Expressed human immunoglobulin ϰ genes and their hypermutation

Abstract

The question of which germ-line V kappa genes are expressed was studied by sequencing 70 different cDNA clones from a human spleen library and one clone from a fetal liver library. The sequences were compared to a data base containing all germ-line V kappa gene and pseudogene sequences. In addition, 51 rearranged genomic V kappa genes, 170 cDNA and 74 kappa proteins from the literature were assigned to specific germ-line V kappa genes and included in the comparisons. Not all the known, potentially functional V kappa genes were found to be expressed, while some genes with minor defects are. The total number of expressed genes is smaller than expected: so far 21 germ-line genes and 5 pairs of duplicated identical genes are known to be transcribed. The corresponding numbers for rearranged genomic V kappa genes and kappa proteins are 17 plus 4 and 7 plus 7, respectively. A second aim of the study was to find out whether the expressed repertoire contains derivatives of germ-line V kappa genes still missing in our data base; no evidence for the existence of such genes was found. Several cDNA clones contained additional nucleotides between the V kappa and J kappa gene segments, which may be germ-line derived, inserted by terminal deoxynucleotidyl transferase or introduced by other mechanisms. Somatic gene conversion seems not to play a major role in creating the human kappa gene diversity. Various aspects of the hypermutation of kappa genes are discussed and the formation of block mutations, i.e. the alterations of two or more adjacent nucleotides is stressed as a remarkable feature of the process.

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

“…The rearranged V genes from the synovial B lymphocyte hybridomas reported here were assigned to the three main V families (I, II and III). Although the number of hybridomas studied is small, and hence insufficient for accurate assessment of frequency, it is nevertheless noteworthy that the frequency of family use was comparable to V gene use in circulating B cells from normal individuals [27,41]. It is also noteworthy that most of the individual genes expressed in the synovial hybridomas were highly homologous to their corresponding germ-line genes and, in the main, had no evidence for somatic point mutations.…”

“…Two of the three V I genes (A2A2 and A1B4) were homologous with the O12-O2 gene, which is frequently expressed in responses to both self and exogenous antigens and in B cells from patients with CLL [30,41,43]. However, only A2A2 reacted with IgG.…”

IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis

“…8 As for heavy-chain complete rearrangements, the frequencies of IGKV and IGKJ families in IGKV-J rearrangements were not significantly different from the data reported for PBLs. 18,19 Moreover, unlike BCP-ALL, 20 no considerable difference was found in IGKV family frequencies between deletional and IGKV-J rearrangements.…”

Persistence of a rheumatoid factor (RF)-producing B cell clone with a somatically mutated Igκ chain in a patient with rheumatoid arthritis

“…The light chain is encoded by a VKIV gene which is known to be the only member of the VKIV gene family [20,21], VKIV germ-line polymorphism could be excluded by comparing the RF-encoding K gene with the VKIV germ-line gene analysed in the same patient [13], We were able to show that the RF light chain had undergone 31 somatic mutations [13,16], Ten of these mutations were arranged in blocks of two mutations next to each other. This phenomenon of block mutations was recently described as characteristic of somatically mutated n genes [22],…”