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HOW MANY IMMUNOGLOBULIN GENE SEGMENTS

IMMUNOGLOBULIN CHAINS ARE ENCODED BY MULTIPLE GENE SEGMENTS. Gene segments Light chain Heavy chain kappa lambda. Variable (V) 40 30 65 Diversity (D) 0 0 27 Joining (J) 5 4 6. ORGANIZATION OF IMMUNOGLOBULIN GENE SEGMENTS.

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HOW MANY IMMUNOGLOBULIN GENE SEGMENTS

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  1. IMMUNOGLOBULIN CHAINS ARE ENCODED BY MULTIPLE GENE SEGMENTS Gene segments Light chain Heavy chain kappa lambda Variable (V) 40 30 65 Diversity (D) 0 0 27 Joining (J) 5 4 6 ORGANIZATION OF IMMUNOGLOBULIN GENE SEGMENTS Chromosome 2 kappa light chain gene segments Chromosome 22 lambda light chain gene segments Chromosome 14 heavy chain gene segments HOW MANY IMMUNOGLOBULIN GENE SEGMENTS

  2. VARIABILITY OF B-CELL ANTIGEN RECEPTORS AND ANTIBODIES VH JH D V-Domains C-Domains VL JL VH-D-JH VL-JL B cells of one individual 1 2 3 4

  3. Estimates of combinatorial diversity Taking account of functional V D and J genes: 65 VH x 27 DH x 6JH = 10,530 combinations 40 Vk x 5 Jk = 200combinations 30 Vl x 4 Jl = 120 combinations = 320 different light chains If H and L chains pair randomly as H2L2 i.e. 10,530x 320 = 3,369,600 possibilities Due only to COMBINATORIAL diversity In practice, some H + L combinations do not occur as they are unstable Certain V and J genes are also used more frequently than others. There are other mechanisms that add diversity at the junctions between genes - JUNCTIONAL diversity GENERATES A POTENTIAL B-CELL REPERTOIRE

  4. Somatic recombination to generate antibody diversity

  5. Severe combined immunodeficiency (SCID) Omenn syndrome - RAG deficiency Lack of T-cells and B cells Early manifestation red rash on the face and shoulders, infections with opportunistic pathogens. (Candida albicans, Pneumocystis carnii pneumonia) Lack of palpable lymph nodes

  6. How does somatic gene rearrangement (recombination) work? • How is an infinite diversity of specificity generated from finite amounts of DNA? • Combinatorial diversity • 2. How do V region find J regions and why don’t they join to C regions?12-23 rule -Special - Recobnitation Signal Sequences (RSS) - Recognized by Recombination Activation Gene coded proteins (RAGs) PALINDROMIC SEQUENCES HEPTAMER CACAGTG CACAGTG GTGACAC GTGACAC NONAMER ACAAAAACC GGTTTTTGT TGTTTTTGG CCAAAAACA

  7. Vl Jl 7 23 12 7 9 9 Vk JH Jk 9 9 7 12 23 23 7 7 9 D 12 7 7 12 9 9 VH 9 7 23 V, D, J flanking sequences Sequencing upstream and downstream of V, D and J elements revealed conserved sequences of 7, 23, 9 and 12 nucleotides in an arrangement that depended upon the locus

  8. HEPTAMER - Always contiguous with coding sequence NONAMER - Separated fromthe heptamer by a 12 or 23 nucleotide spacer   JH JH 9 9 23 23 7 7 D D 12 12 7 7 7 7 12 12 9 9 9 9 VH VH 9 9 7 7 23 23 Recombination signal sequences (RSS) 12-23 RULE – A gene segment flanked by a 23mer RSS can only be linked to a segment flanked by a 12mer RSS

  9. 12-mer = one turn 23-mer = two turns Intervening DNA of any length 23 12 V 7 9 7 D J 9 Molecular explanation of the 12-23 rule

  10. V4 V5 V3 V1 V3 V4 V2 V6 V2 V5 V6 V7 V8 V7 9 V9 D J V8 V9 9 23-mer • Heptamers and nonamers align back-to-back • The shape generated by the RSS’s acts as a target for recombinases 12-mer 7 7 D J V1 Molecular explanation of the 12-23 rule Loop of intervening DNA is excised • An appropriate shape can not be formed if two 23-mer flanked elements attempted to join (i.e. the 12-23 rule)

  11. V4 V5 V3 V6 V2 V7 9 V8 V9 9 23-mer 12-mer 7 7 D J V1 CONSEQUENCES OF RECOMBINATION Generation of P-nucleotides

  12. V4 V5 V3 V6 V2 V7 9 V8 V9 9 23-mer 12-mer 7 7 D J V1 Generation of N-nucleotides Terminal deoxynucleotidyl Transferase (TdT) Loop of intervening DNA is excised

  13. V D J TCGACGTTATAT AGCTGCAATATA Junctional Diversity TTTTT TTTTT TTTTT Germline-encoded nucleotides Palindromic (P) nucleotides - not in the germline Non-template (N) encoded nucleotides - not in the germline Creates an essentially random sequence between the V region, D region and J region in heavy chains and the V region and J region in light chains

  14. How does somatic gene rearrangement (recombination) work? • How is an infinite diversity of specificity generated from finite amounts of DNA? • Combinatorial diversity • 2. How do V region find J regions and why don’t they join to C regions?12-23 rule • How does the DNA break and rejoin? • Imprecisely, with the random removal and addition of nucleotidesto generate sequence diversity • Junctional diversity(P- and N- nucleotides, see above)

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