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Biomedical subjects

A Solomon

Publications and source records attributed to A Solomon.

At least 127 records · Page 7Linked to original sources
PubMed1995

Distinctive serologic, chemical, and molecular properties of human lambda IV light chains.

Through extensive serologic, chemical, and molecular studies involving monoclonal Ig proteins and B cell-related populations, we provide definitive evidence that the V lambda IV subgroup of human light (L) chains is separate and distinct from V lambda III and all other known V lambda gene families. lambda IV and lambda III L chains were differentiated immunochemically using well-characterized polyclonal and monoclonal anti-V lambda subgroup-specific Abs. Prototypic L chains, originally classified as lambda IV on the basis of distinctive framework region 1 residues, were distinguished serologically from lambda IIIa, lambda IIIb, and lambda IIIc proteins and also from lambda I, lambda II, lambda VI, and lambda VIII L chains. Furthermore, by using anti-lambda IV reagents, we identified eight additional monoclonal V lambda IV-related populations, including three IgM rheumatoid factor-producing cell lines. The percentage of homology among the lambda IV proteins ranged from 83 to 100, vs 53 to 72 when compared with lambda III components. Moreover, lambda IV proteins shared particular subgroup-associated FR and complementarity-determining region residues. At the molecular level, the nucleotide sequences encoding two of the IgM lambda IV rheumatoid factors were identical to that found for the genomic counterpart, as well as to the previously reported IGLV3S1 and Humlv418 germ-line genes. Two other lambda IV cDNAs contained additional non-germ-line-encoded nucleotides at the V-J joint. The single or pauci-gene nature of the V lambda IV family was evidenced from Southern blotting and from the extensive sequence homology among lambda IV components. Our studies have provided further evidence for the prevalence of lambda IV L chains among Ig lambda autoantibodies, thus implying a functional significance for the V lambda IV subgroup.

Amino Acid Sequence↗
PubMed1995

Recombinant immunoglobulin variable domains generated from synthetic genes provide a system for in vitro characterization of light-chain amyloid proteins.

The primary structural features that render human monoclonal light chains amyloidogenic are presently unknown. To gain further insight into the physical and biochemical factors that result in the pathologic deposition of these proteins as amyloid fibrils, we have selected for detailed study three closely homologous protein products of the light-chain variable-region single-gene family VkIV. Two of these proteins, REC and SMA, formed amyloid fibrils in vivo. The third protein, LEN, was excreted by the patient at levels of 50 g/day with no indication of amyloid deposits. Sequences of amyloidogenic proteins REC and SMA differed from the sequence of the nonpathogenic protein LEN at 14 and 8 amino acid positions, respectively, and these amino acid differences have been analyzed in terms of the three-dimensional structure of the LEN dimer. To provide a replenishable source of these human proteins, we constructed synthetic genes coding for the REC, SMA, and LEN variable domains and expressed these genes in Escherichia coli. Immunochemical and biophysical comparisons demonstrated that the recombinant VkIV products have tertiary structural features comparable to those of the patient-derived proteins. This well-defined set of three clinically characterized human kIV light chains, together with the capability to produce these kIV proteins recombinantly, provide a system for biophysical and structural comparisons of two different amyloidogenic light-chain proteins and a nonamyloidogenic protein of the same subgroup. This work lays the foundation for future investigations of the structural basis of light-chain amyloidogenicity.

Amino Acid Sequence↗
PubMed1995

IgG anti-F(ab')2 antibodies from SLE patients react with immunodominant residues in kappa CDRs, but show reduced C kappa region reactivity.

We studied reactivity of affinity-purified human IgG anti-F(ab')2 antibodies for antigenic determinants on kappa light chains. Variable (VL) and constant (CL) regions of a human kappa I light chain (EU) were studied for enzyme-linked immunosorbent assay reactivity with monoclonal anti-k antibodies and human IgG antiF(ab')2 using overlapping heptamers of primary sequence synthesized as peptides on polypropylene pins. Polyclonal IgG anti-F(ab')2 antibodies isolated by affinity chromatography from the serum of patients with systemic lupus erythematosus (SLE) were found to react primarily with CDR1- and CDR3-related peptides. The most reactive residues included IL29, TRY32, LEU33, ALA34, GLU90, TYR91, and ASN 92. No striking difference in overall V-region anti-F(ab')2 reactivity profiles was noted when 10 IgG anti-F(ab')2 preparations from normal subjects and SLE patients were compared. In contrast, however, when tested against overlapping C kappa heptamer sequences, the reactivity in SLE-associated anti-F(ab')2 antibodies was markedly decreased. We report that this difference may reflect a defect in anti-idiotypic control mechanisms in SLE.

Amino Acid Sequence↗
PubMed1995

Neural arch tuberculosis: a morbid disease. Radiographic and computed tomographic findings.

We have reviewed the clinical features, together with the radiographs and computerised tomography, in 9 patients with tuberculosis of the vertebral body and neural arch. All presented with paraparesis or paraplegia. The morbidity associated with this disease is so serious that it is essential to have an accurate means of evaluating the lesion as early as possible. Routine radiographs can only indicate the level of the disease and the loss of disc space, but cannot define the full extent of the lesion. Computed tomography shows details of the tuberculous involvement of the neural arch, as well as the vertebral body and spinal canal; the site and extent of the soft tissue lesions can also be seen. This is essential for evaluation of the neural arch involvement which will enable the clinician to select the appropriate treatment, and so prevent neurological complications.

Adult↗
PubMed1995

Molecular localization of human IgG anti-F(ab')2 reactivity with variable- and constant-region lambda light-chain epitopes.

Human IgG antibodies reacting with antigenic determinants on F(ab')2 fragments represent generic antiidiotypic antibodies present in the serum of normal individuals. Additionally, the titers of these antibodies in the sera of patients with systemic lupus erythematosus (SLE) are inversely related to disease activity. Because these autoantibodies recognize predominantly light chain-related epitopes, especially lambda type, we synthesized constant (C)lambda- and variable (V)lambda-related overlapping 7-mer peptides on polypropylene pins to determine anti-F(ab')2-reactive epitopes on human lambda light chains. ELISA reactivity of affinity-purified anti-F(ab')2 antibodies obtained from normal individuals and from patients with SLE, as well as murine anti-human light-chain monoclonal antibodies specific for C lambda and V lambda subgroup-related determinants, was tested using the overlapping 7-mers of human lambda light-chain sequence. The patterns of reactivity against C lambda-related peptides were similar in both normal and SLE-derived anti-F(ab')2 antibodies. However, reactivity profiles against V lambda-related peptides were distinctively different between the normal and the SLE-associated anti-F(ab')2 autoantibodies. A decrease in reactivity among the SLE IgG anti-F(ab')2 antibodies was noted for particular amino acid V lambda complementarity-determining region (CDR) residues, including glycine at positions 27 and 54, alanine at 16 and 37, and tyrosine at 28 and 91. This different pattern of reactivity from normal may indicate that in SLE there is a failure of antiidiotypic control mechanisms, as reflected by a defect in production of antibody to immunodominant V lambda CDR residues.

Alanine↗
PubMed1995

Molecular characterization of a human V lambda VIII germline gene.

Human lambda light chains of the recently recognized variable region (VL) subgroup V lambda VIII can be distinguished from proteins of other V lambda gene families on the basis of distinctive chemical and serologic properties and by their preferential association with certain types of autoantibodies, i.e. rheumatoid factors (RFs). We now report that we have cloned from a human placental library a V lambda VIII-encoding germline gene, designated IGLV8A1, using as a molecular probe a partial V lambda VIII fragment generated by polymerase chain reaction (PCR) from genomic DNA. IGLV8A1 contained all the requisite elements of a potentially functional gene, including a V lambda exon with an open reading frame encoding 103 residues. Its expressed products were identified through analyses of cDNA cloned from two different monoclonal lambda VIII B-cell populations. The primary structure of lambda VIII light chains differed from that of lambda I, lambda II, lambda III, lambda IV and lambda VI proteins by the presence of distinctive residues within the first framework region (FR1) and an 11- rather than 7-residue second complementarity-determining region (CDR2). Remarkably, the IGLV8A1 gene was more homologous to the two functional rabbit V lambda germline genes, RV lambda 2 and RV lambda 3 (including the presence of one extra codon within the leader sequence), and to the murine V lambda x gene. Light chains encoded by the human, rabbit and mouse lambda VIII-related genes shared certain unique primary structural features, notably the four additional CDR2 residues. The evolutionary conserved nature of the human V lambda gene and, in particular, the apparently novel tertiary structural effects induced by an elongated CDR2 provide evidence for the biological and functional importance of the V lambda VIII subgroup.

Amino Acid Sequence↗
PubMed1995

Diseases with ocular and dental abnormalities.

This report gives an overall view on the aspect of numerous diseases and symptom complexes affecting both eyes and teeth. The knowledge of these disorders enables the ophthalmologist to suspect and recognize certain types of dental malformation and enables the dentist to discover certain eye defects. Moreover, it is important that clinicians be aware that simultaneous eye and tooth defects may be the indication of possible disturbances in other, apparently unrelated, organs or systems. Because such disorders are frequently hereditary conditions, their early detection will aid in the diagnosis and treatment of other affected family members. This may also help the parents to cope with the disease and be of benefit to the infants because a cure may be forthcoming.

Eye Abnormalities↗
PubMed1994

Comparison of crystal structures of two homologous proteins: structural origin of altered domain interactions in immunoglobulin light-chain dimers.

The sequence and structure of a second human kappa 1 immunoglobulin light-chain variable domain, Wat, has been determined. The R-factor is 15.7% for 1.9-A data. One hundred and ninety-five water molecules were identified; 30 water molecules were located in identical positions in each of the monomers. Some of the water molecules are integral parts of the domains. This light chain is encoded by the same variable domain gene that encoded the previously characterized kappa I variable domain, Rei. Due to limited somatic mutation, the two highly homologous proteins differ in only 20 of the 108 residues. Wat crystallized in space group P6(4) while Rei crystallized in space group P6(1); in both crystals, the asymmetric unit was the noncovalent dimer. Although the basic domain structure is the same for both proteins, the relative positions of the domains within the two dimers differ. This difference is most likely accounted for by the replacement of Tyr36 in Rei by Phe in the Wat protein. Residue Tyr36 is part of the hydrogen-bonding network in the interface between the domains in Rei. Losing the hydrogen-bonding capability of residue 36 by replacement of Tyr by Phe alters the network of hydrogen bonds between the domains, resulting in a different domain-domain contact. The details of lattice contacts in the two crystals were compared. One type of contact that extends the beta-sheet of the individual domains was conserved, but because it involved different symmetry elements within the crystal, different crystal packing resulted. In the Wat crystal, one of the contacts shows an example of how a symmetrical binding site can "bind" an asymmetrical object. Further, the examination of the Wat crystal also illustrates how the different crystalline environments of the domains of the dimer results in different distributions of temperature factors for the residues within the domains.

Amino Acid Sequence↗
PubMed1994

A novel membrane antigen selectively expressed on terminally differentiated human B cells.

A monoclonal antibody (MoAb) that defines a novel terminal B-cell-restricted antigen, termed HM1.24, was developed against a human plasma cell line. The MoAb, designated anti-HM1.24, reacted with five different human myeloma cell lines, as well as with monoclonal neoplastic plasma cells obtained from the bone marrow or peripheral blood of patients with multiple myeloma or Waldenström's macroglobulinemia. The HM1.24 antigen was also expressed by mature Ig-secreting B cells (plasma cells and lymphoplasmacytoid cells) but not by other cells contained in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non-plasma-cell-related malignancies. The anti-HM1.24 MoAb bound to human myeloma RPMI 8226 cells with an affinity constant of 9.2 x 10(8) M-1, indicating approximately 84,000 sites/cell. By immunoprecipitation assay under reducing conditions, this MoAb identified a membrane glycoprotein that had a molecular weight of 29 to 33 kD. Our studies indicate that the HM1.24-related protein represents a specific marker of late-stage B-cell maturation and potentially serves as a target antigen for the immunotherapy of multiple myeloma and related plasma cell dyscrasias.

Animals↗
PubMed1994

Chemical and serologic characterization of human lambda VIII light chains.

The primary structural features and serologic properties of a newly recognized human lambda light (L) chain V region subgroup (V lambda VIII) were elucidated through study of two monoclonal L chains, Bence Jones proteins HAG and BIV. The V region amino acid sequences of these components were highly homologous to each other and to that deduced from the prototypic V lambda VIII cDNA, Humla8f10, which encodes the L chains of the IgM lambda rheumatoid factor HAF10. Proteins HAG and BIV could be classified as members of the V lambda VIII subgroup and distinguished from L chains of the V lambda I, V lambda II, V lambda III, V lambda IV, and V lambda VI subgroups on the basis of amino acid sequence. In addition to distinctive residues found within the V lambda gene-encoded portion of the molecules, L chains HAG, BIV, and HAF10 contained remarkably different second complementarity-determining regions (CDR2) that consisted of 11 residues, rather than the seven typically found among members of the other five V lambda subgroups. This elongated structure would presumably impart to the ligand-binding site of lambda VIII molecules a markedly different canonical structure compared with those of lambda I, lambda II, lambda III, lambda IV, and lambda VI L chains. By using Bence Jones protein HAG as an immunogen, we obtained polyclonal and monoclonal anti-V lambda VIII subgroup-specific Abs that were used to identify and quantify lambda VIII-related molecules in normal and pathologic states. Among the Ig lambda components present in the serum of normal individuals, approximately 3% had lambda VIII L chains, a frequency comparable to that found among monoclonal Ig lambda proteins or surface(s) Ig lambda+ cells obtained from patients with malignant plasma cell- or B cell-related disorders, respectively. In contrast, lambda VIII L chains were detected on approximately 19% of monoclonal IgM lambda rheumatoid factors produced by B cell lines established from PBLs or synovial cells from patients with rheumatoid arthritis. The results of our studies provide new information on the structural and immunochemical features of lambda VIII L chains and the possible functional importance of the human V lambda VIII subgroup.

Amino Acid Sequence↗
PubMed1994

Recovery of visual response of injured adult rat optic nerves treated with transglutaminase.

Failure of axons of the central nervous system in adult mammals to regenerate spontaneously after injury is attributed in part to inhibitory molecules associated with oligodendrocytes. Regeneration of central nervous system axons in fish is correlated with the presence of a transglutaminase. This enzyme dimerizes interleukin-2, and the product is cytotoxic to oligodendrocytes in vitro. Application of this nerve-derived transglutaminase to rat optic nerves, in which the injury had caused the loss of visual evoked potential response to light, promoted the recovery of that response within 6 weeks after injury. Transmission electron microscopy analysis revealed the concomitant appearance of axons in the distal stump of the optic nerve.

Animals↗
PubMed1994

Human rheumatoid factors with restrictive specificity for rabbit immunoglobulin G: auto- and multi-reactivity, diverse VH gene segment usage and preferential usage of V lambda IIIb.

To determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced high-titer immunoglobulin M (IgM) RF that reacted exclusively with rabbit but not human IgG or IgG of other mammalian species. Certain anti-rabbit IgG RF also had specificity for other mammalian antigens (Ag), including cytoskeletal proteins and intracellular proteins found in HeLa cells, as well as for Ag present in an extract prepared from the cell wall of group A streptococci. 13 of the 17 RF contained lambda-type light (L) chains, of which 12 were classified serologically as members of the lambda-L chain variable region (V lambda) subgroup, designated V lambda III. The heavy chain V region (VH) and V lambda sequences of nine of these IgM lambda RF were determined at the cDNA level. Five VH genes in three VH families were used by these antibodies (Ab), including VH1 (dp21/1-4b and dp10 [51p1]/hv1051), VH3 (dp38/3-15 and dp77/13-21), and VH4 (dp70/4-4b). The deduced V gene-encoded amino acid sequences of the lambda chains of these IgM lambda RF confirmed their serological classification as lambda III, and they were further classified as members of the relatively uncommon V lambda III subgroup, designated V lambda IIIb. Based on cDNA analyses, nine were the product of three different V lambda III b germline genes. Two such genes, designated hsiggll150 and hsiggll295, were cloned and sequenced from genomic DNA. Unique combinations of these VH and V lambda III b genes could be related to distinctive patterns of reactivity among the IgM lambda RF. Although the VH and V lambda regions of these Abs were expressed primarily as germline-encoded sequences, four of nine multireactive Abs had extensive V region mutation, indicative of an Ag-driven process. The finding that lambda IIIb L chains are preferentially found among anti-rabbit IgG RF, and that some of these Ab have specificity for other protein, cellular, and bacterial Ag, provides new insight into the pathogenesis of RA and related diseases.

Animals↗
PubMed1994

Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition.

The deposition of certain Bence Jones proteins as tubular casts, basement membrane precipitates, or amyloid fibrils results in the human light-chain-associated renal and systemic diseases--myeloma (cast) nephropathy, light-chain deposition disease, and immunocyte-derived (primary or AL) amyloidosis. To determine if light-chain nephrotoxicity or amyloidogenicity is related to the propensity of these components to form high molecular weight aggregates under physiological conditions, we used a size-exclusion chromatographic system to study 40 different Bence Jones proteins. Each samples was tested over a wide range of protein concentration in three different buffers varying in pH, osmolality, and the presence or absence of low concentrations of urea. Thirty-three of the 35 proteins found clinically and/or experimentally to form in vivo pathologic light-chain deposits were shown to undergo high-order self-association and form high molecular weight aggregates. In contrast, of five nonpathologic proteins, one showed polymerization under the chromatographic conditions used. The correlation between the in vivo results achieved by size-exclusion chromatography and that found in vivo provides (i) a rapid diagnostic method to identify potential nephrotoxic or amyloidogenic Bence Jones proteins and (ii) an experimental means to gain new insight into the physicochemical basis of light-chain aggregation and the treatment of those invariably fatal disorders associated with pathologic light-chain deposition.

Bence Jones Protein↗
PubMed1994

Primary amyloidosis associated with a novel heavy-chain fragment (AH amyloidosis).

Primary or AL amyloidosis occurs in patients with monoclonal plasma cell-related disorders and is typically associated with the systemic deposition as amyloid fibrils of the light-chain portion of the immunoglobulin molecule. Recently, the discovery that heavy chains could be involved in amyloid formation led to the designation of this type of disease process as AH amyloidosis. We have now identified a second example of heavy chain-associated amyloidosis in a patient (MAD) who had a serum IgG monoclonal gammopathy and Bence Jones proteinuria. In this case, the renal and splenic amyloid deposits consisted solely of the VH-D-encoded portion of the heavy polypeptide chain, in contrast to the first case, where the amyloid contained an immunoglobulin component composed of the entire heavy-chain variable and third constant domains. In this respect, the chemical composition of the amyloid protein MAD differed not only from that of the first reported case of AH amyloidosis but from all other structurally abnormal components found in patients with heavy chain-associated disease. The discovery that certain forms of heavy chains, as well as light chains, can form amyloid provides further information on the chemical basis of amyloidogenicity and the diverse nature of this disease.

Amino Acid Sequence↗
PubMed1994

Preferential utilization of a novel V lambda 3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients.

OBJECTIVE: To further our understanding about the molecular genetics of rheumatoid factor (RF) in rheumatoid arthritis (RA). METHODS: The heavy and light chain variable region (V) genes of 5 new human monoclonal IgM RFs were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide termination method. RESULTS: The results reveal the recurrent usage in two RA patients of a novel V lambda 3 germline gene, designated Humlv3c93. Specifically, in 2 of 3 RFs (C93 and D53) from one patient, the light chains in the V lambda gene-encoded region were identical to each other and to the light chain of an RF (H4) from another patient. Serologically, the light chains of these 3 RFs were classified as members of the V lambda 3b sub-subgroup. Each of the RFs was encoded by a different VH gene. Both C93 and D53 bound specifically with human and rabbit IgG, whereas H4 was monospecific for rabbit IgG. CONCLUSION: Since the lv3c93 gene is not homologous to any reported V lambda sequence from natural autoantibodies, it is possible that lv3c93 may represent a disease-specific RF-related V lambda gene. Moreover, the amino acid sequence CSGGSCY in the third complementarity-determining regions of 2 of the RF heavy chains is encoded by the DLR2 gene segment and has been found previously in 2 other RA-derived RFs, and thus may play a significant role in antigen binding.

Amino Acid Sequence↗
PubMed1994

Variable-region subgroup distribution among lambda-type immunoglobulins in normal human serum.

The distribution of the major VL subgroups (V lambda I, V lambda II, V lambda III, V lambda IV, V lambda VI, and V lambda VIII) among lambda-type immunoglobulins (Igs) in normal serum was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) using a panel of murine anti-human V lambda-subgroup-specific monoclonal antibodies (MoAbs) and appropriate reference standard proteins. The mean concentration of lambda I, lambda II, lambda III, lambda IV, lambda VI, and lambda VIII Igs in serum specimens obtained from 23 adults was 2158, 162, 1958, 264, 225, and 169 micrograms/mL and represented 44, 3, 40, 5, 5, and 3% of the total Ig lambda population, respectively. The low percentage of lambda II Igs in normal serum was in marked contrast to the approximately 40% incidence of this V lambda subgroup found among lambda-type Bence Jones proteins and monoclonal serum Igs obtained from patients with multiple myeloma and AL amyloidosis, or approximately 60% in Waldenström's macroglobulinemia. The non-random expression of the V lambda II subgroup in these diseases implies a relationship between V lambda-gene usage and plasma cell, as well as certain types of lymphocytic dyscrasias.

Adult↗