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Understanding Immunoglobulin Genetics: Mechanisms, Diversity, and Gene Expression

This detailed overview explores the genetics of immunoglobulins (Ig), highlighting the relationship between variable (V) and constant (C) regions and their genetic organization. It covers the processes of gene rearrangement, transcription, and translation involved in producing diverse antibodies, including heavy and light chain genes. The mechanisms of junctional diversity, N-region insertions, and the importance of allelic exclusion are discussed. Various theories on antibody diversity, including germ line and somatic mutation theories, illustrate how B-cells efficiently produce specific antibodies.

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Understanding Immunoglobulin Genetics: Mechanisms, Diversity, and Gene Expression

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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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