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PubMed1987

cDNA clones encoding rabbit immunoglobulin lambda chains. Evidence for length variation of the third hypervariable region and for a novel constant region.

Five cDNA clones designated pDH2, pDH8, pDH9, pDH31 and pDH101 encoding rabbit immunoglobulin lambda light chain sequences have been characterized. Comparison of the V lambda sequences suggests that, in addition to an increased divergence in all of the complementarity-determining regions (CDRs), variable-region diversity is amplified by the length heterogeneity of the CDR3, at the V lambda-J lambda junction. An insertion of four codons at positions 48a-d has been noted in three cDNA sequences. This insert, not found in lambda nor kappa light chains of other species, has a variable sequence, suggesting its possible implication in expanding variability of the CDR2. One of the cDNA clones was shown to encode a novel C lambda region which differs by four amino acid substitutions from the C lambda region common to all the other clones. Thus, the rabbit can use two different C lambda genes, which might correlate with the expression of the two known allotypes of lambda chains, C7 and C21. Southern blotting experiments indicate a small number of germ-line V lambda genes and the cDNA nucleotide sequence data reported here suggest that several of these genes can be expressed. The possibility of at least two V-J-C gene clusters is discussed.

Alleles↗
PubMed1998

Co-existence of somatic hypermutation and gene conversion in hypervariable regions of single Igkappa clones.

In the rabbit, recent investigations have provided evidence that gene conversion leads to the generation of diversity of heavy chain rearranged VH-DH-JH genes. No data have been published on a similar mechanism for rabbit light chains. In our laboratory, we initially infected rabbits with Trypanosoma brucei, which stimulates B-cell hyperplasia and hypergammaglobulinaemia. The heterozygous rabbits exhibited the Ckappa1 b4 and b9 kappa light chain allotypes. After reverse transcription of mRNA, and cloning and sequencing of cDNA, the Vkappa-Jkappa-Ckappa genes provided evidence for both somatic hypermutation and gene conversion. We saw that in each of the b4 and b9 kappa light chain cDNA, CDR1 and CDR3 carried both point mutation and provisional gene conversion traits. In the CDR2 region, point mutation and gene conversion inserts were observed in the b4 genes, with only gene conversion in two b9 genes. In the CDR regions, although some genes exhibited only somatic hypermutation or gene conversion, others showed linkage of both somatic hypermutation and gene conversion in the same sequence. This also marks the first time that somatic hypermutation and gene conversion in the same cloned CDR region has been observed in Vkappa1 genes; however, it has been seen earlier in rabbit heavy chain VH sequences. Furthermore, the addition of several codons to the CDR3 segment by gene conversion may have provided a mechanism for length variation. In addition, we demonstrated that Jkappa and framework region segments contained examples of somatic hypermutation. Confirmation of gene conversion necessitates that donor sequences be identified as providing the templated inserts. Thus after cloning two pseudogenes we found putative CDR3 donor segments for two CDR3 rearranged genes. The results offer additional mechanisms for the generation of diversity among rearranged rabbit kappa light chain genes. Whether there is a relationship or influence of gene conversion upon somatic hypermutation or vice versa is not discernable at present.

Amino Acid Sequence↗
PubMed1989

Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: correlation with restriction fragment length polymorphism in human families and populations.

Direct sequence analysis of the human T-cell antigen receptor (TCR) V beta 1 variable gene identified a single base-pair allelic variation (C/G) located within the coding region. This change results in substitution of a histidine (CAC) for a glutamine (CAG) at position 48 of the TCR beta chain, a position predicted to be in the TCR antigen binding site. The V beta 1 polymorphism was found by DNA sequence analysis of V beta 1 genes from seven unrelated individuals; V beta 1 genes were amplified by the polymerase chain reaction, the amplified fragments were cloned into M13 phage vectors, and sequences were determined. To determine the inheritance patterns of the V beta 1 substitution and to test correlation with V beta 1 restriction fragment length polymorphism detected with Pvu II and Taq I, allele-specific oligonucleotides were constructed and used to characterize amplified DNA samples. Seventy unrelated individuals and six families were tested for both restriction fragment length polymorphism and for the V beta 1 substitution. The correlation was also tested using amplified, size-selected, Pvu II- and Taq I-digested DNA samples from heterozygotes. Pvu II allele 1 (61/70) and Taq I allele 1 (66/70) were found to be correlated with the substitution giving rise to a histidine at position 48. Because there are exceptions to the correlation, the use of specific probes to characterize allelic forms of TCR variable genes will provide important tools for studies of basic TCR genetics and disease associations.

Alleles↗
PubMed1985

Characterization of human rheumatoid factors with seven antiidiotypes induced by synthetic hypervariable region peptides.

Recently, we have used synthetic peptides corresponding to the complementarity-determining regions (CDR) of Ig molecules to induce antiidiotypic antisera. Peptide PSH3, representing the third CDR of the IgM rheumatoid factor (RF) Sie heavy (H) chain, induced a private antiidiotype that reacted with only one out of five IgM-RF. Peptide PSL2, corresponding to the second CDR of Sie light (L) chain, induced an antibody against a crossreactive idiotype (CRI), expressed by 10 out of 12 human IgM-RF analyzed. Herein, we report that five additional antiidiotypic antibodies were generated by immunization with synthetic peptides identical to the third L chain CDR of IgM-RF Sie (PSL3), the second and third H chain CDR of IgM-RF Wol, and the second and third CDR of IgM-RF Pom. As analyzed by immunoblot assay, both anti-PSL3 and anti-PSL2 reacted with the majority of 16 IgM-RF. In contrast, all five antiidiotypes induced by the H chain peptides reacted only with the parent proteins, except anti-PSH3, which reacted weakly with one additional RF. These results suggest that one (or very few) VL gene(s), but a larger number of VH genes, are used to encode IgM-RF autoantibodies.

Antibodies, Anti-Idiotypic↗
PubMed1985

Synthetic peptides corresponding to third hypervariable region of human monoclonal IgM rheumatoid factor heavy chains define an immunodominant idiotype.

Synthetic peptides corresponding to eight individual heavy chain complementarity-determining regions (CDR) of three human monoclonal IgM anti-IgG (rheumatoid factor [RF]) paraproteins elicited rabbit antibodies with markedly different properties. All antisera recognized the immunizing peptide, and several reacted with the isolated IgM heavy chain on immunoblots. However, only the antisera against peptides representing the third CDR bound consistently and specifically to the intact IgM-RF molecule. These data indicate that the third CDR of human mu chains comprises an immunodominant idiotype, and suggest that the D gene segment may be especially important in creating idiotypic diversity. Synthetic peptides corresponding to the third heavy chain CDR of human paraproteins may be clinically useful for the specific induction of antiidiotypic antibodies.

Amino Acid Sequence↗
PubMed1990

Characterization of the DA26 gene in a hypervariable region of the Autographa californica nuclear polyhedrosis virus genome.

A region of the baculovirus Autographa californica nuclear polyhedrosis virus genome that is frequently found to be altered after serial passage of the virus in cell culture was characterized. Sequence analysis of this region of the genome in wild-type and mutant viruses revealed that some of the mutations affected a 675 bp open reading frame, designated DA26. The DA26 gene was disrupted both by deletion and by insertion of sequences that resembled transposable elements. Northern blot analysis of DA26 showed that it was expressed very early after infection. DA26-specific transcripts could be detected after the 1 h viral adsorption period upon infection of cultured Trichoplusia ni cells. These transcripts were mapped by nuclease protection assays. A recombinant virus was constructed in which DA26 was disrupted by insertion of the Escherichia coli lacZ gene. This virus was viable in both T. ni and Spodoptera frugiperda cells and analysis of the kinetics of protein synthesis revealed no differences between wild-type and recombinant viruses. The disruption of DA26 also did not interfere with the ability of the virus to infect T. ni or S. frugiperda larvae.

Amino Acid Sequence↗
PubMed1992

Lack of association between the apolipoprotein B gene 3' hypervariable region alleles and coronary artery disease in Finnish patients with angiographically documented coronary artery disease.

Previous studies have suggested that some apolipoprotein B (apoB) 3' variable number of tandem repeats (3'VNTR) locus alleles are associated with coronary artery disease (CAD). We examined the possible association between the apoB 3'VNTR alleles and CAD in 387 Finnish subjects. Using the polymerase chain reaction and polyacrylamide gel electrophoresis, the 3'VNTR genotype was determined in 187 individuals with severe CAD confirmed by coronary angiography (patients), in 121 individuals with normal coronary angiograms (controls), and in 79 apparently healthy subjects (normals). In contrast to previous reports from other populations, the larger apoB 3'VNTR alleles were not significantly more frequent among CAD patients than among controls or normals. In addition, there was no significant association between the 3'VNTR alleles and serum lipid levels in this Finnish population.

Alleles↗
PubMed2001

Characterization of a hypervariable region in the genome of Chlamydophila pneumoniae.

Chlamydophila pneumoniae displays surprisingly little genomic variation, as seen by comparisons of the published genomes from three different isolates and sequencing of four different genes from different isolates. We have in the present study, however, demonstrated genomic variation between 10 C. pneumoniae isolates in the 11690-bp region between the two outer membrane protein genes pmp1 and pmp2. This region of the C. pneumoniae CWL-029 isolate contains seven C. pneumoniae-specific open reading frames (hb1-7, encoding hydrophobic beta-sheet-containing proteins). We identified additionally 12 open reading frames in the C. pneumoniae CWL-029 genome encoding hypothetical proteins with similarity to the seven hypothetical Hb-proteins. Compared to other isolates, genomic variation is seen to cause frame-shifting of three of the 19 hb-open reading frames, which are proposed to be three full-length genes and eight frame-shifted pseudogenes. The hypothetical proteins encoded by these proposed genes contain an N-terminally located highly hydrophobic stretch of 50-60 residues. A similar motif is found in all identified Chlamydia inclusion membrane proteins and therefore the Hb-proteins are candidate inclusion proteins.

Bacterial Outer Membrane Proteins↗
PubMed1995

Neutralization of feline immunodeficiency virus by polyclonal feline antibody: simultaneous involvement of hypervariable regions 4 and 5 of the surface glycoprotein.

Sites involved in antibody-mediated neutralization of feline immunodeficiency virus were mapped by reciprocal exchange of envelope fragments or amino acids between molecular clones of feline immunodeficiency virus with different susceptibilities to neutralization by a polyclonal cat serum. Combinations of mutations within HV-4 or within HV-4 and HV-5 changed the susceptibility of the viruses to neutralizing antibody.

Animals↗
PubMed2003

Changes in the immunogenic properties of soluble gp140 human immunodeficiency virus envelope constructs upon partial deletion of the second hypervariable region.

Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (DeltaV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75:5526-5540, 2001). However, the DeltaV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the DeltaV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

AIDS Vaccines↗
PubMed2000

Molecular evolution in the hypervariable regions of fetuin: comparison between human and African green monkey fetuin.

Sequences of fetuin cDNA and its deduced amino acid residues from the African green monkey cell line Vero were found to differ by 7.3% and 12.9%, respectively, from the corresponding human sequences. Most amino acid substitutions were clustered within a small segment of the third domain (D3). Calculations of nonsynonymous and synonymous nucleotide substitution rates suggest that this small segment was mutated under positive selection. cDNAs encoding alpha1-antitrypsin, beta-actin and the sequences of intron 4 of alpha1-antitrypsin gene in human liver and Vero cells were also investigated. The results substantiated the positive selection imposed on the D3 segment.

Actins↗
PubMed1982

Primary structure of the variable part of an amyloidogenic Bence-Jones Protein (Mev.). An unusual insertion in the third hypervariable region of a human kappa-immunoglobulin light chain.

The complete amino acid sequence of the variable region of Bence-Jones protein Mev. from a patient suffering from multiple myeloma and generalized amyloidosis is presented. The amino acid sequence of the Bence-Jones protein Mev. is related to other human kappa-immunoglobulin L-chains of subgroup I. With valine established in Position 191 of the constant region, it is of the Inv (3) allotype. Two types of the Bence-Jones protein Mev. were found, one beginning with the typical N-terminal aspartic acid, and another lacking the N-terminal tripeptide and commencing with methionine in Position 4. A unique insertion of glutamic acid after Position 95 was found in the Bence-Jones protein. This is the position where the V- and J-gene segments join. The J-region of Bence-Jones protein Mev. exhibits some marked differences to the five J-regions recently established by nucleic acid sequencing. This suggests, that there must be considerable polymorphism in human kappa-J-genes. The amyloid fibril protein from the same patient (A Mev.) has also been sequenced up to Position 27. It was found to be identical to the sequence of Bence-Jones protein Mev. commencing with aspartic acid. The molecular mass of the amyloid fibril protein was found to be between 11 000 and 12 000 Da as estimated by gelfiltration and dodecyl sulfate-polyacrylamide electrophoresis.

Amino Acid Sequence↗