Human germline Vx and segments

In humans, approximately 40% of light chains arc of the X. type. The human immunoglobulin A locus is located on chromosome 22qll.2 and contains 30 functional VK segments (Table 1) from ten VA families (Vxl to VA10) (Figure 1C). The transcriptional orientation of all segments in the locus (5' to 3' with respect to the constant region genes) is consistent with joining occurring by a deletional mech anism. As with the human VH and VK segments, many pseudogenes are scattered throughout the locus. The Jx segments in the X locus are each paired with their own gene, such that there are four functional Jx-Cx pairs (Table 1 and Figure 1C). The choice of Cx gene expression is therefore determined by Vx-Jx rearrangement. In contrast to the human heavy chain and k light chain loci, where members of different VH and VK families are interspersed throughout the locus, the Vx families are arranged in three distinct clusters. Cluster A (closest to the Jx segments) contains the Vx2 and Vk3 families, cluster B (in the middle of the locus) contains the Vxl, Vx5, Vx7 and Vx9 families and cluster C (furthest from the Jx segments) contains the Vx4, Vx6, Vx8 and Vx10 families. In addition to the functional genes on chromosome 22 at least one nonfunctional 'orphon' V^ segment is located on chromosome 8.

For further details on the sequences and organization of the human V, D and J segments see on the World Wide Web.

The creation of antibody diversity

Early studies on rearranged genes by Kabat and colleagues demonstrated that sequence diversity in antibodies is concentrated in six complementarity-determining regions (CDRs), three from the heavy chain variable domain (CDRH1, CDRH2 and CDRH3) and three from the light chain variable domain (CDRL1, CDRL2 and CDRL3). In the primary repertoire the CDRH1 and CDRH2 regions are encoded by the VH segment, whereas CDRH3 is the product of Vh-D-Jh recombination. For the light chain, CDRL1, CDRL2 and the beginning of CDRL3 are encoded by the VK or \K segment, whereas the end of CDRL3 is the product of VK-JK or Vx-Jx recombination. Subsequent crystallographic analyses have shown that these six CDRs correspond to the six antigen-binding loops that together form the antigen binding site of the antibody. As we have seen, this diversity is the result of germline diversity and junctional diversity in the primary repertoire and somatic hypermutation introduced during the process of affinity maturation. Since all human VH, VK and Vx segments have now been sequenced and mapped it is possible to dissect their respective contributions in response to a wide range of antigens. A large database of rearranged genes was compiled and each was automatically assigned to its germline Vn, VK and Vx counterpart, thereby identifying the location of the somatic mutations in each rearranged gene. The percentage somatic hypermutation at each position in the heavy and light chain variable



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