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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↗
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↗
PubMed2000

Preferential recognition of TCR hypervariable regions by human anti-idiotypic T cells induced by T cell vaccination.

T cell responses to myelin basic protein (MBP) are potentially involved in the pathogenesis of multiple sclerosis (MS). Immunization with irradiated MBP-reactive T cells (T cell vaccination) induces anti-idiotypic T cell responses that suppress circulating MBP-reactive T cells. This T cell-T cell interaction is thought to involve the recognition of TCR expressed on target T cells. The study was undertaken to define the idiotypic determinants responsible for triggering CD8+ cytotoxic anti-idiotypic T cell responses by T cell vaccination in patients with MS. A panel of 9-mer synthetic TCR peptides corresponding to complementarity-determining region 2 (CDR2) and CDR3 of the immunizing MBP-reactive T cell clones were used to isolate anti-idiotypic T cell lines from immunized MS patients. The resulting TCR-specific T cell lines expressed exclusively the CD8 phenotype and recognized preferentially the CDR3 peptides. CDR3-specific T cell lines were found to lyze specifically autologous immunizing MBP-reactive T cell clones. The findings suggest that CDR3-specific T cells represented anti-idiotypic T cell population induced by T cell vaccination. In contrast, the CDR2 peptides were less immunogenic and contained cryptic determinants as the CDR2-specific T cell lines did not recognize autologous immunizing T cell clones from which the peptide sequence was derived. The study has important implications in our understanding of in vivo idiotypic regulation of autoimmune T cells and the regulatory mechanism underlying T cell vaccination.

Amino Acid Sequence↗
PubMed1999

[Polymorphism of hypervariable region in D-loop of mitochondrial DNA].

DNA sequences of PCR products from mitochondrial DNA (mtDNA) of 80 healthy Japanese volunteers (40 pairs, mother and child) were determined by the direct sequencing method for polymorphism. Thirty (15 pairs) of 80 samples analyzed showed a T-to-C transition at position 16189 (T16189C) of the C-stretch region in the hyper-variable region of mtDNA. For seven pairs randomly selected from the 15 T16189C pairs (C-stretch) and a single pair without the transition (non C-stretch), PCR products from the D-loop region were cloned and then sequenced. The repeat number of C in the C-stretch region was found to show heteroplasmy by sequencing multiples clones from each mtDNA. Statistical analyses of the distribution patterns of the repeat number revealed no significant differences between the mother and child in each lineage but significant differences between the lineages. The seven lineages could be then classified into four groups. The result of our data confirmed the existence of heteroplasmic polymorphism in the C-stretch region and the inheritance of the heteroplasmy from mother to child. Therefore, the analysis of heteroplasmy is applicable to individual identification.

Child↗
PubMed1992

Peptide sequences from the hypervariable regions of two monoclonal anti-idiotypic antibodies against the thyrotropin (TSH) receptor are similar to TSH and inhibit TSH-increased cAMP production in FRTL-5 thyroid cells.

Monoclonal antibodies, D2 and 4G11, selected by the autoantiidiotypic approach following injection of thyrotropin (TSH) into mice, mimic TSH in binding to receptors on thyroid membranes. Based on TSH receptor transfection studies, D2 and 4G11 show unequivocal specificity for the TSH receptor. To see if the complementary determining regions (CDRs) of these antibodies share any primary sequence similarities to regions of TSH critical for receptor binding, we deduced the primary structure of the variable regions of D2 and 4G11 by sequencing the immunoglobulin mRNA. We found that CDR1 of 4G11K and CDR2 of D2 mu show sequence similarity to regions of TSH alpha and TSH beta that had been previously implicated in the interaction of the hormone with its receptor. We tested the inhibitory effects of synthetic peptides from D2 mu-CDR2 and 4G11K-CDR1 on the binding of the corresponding antibodies to rat thyroid FRTL-5 cells and found an EC50 of 0.1 and 1 microM, respectively. TSH-derived peptides with similarity to D2 mu-CDR2 and 4G11K-CDR1 showed a significant but lesser effect on the binding of 4G11 or D2 to thyroid cells. Additionally, we tested the effects of the CDR peptides and TSH-derived peptides on TSH-stimulated cAMP production in FRTL-5 cells and found that D2 mu-CDR2 and 4G11K-CDR1 inhibited this activity, D2 mu-CDR2 most strongly (EC50 10 microM). Thus, linear sequences from the CDRs of these autoantiidiotypic antibodies with similarity to sequences from both subunits of TSH appear to interact with the TSH receptor. These data support previous studies indicating the complexity of the interaction between TSH and its receptor and advance earlier findings that such immunologic approaches are useful in dissecting receptor-ligand interactions.

Animals↗
PubMed1991

Amplification by the polymerase chain reaction of hypervariable regions of the human genome for evaluation of chimerism after bone marrow transplantation.

We combined the polymerase chain reaction (PCR) with oligonucleotide hybridization as a novel and sensitive technique to evaluate posttransplant chimerism. Specific oligonucleotides for hybridization were synthesized homologous to tandemly repetitive core sequences of regions with a variable number of tandem repeats (VNTRs). Polymorphisms at such loci result from allelic differences in the number of repeats. Primers flanking the repeat region of each of the corresponding VNTRs were used for amplification. Recipient and donor pretransplant DNA and recipient posttransplant DNA were amplified. The resultant fragments were analyzed after gel electrophoresis either by hybridization in-gel or after Southern transfer. To confirm our findings, we also performed standard assays of restriction fragment length polymorphisms (RFLPs). Evaluation of 13 selected cases indicated mixed chimerism (4), complete chimerism (5), recurrence of leukemia (2), and endogenous repopulation of hematopoiesis (2) after marrow transplantation. Sensitivity of the method was determined by mixing various proportions of recipient and donor DNA; the limit of detection of the minor component in a mixture was 0.1%. PCR data correlated with RFLP data in all cases except two in which PCR proved more sensitive than RFLP. PCR amplification of VNTRs combined with oligonucleotide hybridization is a novel technique for documenting posttransplant chimerism and has advantages over RFLP analysis: high sensitivity, use of small amounts of DNA (250 ng), ease of preparation of DNA, elimination of need for restriction enzymes, and the ability to complete studies in 2 days.

Base Sequence↗
PubMed1991

[Use of DNA amplification by PCR in the study of the hypervariable region (VNTR) in a forensic medicine setting. Experience with 2 systems: Apo B and YNZ 22].

The PCR method has been applied to amplify two Variable-number-Tandem-Repeat (VNTR) sequences. The high polymorphism of these VNTR systems can be usefully applied in medical legal fields such as paternity testing and individual identification. The VNTR systems utilized were: ApoB and YNZ 22. The study was conducted on a three-generation family of thirteen members, whose relationship was previously established using conventional blood systems. The results confirm the Mendelian inheritance of the alleles found and the suitability of the PCR method for forensic purposes.

Alleles↗
PubMed1991

Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses.

In order to define the HLA-DR and DQ alleles, as well as the specific DQA1 and DQB1 chain genes involved in the anti-Ro/La autoantibody responses, RFLP analysis and sequence-specific oligonucleotide typing was carried out on 58 Caucasians and 48 American blacks with SLE or Sjögren's syndrome and anti-Ro antibodies. Among both Caucasian and black patients, the highest relative risk for the anti-Ro response (both with and without accompanying anti-La) was conferred by heterozygosity for the DQw2.1 (in linkage disequilibrium with HLA-DR3) and DQw6 (a subtype of DQw1) alleles compared with either 269 normal race-matched controls or 80 anti-Ro negative SLE/Sjögren's syndrome patients. Analysis of individual DQA1 and DQB1 chain alleles revealed that DQA1*0501 and DQB1*0201 were most frequent, followed by DQA1 and DQB1 alleles comprising DQw6. In patients not possessing DQw2.1 and/or DQw6 alleles, HLA-DQB1*0302 and HLA-DQA1*0401 (especially in blacks) were significantly increased. Nucleotide sequence analysis of these associated alleles showed that 100% of patients with anti-Ro had a glutamine residue at position 34 of the outermost domain of the DQA1 chain and/or a leucine at position 26 of the outermost domain of the DQB1 chain. Patients with anti-Ro plus La were more likely to have all four of their DQA1/DQB1 chains containing these amino acid residues than either anti-Ro-negative SLE patients or controls. These data implicate specific amino acid residues on both DQA1 and DQB1 chains located in the floor of the Ag binding cleft of the HLA-DQA1:B1 heterodimer and further suggest a role for "gene dosage" in the anti-Ro (+/- La) autoantibody response.

Alleles↗