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Ig Genetics 2001
 

Ig Genetics 2001

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    Ig Genetics 2001 Ig Genetics 2001 Presentation Transcript

    • 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
    • Light Chain Gene Families Germ line gene organization J  1 C  1 E J  2 C  2 E J  3 C  3 E J  4 C  4 E P L V  1 P L V  n P L V  2 Lambda light chain genes; n=30 P L V  1 P L V  n P L V  2 J  2 J  3 J  5 C  E J  1 J  4 Kappa light chain genes; n=300
    • Light Chain Gene Families Gene rearrangement and expression L V  1 L V  n L V  2 J  2 J  3 J  5 C  J  1 J  4 DNA P P P E P P E L V  1 L J  5 C  V  2 J  4 DNA DNA Rearrangement V C J V C Protein Transport to ER Protein Translation C L V J E L V C J RNA Transcription Primary transcript C L V J RNA Processing RNA mRNA
    • Heavy Chain Gene Family Germ line gene organization Introns separate exons coding for H chain domains Heavy chain genes; Vn=1000, Dn=15 P L V1 P L Vn P L V2 D2 D3 D1 Dn C  C  C  3 C  C  2 C  1 C  4 C  1 C  2 J2 J3 J5 J1 J4 E C H 1 H C H 2 C H 3 C H 4
    • Heavy Chain Gene Family Gene rearrangement and expression P L V1 P L Vn P L V2 D2 D3 D1 Dn C  C  J2 J3 J5 J1 J4 E DJ rearrangement P L Vn P L V1 P L V2 D2 D1 C  C  J5 J4 E DNA VDJ rearrangement D2 C  C  J5 J4 E P L V1 P L V2 DNA Transcription D2 C  C  J5 J4 E L V2 RNA Primary transcript
    • Heavy Chain Gene Family Gene rearrangement and expression E Primary transcript E J4 D2 V2 C  C  J5 L C  C  J5 L D2 J4 V2 RNA Processing A n mRNA for C  C  L D J V C  L D J V A n mRNA for C  Translation C  heavy chain C  L D J V C  L D J V C  heavy chain Transport to ER C  heavy chain V C C  D J V C  D J V C  heavy chain V C
    • Mechanism of DNA Rearrangements
      • Recombination signal sequences (RSS)
        • Nonmer
        • Heptamer
        • 1 or 2 turn signals
      • Rag-1 and Rag-2
      L V 2 J C 1 Lambda light chains L V 1 J C 2 Kappa light chains Heavy chains L V 2 J C 2 1 1 D Heptamer CACAGTG GTGTCAC Nonamer ACAAAAACC TGTTTTTGG 23 bp 23 bp Two turn RSS 2 Nonamer GGTTTTTGT CCAAAAACA Heptamer CACTGTG GTGACAC 12 bp 12 bp One turn RSS 1
    • Order of Ig Gene Expression + - Heavy chain gene VDJ recombination Productive rearrangement ? Yes No Transcribe/translate 1st 2nd or Apoptosis Progenitor B cell Pre B cell    (  ) Heavy chain Paternal Maternal
    • Order of Ig Gene Expression + - Light chain gene VJ recombination Productive rearrangement ? Yes No Transcribe/translate Light chain 4 th Apoptosis 1st -  2nd -  3rd -  4th -  or Pre B cell Mature B cell     + 
    • Order of Ig Gene Expression Explains:
      • Why an individual B cell only produces one kind of Ig with one kind of heavy and one kind of light chain
      • Why an individual B cell makes only makes antibodies of one specificity
      • Why there is allelic exclusion
    • Origin of Antibody Diversity History
      • 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
    • Origin of Antibody Diversity Current 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
      D region T G G C C C Pro Trp C C C C C C V gene T G G D region C C C C C C V gene T G G C G G C C C Pro Arg C C C C C C V gene T G G D region C G C C C C Pro Pro
    • - GTCAATG - GTCAATG - + Break DNA TdT adds nucleotides Ligate N region insertion Intron J D J J J D D D Generation of N region insertions
    • Origin of Antibody Diversity Current concepts
      • Multiple V genes
      • V-J and V-D-J joining
      • Junctional diversity
      • N region insertions
      • Somatic mutation
      • Combinatorial association
      • Multispecificity
    • Generation of Diversity
      • Ag independent process
      • Clonal selection
    • T Cell Antigen Receptor
      • Heterodimer of an  and a  chain
      • Gene structure and expression of the  chain is analogous to the immunoglobulin heavy chain
      • Gene structure and expression of the  chain is analogous to the immunoglobulin light chain
      • No somatic mutation in T cells