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The genetic basis of antibody structure

The genetic basis of antibody structure. Overview of B cell development. Immune response system extremely diverse (10 6 - 10 7 B & T cells) Genes coding for Ig & TCR use unique strategy to attain diversity; mechanisms unique to B & T cells

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The genetic basis of antibody structure

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  1. The genetic basis of antibody structure

  2. Overview of B cell development

  3. Immune response system extremely diverse (106 - 107 B & T cells) • Genes coding for Ig & TCR use unique strategy to attain diversity; mechanisms unique to B & T cells • Variable & constant region genes coded for by different genes, & different V genes can be linked to single C gene (instead of having 1 gene coding/Ab molecule) • Ab genes can move & rearrange in genome of differentiating cell; brings together genes for V & C regions for transcription-translation to complete H & L chains • Generation of diversity of antigen specific receptors on B & T cells have many common features

  4. Figure 6.1 A prototypical gene coding for a membrane protein.

  5. Experimental demonstration of kappa gene rearrangement

  6. Organization of germline Ig gene segments in the mouse (In mouse, 2 Vl, 4 Jl & 4Cl ; In human, 30 Vl, 4 Jl & 4Cl) (In mouse, 85 Vk, 5 Jk & 1 Ck ; In human, 40 Vk, 5 Jk & 1 Ck) (In mouse, 134 VH, 13 DH & 4 JH ; In human, 51 VH, 27 DH & 6 JH)

  7. Organization & rearrangement of light chain genes Variable region (N terminal) coded for by two separate gene segments 1) V (variable) gene --- codes for N-term 96 residues 2) J (joining) gene --- codes for C-term  13 res. To generate Ig L chain, 1 V gene & 1 J gene brought together & joined with C-region gene creating a gene unit coding for Ig L chain. Occur in the absence of antigen.

  8. Figure 6.2 The genetic events leading to the synthesis of a kappa light chain.

  9. - Occur only in B cells. - Antigenic specificity of lymphocyte becomes fixed. Figure 6.3 Rearrangement of DNA coding for a kappa light chain.

  10. Organization of H chain genes is different from L chain genes. - Involves 3 gene segments (V, J & D); J & D code for 3rd hypervariable region (CDR3) of H chain. - Multiple genes code for C region in germ line; C region determines class, biological function of Ig

  11. Figure 6.4 The genetic events leading to the synthesis of a human heavy chain.

  12. A single B cell produces an Ig of only one antigenic specificity --- allelic exclusion

  13. Switching • One B cell forms specific Ab determined by nature of VJ & VDJ. • Cell can switch to make different class Ig (e.g., IgG or IgE) while retaining the same antigenic specificity = class or isotype switch • VJ & VDJ rearrangements occur prior to Ag exposure in development of B cells; switching occurs in mature B cells depending on Ag stimulation & factors released by T cells (cytokines)

  14. Figure 6.5 Mechanism of class switching in immunoglobulin synthesis. S ;eq switch region, upstream of each heavy-chain constant region.

  15. Regulation of Ig-gene transcription Enhancer is unable to turn on promoter because of long distance. Effective only after VDJ rearrangement

  16. Differential RNA processing of heavy-chain primary transcripts m

  17. Secreted & membrane forms of the heavy chain m

  18. Generation of Antibody Diversity • Multiple V genes in the germ line • constitutes baseline & minimum number of different Ab that could be produced. • VJ & VDJ combinatorial association • any V  any J, any V  any D any J • Random assortment of H and L chains • any H  any L • Junctional & insertional diversity • imprecise joining and insertion of small sets of nucleotides at the junctions • Somatic hypermutaion • occurs in germinal centers, 104 higher than normal mutation rate, largely random, substitutions rather than deletion or insertion, resulting in affinity maturation • Somatic gene conversion • most notably in birds and rabbits

  19. Figure 6.6 Somatic gene conversion generates diversity in Ig genes of several species. The Figure illustrates the phenomenon in the chicken Ig heavy-chain locus: short sequences of DNA from one or more pseudogenes (3 and 8 in the Figure) are copied into the rearranged B-cell VDJ unit.

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