis Yes Transcribe/translate Light chain µ+ δ Mature B cell Order of Ig Gene Expression

  11. Order of Ig Gene Expression Explains: • Why an individual B cell only produces one kind of Ig with one kind of light chain • Why an individual B cell makes only makes antibodies of one specificity • Why there is allelic exclusion Importance of allelic exclusion??

  12. Origin of Antibody DiversityHistory • Definition – Diversity (repitoire) is the total of all the Ab specificities that an organism is capable of expressing • Theories • Germ line theory • Somatic mutation theory

  13. V gene V gene D region D region C C C C C C C C C C C C T G G T G G C C C T G G C C C C G G Pro Trp Pro Arg V gene D region C C C C C C T G G C C C C C G Pro Pro Origin of Antibody DiversityCurrent concepts • Multiple V genes • V-J and V-D-J joining • Junctional diversity • N region insertions • Amino acid sequences not encoded in the germ line

  14. Generation of N region insertions D J Break DNA D J J - OH D TdT adds nucleotides -GTCAATG D J Ligate -GTCAATG- + D J N region insertion Intron

  15. Origin of Antibody DiversityCurrent concepts • Multiple V genes • V-J and V-D-J joining • Junctional diversity • N region insertions • Somatic mutation • Combinatorial association • Multispecificity

  16. Generation of Diversity • Ag independent process • Clonal selection

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