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Biomedical subjects

A Schattner

Publications and source records attributed to A Schattner.

At least 145 records · Page 8Linked to original sources
PubMed1987

The origin of autoantibodies.

Autoimmune diseases are characterized by the appearance of autoantibodies (autoAb) which may participate in their pathogenesis, but autoAb have also been found in normals with a variety of other conditions. The production of hybridomas from lymphocytes of unimmunized normal mice and healthy humans and analysis of the monoclonal autoAb (m-autoAb) obtained, showed that many had polyspecific autoAb reactivity, binding to many seemingly unrelated self-antigens, or to several organs. Most m-autoAb were of the IgM class and shared a common cross-reactive idiotype (CRI). Low levels of Ab with similar binding pattern and idiotype are continuously represented in the serum of mice and humans who have no evidence of autoimmune or other disease. Very similar Ab appear in autoimmune diseases. Studies of m-autoAb derived from lupus-prone mice and from patients with systemic lupus erythematosus (SLE) and other autoimmune diseases also revealed polyspecific binding, IgM isotype and CRI. Moreover, these CRI, which were almost identical with the idiotypes of natural autoAb in normals, may identify a group of pathogenic Ab in the lupus mice and SLE patients. Since the data clearly suggest that lymphocytes that make autoAb are common and are part of the normal B cell repertoire coded by widely dispersed germline genes, there remain the basic problems of the function of these autoAb in health, as well as the question of their regulation and activation in vivo. Several postulated functions and immunoregulatory mechanisms are discussed and the possible role of certain factors, especially viruses, in enhancing autoAb production and autoimmunity, is assessed.

Animals↗
PubMed1987

Differences in susceptibility to NK cell killing of two cloned sublines derived from a single clone.

The ability of natural killer (NK) cells to discriminate between virus infected or tumor cells and their normal counterparts indicates a highly selective recognition, but the exact target structure remains unknown. We have examined two clones of measles virus persistently infected HeLa cells derived from the same parental clone, one of which, HeLa-mss, is highly susceptible to NK killing, (35% specific lysis at 80:1 lymphocyte to target ratio), whilst the other, HeLa-msr, is totally resistant (0.4-2.4% specific lysis). The HeLa-msr cells also failed to inhibit lysis of the HeLa-mss target cells, indicating that HeLa-msr cells did not share the receptor of HeLa-mss for NK cells. The expression of the two measles virus-encoded surface antigens, the hemagglutinin (HA) and fusion (F) proteins on the plasma membrane was examined by immunofluorescent staining and FACS analysis using monoclonal antibodies to the respective proteins. Approximately equivalent amounts of HA and F antigens were found on the cells of the HeLa-msr and HeLa-mss clones. Immunoprecipitation and PAGE analysis also failed to reveal any qualitative differences in the migration patterns or relative proportion of the measles virus proteins between these cell lines. Nevertheless, the in vitro differences in susceptibility of the two cell lines to NK lysis were found to be important in vivo, since HeLa-mss cells failed to grow as tumors in nude mice while HeLa-msr were highly tumorigenic. Thus, NK cells may either recognize very subtle differences in viral encoded polypeptides, possibly point mutations, or alternatively, they may recognize changes in the host cell membrane induced by insertion of certain viral encoded polypeptides.

Animals↗
PubMed1986

Lysis by natural killer cells requires viral replication and glycoprotein expression.

Several lines of evidence suggest that natural killer cells (NK) have an important role in antiviral defense. To be thus effective, NK cells have to recognize and cause lysis of virus-infected cells. The mechanism underlying this interaction was investigated in a murine system using vesicular stomatitis virus (VSV). A large number of cell lines was screened to identify a permissive target for VSV infection and the B16 murine melanoma cells were chosen since VSV replicates in these cells without producing cytopathic effects 24 h after infection. Spontaneous lysis of B16 melanoma cells by spleen cells occurred only if the target cells were previously infected with VSV. Treatment of spleen cells with anti NK 1.1 or anti Thy 1.2 plus complement decreased the specific lysis by 50%, therefore, the phenotype of the effector cells in this system corresponds to the NK cell subset. Immunofluorescent staining with polyclonal and monoclonal anti-VSV antibodies demonstrated that the viral glycoprotein G is abundantly expressed on the target cell surface. Treatment of the VSV-infected targets with tunicamycin prevented glycosylation of newly synthesized VSV glycoprotein G on the cell membrane. This treatment abrogated completely NK-mediated killing of the infected B16 melanoma cells. These results indicate that virus replication and membrane expression of glycosylated protein G are essential for recognition and lysis of VSV-infected targets by NK cells.

Animals↗
PubMed1986

Lupus serum and normal human serum contain anti-DNA antibodies with the same idiotypic marker.

We have previously shown that serum from patients with active SLE contain high levels of Id-16/6 and anti-DNA antibodies. In this study we investigated whether serum Id 16/6 is related to anti-DNA antibodies. Sera from 12 patients with active SLE were absorbed individually with poly(dT) cellulose (to purify anti-DNA antibodies) and rabbit (R) anti-Id-16/6 Sepharose (to purify Id 16/6 Ig). Removal of all anti-DNA activity removed most of the Id-16/6. Conversely, removal of all Id 16/6 removed most of the anti-DNA activity. Although there was no measurable anti-DNA antibody activity in normal serum, such antibodies were isolated by absorption with poly(dT) cellulose. The eluted immunoglobulins also had Id 16/6 activity. Similarly, Id 16/6 with anti-DNA activity were isolated from normal serum by absorption with R anti-Id 16/6 Sepharose. We conclude that a large fraction of anti-DNA antibodies in SLE serum are Id-16/6+, and that most Id 16/6 immunoglobulins in lupus serum have anti-DNA activity. Our observations suggest that lupus anti-DNA antibodies result from an overproduction of autoantibodies that are present in normal people.

Antigen-Antibody Complex↗
PubMed1986

The detection of a common idiotype of anti-DNA antibodies in the sera of patients with monoclonal gammopathies.

The sera of 265 patients with monoclonal gammopathies were examined for the presence of a dominant idiotype of the anti-DNA antibody [16/6 idiotype (Id)] and for anti-DNA activity. An enzyme-linked immunosorbent assay (ELISA) with a rabbit anti-16/6 antibody revealed 23 (8.7%) sera that contained increased concentrations of the idiotype. Seven of the patients had benign monoclonal gammopathy, three multiple myeloma, three Waldenström macroglobulinemia, five essential mixed cryoglobulinemia, and five monoclonal cryoglobulinemia. In 5 of the 23 sera, antinuclear activity was also noted. In 11 of the 16/6 Id-positive sera the anti-nucleic acid antibody reactions were found to be polyspecific, reacting with polydeoxythymidilic acid and polyinosinic acid, in addition to single-stranded DNA and double-stranded DNA. Similar results were achieved with the purified serum monoclonal components. The specificity of the idiotype analysis was demonstrated with an unrelated dominant idiotype of anti-HBsAg antibody. In none of the patients, except one (with essential mixed cryoglobulinemia), was lupus symptomatology noted.

Antibodies, Anti-Idiotypic↗
PubMed1986

Unusual manifestations of monoclonal gammopathies. Autoimmune and idiopathic syndromes.

Manifestations of monoclonal gammopathies are due to four broad mechanisms: destruction of bones, bone marrow, and normal tissues by an expanding tumor; nonspecific effects of large amounts of circulating paraproteins leading to hyperviscosity; autoantibody specificity of paraproteins that give rise to cryoglobulinemia, cold agglutinin disease, and other autoimmune phenomena, as well as incidental binding to bacterial antigens and haptens; and idiopathic syndromes due to as yet unidentified tumor products or other mechanisms. A review with an emphasis on the autoimmune and idiopathic manifestations of monoclonal gammopathies is presented.

Antibodies↗
PubMed1986

Suppressor cell function and anti-DNA antibody idiotypes in the serum of SLE patients and their first-degree relatives.

Sixteen-six (16/6) is a major cross-reactive idiotype of monoclonal anti-DNA antibodies, which was derived from the fusion of lymphocytes of a patient with systemic lupus erythematosus (SLE). Antibodies with the 16/6 idiotype (16/6 Id) are increased in the sera of patients with SLE and deposited in their gomeruli and skin. Since stimulated lymphocytes from healthy persons have the capacity to produce 16/6 Id, the mechanisms controlling its expression in health and their possible failure in SLE are of considerable interest. A defect in suppressor cell function was found in a high proportion of patients with SLE and in some of their first-degree relatives. Suppressor cell function in 15 SLE patients and in 53 relatives was compared with the level of 16/6 Id as well as with immunoglobulin levels and anti-DNA antibodies. Ten of 15 SLE patients and 26 of 53 first-degree relatives had increased serum 16/6 levels, which was found in only 1 of 35 healthy controls and household members. Of the 10 SLE patients with increased 16/6, six had a suppressor cell defect (P less than 0.1). Among the 26 first-degree relatives with elevated 16/6 Id levels, 12 had associated suppressor defect and in only two cases was a suppressor cell defect unaccompanied by increased 16/6 (P less than 0.005). For the group of 18 patients and relatives showing concomitant suppressor cell defect and increased 16/6, a correlation was found between the severity of the suppressor cell defect and the level of 16/6 Id in the serum. The increased 16/6 in the relatives was not associated with hypergammaglobulinemia or with measurable anti-DNA activity in the serum. We conclude that the suppressor cell defect in relatives of SLE patients is often associated with increased expression of antibodies with the 16/6 idiotype. However, additional mechanisms are involved in the regulation of 16/6 Id and the development of clinical SLE, since increased 16/6 was commonly found in the presence of a normal suppressor T-cell function.

Antibodies, Antinuclear↗
PubMed1986

Effects of interferon-alpha on the expression of a lupus idiotype in normal humans.

Interferon (IFN) has extensive immunoregulatory effects but its role in systemic lupus erythematosus (SLE) remains obscure. The observations that a high proportion of patients with active SLE have increased IFN levels in their sera, and that IFN injected to lupus-prone mice aggrevates their disease, led us to examine the effects of IFN on the production of 16/6--a high frequency idiotype of monoclonal anti-DNA antibodies produced by human-human hybridomas derived from SLE patients. Peripheral blood mononuclear cells (PBMC) of healthy donors or of patients with SLE were incubated with IFN and pokeweed mitogen (PWM). Seven-day supernatants were assayed for total IgM, for IgM with 16/6 idiotype, and for IgM anti-DNA activity. PWM-stimulated PBMC of all healthy donors examined produced the 16/6 idiotype (mean 2.5 ng/ml). A significant increase of 16/6 in normals (above the level with PWM alone) was noted with 10-100 u/ml of IFN-alpha but not with 500 u/ml. In 3/10 normals the addition of IFN-alpha resulted in detectable anti-DNA activity. The IFN-induced increase in 16/6 idiotype was significantly more than the increase in IgM (335% vs 47% above baseline, with 10 u/ml of IFN). These effects of IFN could not be demonstrated in the absence of PWM nor in T-cell-depleted preparations. Recombinant IFN-gamma had no augmenting effect on 16/6 production. Three SLE patients in remission had elevated levels of 16/6 in their PBMC supernatant (15-200 ng/ml) which could not be further augmented by IFN. Thus, we have demonstrated the potential of PWM-stimulated normal lymphocytes to generate a "lupus" idiotype and shown that production of this idiotype requires T cells and is preferentially enhanced by IFN-alpha. Further studies of the effects of IFN on the expression of anti-DNA antibodies may clarify a postulated role of IFN in autoimmune diseases.

Adult↗
PubMed1985

Immunochemical similarities between monoclonal antibacterial Waldenstrom's macroglobulins and monoclonal anti-DNA lupus autoantibodies.

Six monoclonal IgM from patients with Waldenstrom's macroglobulinemia that react with Klebsiella polysaccharides were tested for their ability to bind to nucleic acid antigens. One of the macroglobulins bound to the polynucleotide poly(G), and one bound to poly(G), poly(I), and single-stranded DNA. The reaction with the polynucleotides was specifically inhibited by the Klebsiella polysaccharide K30. A monoclonal lupus anti-DNA antibody (16/6) was found to react weakly with the Klebsiella polysaccharides K30 and K21. Five of the Waldenstrom macroglobulins shared an idiotypic determinant with the 16/6 anti-DNA antibody. The reaction between the macroglobulins and the antiidiotype serum was specifically inhibited by Klebsiella polysaccharides, an indication that the idiotypic marker was in the antigen-binding site of the macroglobulins. These results indicate the existence of widely dispersed conserved variable region genes that encode idiotypically related immunoglobulins with the capacity to bind to both bacterial polysaccharides and nucleic acids. Such genes can be expressed by patients with either Waldenstrom's macroglobulinemia or systemic lupus erythematosus.

Antibodies, Bacterial↗
PubMed1985

Natural killer cells--toward clinical application.

Natural killer (NK) cells are non-B, non-T lymphoid cells of uncertain lineage that rapidly recognize and lyse a large variety of tumor or virus-infected cells, without the need for either prior sensitization or major histocompatibility complex (MHC)-dependent recognition. Though some essential problems in understanding NK cell function are still unsolved, considerable progress has been achieved in recent years following the identification of the characteristic large granular lymphocyte (LGL) morphology of NK cells and their purification, the study of their function at the single-cell level, and the cloning of mouse and human NK cell lines. Activated mainly by interferon (IFN), as well as important producers of IFN, NK cells appear to have a distinct role in immunoregulation in addition to their postulated major role in "immune surveillance," for which convincing in vivo data has accumulated. Future clinical applications may therefore include manipulations of the NK system through expansion and activation of patient's LGL or the use of cloned human NK cell lines.

Animals↗
PubMed1985

Persistent viral infection affects tumorigenicity of a neuroblastoma cell line.

A mouse neuroblastoma cell line (clone NS20Y) is highly tumorigenic in syngeneic A/J mice. When this clone was persistently infected with measles virus (NS20Y/MS) it failed to grow or form tumors in conventional A/J or nude mice, even when large numbers of cells were inoculated. As doubling time, serum dependence, and anchorage-independent growth on agar did not differ significantly between NS20Y and NS20Y/MS, lack of tumorigenicity of the persistently infected cells is unlikely to be due to an intrinsic property of the cells. NS20Y/MS cells were found to be effectively rejected in athymic nude as well as conventional syngeneic mice. However, injection of mice with either anti-interferon or anti-asialo GM1 serum, both of which have been shown to deplete natural killer (NK) cells in vivo, enabled NS20Y/MS cells to form large tumors. Unexpectedly, treatment of mice with silica also allowed the NS20Y/MS cells to form tumors. Under these conditions, it was shown that silica caused a significant decrease in NK activity as late as 7 days after a single injection. Although NS20Y/MS were not susceptible to NK cell lysis in vitro, the in vivo data suggest that NK cells are in fact the prime mechanism in the rejection of this persistently virus-infected neuroblastoma cell line by athymic and conventional syngeneic mice. The results indicate that NK activity may be greater or more sensitively detected in vivo than in vitro.

Animals↗
PubMed1985

Identification of viral infections in pregnancy by assay of (2'-5')-oligo-isoadenylate synthetase.

Interferons are produced in response to viral infections. Among the biochemical changes they cause in cells is the induction of the enzyme (2'-5')-oligo-isoadenylate synthetase. The activity of this enzyme can be measured and this can indicate exposure and response of cells to interferon. The efficacy of such an assay of peripheral blood of pregnant women may aid in establishing screening guidelines for potentially teratogenic viral infections. The blood of 44 primigravidas with complaints of fever, myalgia, cough, vaginal discharge and/or costovertebral angle tenderness was assayed for activity of the enzyme (2'-5')-oligo-isoadenylate synthetase and compared to assays of the enzyme activity in a group of 37 healthy primigravidas which served as a control group. It was found that the group with viral infections had an increase in enzyme activity from twice to 15 times the normal value, with characteristic rises of enzyme activity in several viruses known or suspected to cause human defects. Several general guidelines are proposed to assist the obstetrician in determining a viral etiology of acute illness in pregnancy, It is suggested that the assay of enzyme activity of (2'-5')-oligo-isoadenylate synthetase may provide a simple tool for rapid diagnosis of viral infections in pregnancy.

Adult↗
PubMed1985

Natural killer cell recognition of target cells expressing different antigens of vesicular stomatitis virus.

Natural killer (NK) cells have the capability of lysing virus-infected, transformed, and embryonal cells, yet the nature of the target structure(s) recognized remains unclear. The availability of well-characterized temperature-sensitive (ts) mutants of vesicular stomatitis virus, defective in expression of individual viral-encoded polypeptides at the nonpermissive temperature (39 degrees C), offered an approach to elucidating NK-cell recognition of virus-infected cells. Target cells were infected with ts mutants in three functions: the viral surface glycoprotein (G protein; ts 045); the matrix (M) protein (ts G31, ts G33), and the polymerase (ts G11). Cells infected with wild-type virus and all ts mutants at the permissive temperature (31 degrees C) were killed by murine spleen cells. Similar to results on cytotoxic T lymphocytes, target cells infected by ts 045 defective in expression of G protein at 39 degrees C were not killed by NK cells. Unexpectedly, cells infected at 39 degrees C with the M-protein mutants also were not killed, although G protein was expressed at the cell surface. Target binding studies indicated that conjugates were not formed by cells infected with the ts mutants at the nonpermissive temperature. That expression of G protein was not sufficient for NK cell-mediated cytotoxicity was established in experiments in which a plasmid (pSVGL) containing the gene for vesicular stomatitis virus G protein was transfected into COS cells. Although G antigen was expressed on the plasma membrane, the cells were not lysed. These results suggest either that recognition of virus-infected cells depends on an appropriate conformation imparted to the viral G protein by association with the M protein or that NK cells can recognize alterations in the structure of the cell membrane induced by insertion of viral M and G molecules.

Animals↗