The genetic basis of antibody structure
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Transcript of The genetic basis of antibody structure
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The genetic basis of antibody structure
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Overview of B cell development
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• 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
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Figure 6.1A prototypical gene coding for a membrane protein.
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Experimental demonstration of kappa gene rearrangement
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Organization of germline Ig gene segments in the mouse
(In mouse, 2 V, 4 J & 4C ; In human, 30 V, 4 J & 4C)
(In mouse, 85 V, 5 J & 1 C ; In human, 40 V, 5 J & 1 C)
(In mouse, 134 VH, 13 DH & 4 JH ; In human, 51 VH, 27 DH & 6 JH )
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Organization & rearrangement of light chain genes
Variable region (N terminal) codedfor by two separate gene segments1) V (variable) gene --- codes for N-term 96 residues2) J (joining) gene --- codes for C-term 13 res.
To generate Ig L chain, 1 V gene & 1 J gene brought together & joinedwith C-region gene creating a gene unit coding for Ig L chain.
Occur in the absence of antigen.
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Figure 6.2The genetic events leading to the synthesis of a kappa light
chain.
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Figure 6.3
Rearrangement of DNA coding for a kappa light chain.
- Occur only in B cells.- Antigenic specificity of lymphocyte becomes fixed.
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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
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Figure 6.4The genetic events leading to the synthesis of a human heavy chain.
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A single B cell produces an Ig of only one antigenic specificity --- allelic exclusion
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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)
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Figure 6.5Mechanism of class switching in immunoglobulin synthesis. S ;eq switch region, upstream of each heavy-chain constant region.
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Regulation of Ig-gene transcription
Enhancer is unable to turn on promoterbecause of long distance.
Effective only after VDJ rearrangement
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Differential RNA processing of heavy-chain primary transcripts
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Secreted & membrane forms of the heavy chain
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Generation of Antibody Diversity
• Multiple V genes in the germ line– constitutes baseline & minimum number of different Ab that could be pro
duced.
• 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 junction
s
• Somatic hypermutaion– occurs in germinal centers, 104 higher than normal mutation rate, largely r
andom, substitutions rather than deletion or insertion, resulting in affinity maturation
• Somatic gene conversion– most notably in birds and rabbits
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Figure 6.6Somatic 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.