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PubMed1975

Structure and specificity of antibody molecules.

The structure of the Fab' fragment of a human myeloma protein (IgG1 (lambda) New) has been determined by X-ray crystallographic analysis to a nominal resolution of 0.2 nm. Each of the structure subunits corresponding to the variable and to the constant homology regions of the light and heavy polypeptide chains contains two irregular beta-sheets which are roughly parallel to each other and surround a tighly packed interior of hydrophobic side chains. The regions of the hypervariable sequences in the light and heavy chains occur in close spatial proximity at one end of the molecule, defining the active site of IgG New. The role of these hypervariable regions in defining the size and shape of the active site of different immunoglobulins is discussed on the basis of the three-dimensional model of Fab' New. Several ligands that bind to the active centre of IgG New have been used to obtain crystalline ligand-Fab' New complexes which were investigated by difference Fourier maps. These studies are analysed in terms of the biological function and specificity of antibodies.

Amino Acid Sequence↗

PubMed1991

The Staphylococcus aureus mec determinant comprises an unusual cluster of direct repeats and codes for a gene product similar to the Escherichia coli sn-glycerophosphoryl diester phosphodiesterase.

The DNA sequence located between mecA, the gene that codes for penicillin-binding protein PBP2', and insertion sequence-like element IS431mec has been termed hypervariable because of its length polymorphism among different staphylococcal isolates. We sequenced and characterized the hypervariable region of the methicillin resistance determinant (mec) isolated from Staphylococcus aureus BB270. Within the 2,040-bp hypervariable region, we identified an unusual accumulation of long direct repeats. Analysis of the DNA sequence revealed a minimal direct repeat unit (dru) of 40 bp which was repeated 10 times within 500 bp. The dru sequences are responsible for the length polymorphism of mec. Moreover, we identified an open reading frame that codes for 145 amino acids (ORF145), whose deduced amino acid sequence showed 57% amino acid sequence similarity to the N terminus of the glycerophosphoryl diester phosphodiesterase (UgpQ) of Escherichia coli.

Amino Acid Sequence↗

PubMed1977

Heavy-chain variable-region sequence from an inulin-binding myeloma protein.

The entire variable-region sequence of the heavy chain from ABE-47N, a BALB/c inulin-binding myeloma protein, has been determined. This protein is unusual in that the third complementarity region (H3) is extremely short, consisting of at the most three and probably only one amino acid. A comparison of the heavy-chain hypervariable regions from mouse, human, and rabbit proteins shows that the variability in length of H3 is greater than that seen in the first or second hypervariable regions. This variability in H3 length suggests a specialized function for this region.

Amino Acid Sequence↗

PubMed1977

Towards a chemical definition of idiotypy.

The idiotypic determinants have been precisely located to the variable regions of immunoglobulin polypeptide chains. Both chains are generally required to express the idiotype. The major idiotypic determinants are the result of the amino acid sequence of the hypervaiable regions, although some idiotypic determinants reside outside the antibody combining site and these so called "framework idiotypes" are important markers. In my view the hypervariable regions are spatially disposed so as to present adequate antigenic stimulation, and they display enough structural heterogeneity to account for the uniqueness of the idiotype in the general population of immunoglobulin molecules. Hypervariable regions, the antibody combining site, and the idiotypic determinants thus amalgamate three formerly diverse concepts into a unified theoretical construct.

Binding Sites, Antibody↗

PubMed1992

Interaction of immune sera with synthetic peptides corresponding to the structural protein region of hepatitis C virus.

Comparison of the deduced amino acid sequence from the structural region of the Hutchinson strain of hepatitis C virus (HCV-H) with four other HCV isolates clearly divides the five isolates into two groups based on sequence homology. The first group includes HCV-H, HCV-1, and HC-J1, while the second includes HCV-J1 and HC-J4. Among the five isolates the first 190 residues (putative nucleocapsid) are highly conserved whereas residues 196-513 exhibit significant diversity and include a hypervariable region encompassing residues 386-404. A series of overlapping decapeptides were synthesized by solid-phase pin technology according to sequence from HCV-H (amino acids 1-513), HC-J4 (amino acids 181-513), and regions from the three other isolates which exhibited sequence variation. A modified ELISA was used to measure immunoreactivity of sera from clinical posttransfusion cases and experimentally infected chimpanzees. Comparison of pre- and postinfection samples revealed 16 clusters of immunoreactive peptides within the structural region, none of which was found in the hypervariable region. Only one cluster (amino acids 73-89) was recognized by all human and chimpanzee sera. Clear variation in the immune response was observed between individuals, although no obvious difference in reactivity between acute and chronic cases was observed. Within individual profiles, the reactivity to each peptide cluster and the total number of reactive clusters increased over time.

Amino Acid Sequence↗

PubMed1976

Studies on the structural localization of rabbit H chain allotypic determinants controlled by the a locus. Purification and immunological properties of an immunopeptide bearing a3 allotypic determinants.

An immunopeptide bearing a3 allotypic determinant(s) was isolated from the gamma chain of an a3 homozygous rabbit (G222-2) immunized with type III pneumococcal vaccine. Immunocogical properties of peptides were studied using a radioimmunoassay that involved inhibition by these peptides of a reaction between 125I-labeled anti-a3 antibody and Sepharose-bound a3 immunoglobulin G (IgG). The gamma chain was isolated from IgG of restricted heterogeneity and then citraconylated and digested with trypsin. The tryptic digest (TD1) was passed through an anti-a3 immunoabsorbent column either directly or after an intermediate step of Sephadex G-75 chromatography. The bound peptides (T1) were eluted with 0.1 M acetic acid and further digested with trypsin. The digest (TD2) was again run on the anti-a3 immunoabsorbent column to purify the bound immunopeptide T2. In the radioimmunossay this immunopeptide was found to have major a3 determinant(s). Its molecular weight was found to be approximately 6,000, which decreased to about 3,000 after reduction and alkylation. These data, together with NH2- and COOH-terminal analyses and cysteine peptide mapping, demonstrated that T2 is composed of two polypeptide chains linked by a disulfide bond, one from the cysteine 22 region having lysine at the COOH terminus and the other from the cysteine 92 region arginine at the COOH terminus. The lysine peptide was separated from the arginine peptide and its NH2-terminal sequence was found to be Gly-Asx-Glx-Ser-Thr-Cys. Since the cysteine is at position 22, the lysine peptide starts at position 17. It has approximately 22 residues. The framework sequence from 17 to 20 is different from those reported so far. In addition, the heavy chain used in these studies has some other unusual features including a histidine, probably in the first hypervariable region. The presence of histidine in the first hypervariable region of rabbit heavy chain has not been reported previously. The other peptide which is about 30 amino acids in length and ends with arginine 94, probably includes positions 67, 70, 71, 84, and 85 that are believed to have substitutions correlating with a allotypes. In a hypothetical three-deminsional model of the Fv portion of rabbit anti-SIII antibody BS-5, residues 17 to 33 of the lysine peptide and 67 to 79 and 84 to 85 which may be present in the arginine peptide are fully exposed on the surface and are far removed from the antibody combining site.

Amino Acids↗

PubMed1992

An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5' end of the monoamine oxidase A gene.

A CpG island has been identified just upstream of the first exon of the human monoamine oxidase A (MAOA) gene, localized to Xp11.4-Xp11.23. Southern blotting following digestion with the methylation sensitive restriction endonucleases SmaI, HpaII and HhaI, indicated that CpG dinucleotides within the CpG island were unmethylated on the active X chromosome and extensively methylated on the inactive X chromosome. These sites of differential methylation were close to a polymorphic GT-dinucleotide/VNTR region, which is located 1 kb 3' of the first exon and has a heterozygosity value of 75%. PCR primers were designed for amplification of 1.2-1.3 kb DNA fragments, encompassing both the hypervariable region and a cluster of six HpaII sites within the CpG-rich region. Cleavage of HpaII sites was found to be restricted to active X chromosomes. Therefore, following HpaII digestion, DNA fragments were exclusively amplified from inactive X chromosomes. The resulting PCR products were digested with SacI, which reduced the size of the DNA fragments containing the hypervariable region to 230-330 bp, and were subsequently analyzed on denaturating polyacrylamide gels. Because amplified fragments were exclusively derived from the inactive X chromosome, the relative densities of the two allelic fragments should reflect the proportions of cells that have either of the two X chromosome inactivated. The results of this PCR-based X chromosome inactivation assay were fully concordant with Southern blotting methylation analyses at the PGK locus. It therefore provides a rapid and informative method in tumour clonality analysis and carrier detection in X-linked diseases.

Base Sequence↗

PubMedDate not supplied

The HLA association with rheumatoid arthritis.

Rheumatoid arthritis (RA) is primarily associated with HLA-DR4 in a wide range of ethnic groups. DNA analysis of HLA-DRB1 sequences shows that a limited set of alleles are positively associated with the disease. Third hypervariable region sequences QRRAA, QKRAA and RRRAA are found in up to 85% of RA patients and may constitute the basic unit of association. Risk estimates for alleles and hypervariable regions differ between ethnic groups and subsets of patients. Severe RA and Felty's syndrome are significantly associated with DR4 Dw4 and, to a lesser extent, with DR4 Dw14. In patients the latter allele is almost exclusively found in combination with Dw4, suggesting that complementation is occurring. Critical substitutions in the peptide binding groove correlate with the presence of RA, suggesting that the disease may be driven by the presentation of specifically bound peptide and/or may be influenced by differential selection of the T cell repertoire.

Arthritis, Rheumatoid↗

PubMed1976

Demonstration of an idiotypic antigen on a monoclonal cold agglutinin and on its isolated heavy and light chains.

A potent anti-idiotype serum produced in a rabbit immunized with the isolated heavy chains of an IgM cold agglutinin "Col" was rendered specific by solid-state adsorptions. The anit-Col idiotype was shown to bind specifically to both isolated Col heavy (mu) and light (kappa) chains as well as to intact Col IgM by three methods: (i) reversal of anti-idiotype inhibition of Col cold agglutinin in an automated hemagglutination-inhibition assay system; (ii) adsorption of the anti-idiotype by affinity gels consisting of Col IgM, mu, or kappa chains covalently coupled to Sepharose 2B; (iii) binding of Col IgM and its isolated chains by an anti-idiotype affinity gel. Fragments of Col light chain lacking constant region determinants but still capable of inhibiting anti-idiotype were produced by limited pepsin digestion of the light chains. The finding of shared idiotypic determinants on isolated heavy and light chains of a monoclonal antibody suggests that these chains share a common sequence in a hypervariable region. As an extension of the gene insertion theory of Wu and Kabat, we postulate that genes coding for hypervariable regions may be available for insertion into the DNA for both heavy and light chains.

Agglutinins↗

PubMedDate not supplied

The amino acid sequence of the variable regions of the light chains from two idiotypically cross reactive IgM anti-gamma globulins.

Amino acid sequence analysis of the light chains of two IgM rheumatoid factors is presented. The parent molecules of these chains are human IgM proteins with specificity for human IgG and sharing idiotypic cross reactivity. The heavy chains had previously been shown to have extremely similar hypervariable regions. This communication presents data indicating that the light chains, even though representing two different kappa subgroups, also share identities in their hypervariable regions. These data can be most easily interpreted in terms of a gene interaction model for immunoglobulin V region assembly.

Amino Acid Sequence↗

PubMed1991

Additional complexity within the HLA-D region: sequence analysis of two new DRw13-DQw7 haplotypes.

HLA-DRB1 is by far the most polymorphic locus within the HLA-D region with now well over 40 alleles. Nearly one fourth of these alleles are subtypes of DRw6, and these are in most cases undetectable by routine typing procedures. In this paper we present the molecular characterization of two new Caucasian DRw13-DQw7 haplotypes by DNA sequencing of the polymorphic first domain exons of DRB1 and DRB3 loci. The first haplotype, DRB1*1301-DRB3*0101-DQB1*0301, has arisen by a recombination between locus DRB1 from a DRw13-DQw6 haplotype and DQA1 from a DR4-DQw7 haplotype, as determined by DNA sequencing, DQ oligotyping, and restriction fragment length polymorphism typing. The second haplotype, DRB1*1305-DQB1*0301, is characterized by the novel DRB1*1305 allele differing from DRB1*1301 by three amino acids. It probably arose by a gene conversion event between a DRw13-DQw6 allele and DRB1*1101. This allele represents a DRw11/DRw13 hybrid DR molecule with a DRw13 serological epitope in the second hypervariable region and a Dw5 cellular epitope in the third hypervariable region. As determined by sequencing of locus DRB3, this allele is associated with DRw52b. Our molecular analysis of the complex HLA-DRw13 group now allows unambiguous DNA typing of all five DRw13 alleles with seven oligonucleotides, a significant improvement in the context of organ transplantation.

Amino Acid Sequence↗

PubMed1990

Glycosylation governs the binding of antipeptide antibodies to regions of hypervariable amino acid sequence within recombinant gp120 of human immunodeficiency virus type 1.

Antibodies raised to an overlapping series of peptides following the amino acid sequence of the external envelope glycoprotein (gp 120) of human immunodeficiency virus type 1 (HIV-1) recognize eight regions in recombinant gp 120 molecules. If the recombinant molecules are glycosylated, three of these regions show a reduced capacity to bind antibody. Of the other five regions, two are strain-specific and carbohydrate restricts antibody binding to their N-terminal flanks, and three can be recognized by antibodies in recombinant gp 120 from an unrelated strain of HIV-1. Antibodies in sera from HIV-1-infected patients bind at high levels to peptides from five regions of gp 120. Of these regions, two coincide with those recognized by antibodies raised to peptides. Four of the five epitopes recognized by the rat antipeptide sera whose ability to bind antibody is influenced most by glycosylation, and three of the five regions which induce high levels of antibodies in patients' sera, contain putative glycosylation sites which are variable between strains of HIV-1. Such sites flank the putative neutralization and CD4-binding regions of gp 120. It is suggested that changes in the number and position of carbohydrate moieties following mutation can alternately mask and reveal epitopes. Masking an epitope can render a virus resistant to neutralization, whereas virus which binds antibody without being neutralized is able to gain entry to cells bearing antibody and complement receptors. Changes in the glycosylation pattern of gp 120 may therefore contribute to the control of HIV-1 spread within its host.

Amino Acid Sequence↗

PubMed1992

Amplification of three hypervariable DNA regions by polymerase chain reaction for paternity determinations: comparison with conventional methods and DNA fingerprinting.

The present study evaluates the usefulness of a PCR-based method for routine paternity testing in 35 paternity cases. This identification method which is based on amplification of three hypervariable genetic loci, apoB, D1S80 and HLA-DQ alpha, is compared, with regard to reliability and technical feasibility, to the conventional identification methods based on protein polymorphisms and to Southern blot hybridizations with multi- and single locus probes. Data obtained by PCR-amplification of these three loci resulted in paternity indices (56.1, geometric mean value) which are at the same level as the corresponding values derived from standard genetic blood group markers (42.7). The geometric mean value of the paternity indices obtained by Southern blot hybridization using three single locus probes (190.6) was more informative, and the most informative analysis proved to be Southern blot hybridization with multilocus probes. The technical feasibility and the reproducibility of the PCR-based analysis is, however, overwhelming, and if several highly polymorphic loci are amplified, the resolving power of PCR-analysis is similar to that obtained using multilocus probes.

Blood Grouping and Crossmatching↗

PubMed1976

Variable region sequence of the light chain from a Waldenströms IgM with specificity for phosphorylcholine.

The variable region sequence of the light chain from the human IgM FR with binding activity for phosphorylcholine has been determined. Automated Edman degradation was used for the whole chain and for a large cyanogen bromide fragment comprising the third hypervariable region and the entire constant part. The rest of the sequence was established by means of the "Dansyl-Edman" technique with tryptic peptides. The sequence of light chain FR can be assigned to the subgroup II of human light chains with which it shares 92% homology within the nonhypervariable (frame-work) residues. There is no apparent sequence homology betweeen the variable region of the human light chain FR and the aminoterminal 41 residues of the light chains published so far from the mouse myeloma proteins TEPC 15, HOPC 8, S 107, and McPC 603 with phosphorylcholine binding activity. Recent data on the light chain of the phosphorylcholin binding mouse myeloma protein MOPC 167 (see Conclusion), however, indicate a considerable structural homology between the first hypervariable region of this murine protein and that of the human IgM FR, suggesting that both IgM FR and IgA MOPC 167 might have been selected by similar antigens.

Amino Acid Sequence↗

PubMed1977

Structural studies on induced antibodies with defined idiotypic specificities. V. The complete amino acid sequence of the light chain variable regions of anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype.

The complete amino acid sequence of the variable regions of light chains derived from anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype is reported. At least two and probably more than three distinct light chains are associated with this idiotypically characterized antibody. The antibodies have several differences in their "framework" structures but evidence is presented indicating that all three light chain hypervariable regions have a homogeneous sequence. The data are discussed in relation to the various theories of antibody diversity. In addition, the findings support the view that hypervariable regions, idiotypic determinants, and the antibody-combining site involve, to a large extent, the same molecular structures.

Amino Acid Sequence↗

PubMed1991

Multiple sclerosis and HLA: is the susceptibility gene really HLA-DR or -DQ?

Seventy-one patients with multiple sclerosis (MS) were classified into four subgroups according to the clinical pattern of their disease; their HLA-DR and DQ polymorphisms were defined by serological methods and analysis of Taq1 digestion fragments hybridizing with DRB, DQA, and DQB cDNA probes. The frequencies of the polymorphisms in the patients were compared with those of 100 control subjects. The frequencies of a 3.25-kb fragment from Mspl digests of genomic DNA which hybridized to DQA were also defined in the same groups of patients and control subjects. HLA-DR2 (DRw 15 subtype) and the associated HLA-DQw6 were observed in significant excess in the patients compared with the normal subjects (63% vs. 32% for DRw15; 65% vs. 42% for DQw6). There were no significant differences in the distribution of the DR or DQ alleles between the groups of patients showing different clinical patterns of disease, nor was there an excess in the patients of DQw8 and DQw9 which share hypervariable region sequences of the DQB chain in common with DQw6. The results argue against two recently proposed hypotheses of MS. First, they are not consistent with the proposal that susceptibility to MS is associated with expression of a hypervariable region of DQB shared by DQw6, 8, and 9. Second, they do not support the concept that primarily chronic progressive and relapsing/remitting MS are two immunogenetically distinct disease entities. Our evidence is consistent with the hypothesis that one of the true disease susceptibility genes for MS lies elsewhere within the HLA region and in Northern European populations is found in significant association with DRw15 and DQw6.

Adult↗

PubMed1975

Structural, functional, and idiotypic characteristics of a phosphorylcholine-binding IgA myeloma protein of C57BL/ka allotype.

An IgA phosphorylcholine (PC)-binding myeloma protein with IgCH allotypic determinants different from those of BALB/c mice is characterized. The myeloma, CBPC 2, was induced in the CB-20 strain of mice which is congenic to BALB/c but differs from it by carrying the A15 allotypic determinant of C57BL/ka mice. Sequence analysis of the CBPC 2 light chain through the first hypervariable region, as well as isoelectric point analysis, show that this chain is indistinguishable from that of T15, a PC-binding myeloma protein of BALB/c origin. The heavy chains of CBPC 2 and T15 differ by only two amino acids (positions 14 and 16) through the first hypervariable region. As measured by inhibition of precipitation, both CBPC 2 and T15 have the same specificity for PC, glycerophosphorylcholine, acetylcholine, and choline. In addition, CBPC 2 possesses the binding site-associated idiotypic determinant which is present on T15. However, like normal or induced C57BL/6 anti-PC antibody, it does not possess the nonbinding site idiotypic determinant.

Amino Acid Sequence↗

PubMed1991

T-cell clones identify three distinct epitopes associated with HLA-Dw14.

Alloreactive T-cell clones were used to study allodeterminants associated with the HLA-DR1, -DR4, and -DRw14 allelic families. Three clones derived by priming against the DR4,Dw14 alloantigen were tested against a panel of HLA-D homozygous B-cell lines and homozygous and heterozygous peripheral blood lymphocytes. Each clone was blocked by monoclonal antibodies specific for HLA-DR, but not HLA-DQ or -DP, molecules, and each showed a unique pattern of allorecognition when tested against the cell panel. Clone 14B appeared to recognize a specific sequence, termed L67-A74, comprised of amino acids in the third hypervariable region of the alpha-helix of the DR beta 1 molecule, and expressed on certain DR1-, DR4-, and DRw14-positive cells. Clone EMO25 recognized the same L67-A74 sequence, but only when expressed on DR4-positive cells, suggesting a role for residues in the first and second hypervariable regions of DR4-positive DR beta 1 molecules in T-cell recognition. Clone EM036 also recognized the L67-A74 sequence, but only when expressed on DR4,Dw14.1-positive cells, implicating residues at positions 57 and 86 of the alpha-helix in T-cell recognition. These results demonstrate the range of specific T-cell responses that are possible against alloepitopes expressed by a single class II allele (Dw14), and are an indication of the diverse regions of the class II molecule that can contribute to allorecognition sites.

Amino Acid Sequence↗