The structural repertoire of the human V kappa domain.

Abstract

In humans, the gene for the V kappa domain is produced by the recombination of one of 40 functional V kappa segments and one of five functional J kappa segments. We have analysed the sequences of these germline segments and of 736 rearranged V kappa genes to determine the repertoire of main chain conformations, or canonical structures, they encode. Over 96% of the sequences correspond to one of four canonical structures for the first antigen binding loop (L1) and one canonical structure for the second antigen binding loop (L2). Junctional diversity produces some variation in the length of the third antigen binding loop (L3) and in the identity of residues at the V kappa‐J kappa join. However, this is limited and 70% of the rearranged sequences correspond to one of three known canonical structures for the L3 region. Furthermore, we show that the canonical structures selected during the primary response are conserved during affinity maturation: the key residues that determine the conformations of the antigen binding loops are unmutated or undergo conservative mutation. The implications of these results for immune recognition are discussed.

DNA polymerases in adaptive immunity

“…For light chains, a restricted heterogeneity of CDR3 sizes is indeed required to maintain a semi-invariant residue encoded at the 3' end of Vκ genes 29 , whereas CDR3 heterogeneity is key for the heavy-chain repertoire. Minimal processing of light-chain coding ends would be tightly controlled by Polµ, whereas a less potent activity of Polλ would allow for the large size diversity that is characteristic of CDR3s of immunoglobulin heavy chains.…”

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

“…8 One important driver of the breakthrough of antibody-based therapeutics was the sequencing/characterization of human, rodent and other species germline immunoglobulin (Ig) heavy and light chain (V, (D), J and C) genes. [10][11][12] This revealed the extensive diversity of the Ig repertoire and explained its ability to recognize and bind virtually any antigen with a different level of affinity. 13 Numerous antibody discovery platforms generating human therapeutic antibodies are now available, including transgenic mouse systems as well as non-immune and synthetic human antibody libraries that can be screened by various display technologies.…”

The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig VL germ line gene use and clonal plasma cell burden

“…In addition, investigators have determined the relative contributions of germ line genes to the circulating B-cell pool in healthy individuals (the normal expressed repertoire). [15][16][17][18][19] By such approaches, a germ line gene rarely used in the normal repertoire may be shown to be used preferentially in a particular B-cell disorder. 20 In this report we identify clonal Ig V L genes from patients with AL to test the hypothesis that the tropism of organ involvement is a function of Ig V L germ line gene use and plasma cell burden.…”