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Biomedical subjects

F Hirsch

Publications and source records attributed to F Hirsch.

At least 55 records · Page 3Linked to original sources
PubMed1991

Increased expression of class II major histocompatibility complex molecules on B cells in rats susceptible or resistant to HgCl2-induced autoimmunity.

Administration of HgCl2 to the susceptible Brown-Norway (BN) rats induces an autoimmune disease characterized by a T-dependent polyclonal activation of B cells responsible for a dramatic increase in serum IgE concentration. The resistant Lewis (LEW) rats injected with HgCl2 do not exhibit such autoimmune manifestations. We show here that, upon HgCl2 injections, major histocompatibility complex (MHC) class II molecule expression is increased very early in lymph nodes and spleen B cells from both strains. So far, it is the earliest marker (day 3) of the effect of HgCl2 on the immune system. In both strains this enhancement is transient, but regulatory mechanisms are much more efficient in the resistant LEW strain than in the susceptible BN strain. In addition, we observed that MHC class II molecule expression on B cells differs according to the organ and the rat strain tested. All these findings are discussed in an attempt to underline the role of MHC class II molecule expression in the occurrence of mercury-induced autoimmunity.

Animals↗
PubMed1990

Class II genes of miniature swine. IV. Characterization and expression of two allelic class II DQB cDNA clones.

Two cDNA clones coding for allelic miniature swine MHC class II Ag DQB chains have been isolated, characterized, and shown to be expressed after transfection into mouse fibroblasts. The two alleles differ at the nucleotide level by an overwhelming proportion of replacement substitutions, suggesting the influence of selection for polymorphism. Most of the resulting predicted amino acid replacements are in regions commonly polymorphic in mouse Ab and human DQB sequences, corresponding to the predicted Ag recognition site. Nucleotide and amino acid sequence comparisons to homologous mouse and human sequences show more similarity between swine and man than between either swine and mouse or man and mouse. This tendency is most pronounced when comparing the 3' untranslated regions. However, an examination of unique cross-species sharing of amino acid residues suggests a closer relationship between both man and miniature swine and man and mouse than between miniature swine and mouse. The simplest explanation we can envision for these findings is that the mouse DQB gene homologue (Ab) has been subject to a higher substitution rate than either swine or human DQB genes. An additional cytoplasmic exon expressed in mouse Ab gene products and in putative human DQB2 gene products is lacking in both swine and human DQB cDNA clones. Its absence suggests either that the expression of this exon in mouse Ab genes was activated after mammalian speciation or that the expression of this exon was independently inactivated in swine DQB and human DQB1 genes. Alternatively, the mouse Ab gene may be derived from the same primordial gene as human DQB2, whereas the pig DQB gene may be derived from the same primordial gene as the human DQB1 gene.

Alleles↗
PubMed1990

Specificity and cross-reactive idiotypes of anti-glomerular basement membrane autoantibodies in HgCl2-induced autoimmune glomerulonephritis.

Mercury-induced autoimmune glomerulonephritis in the Brown-Norway (BN) rat is characterized by the successive appearance of linear and granular glomerular IgG deposits. Anti-laminin autoantibodies represent the major part of the anti-glomerular basement membrane (GBM) antibodies produced in this model. Fusions were performed in this model and four anti-GBM monoclonal antibodies (mAb) were obtained. Three of them were laminin specific. Using rabbit anti-idiotype antibodies, cross-reactive idiotypes (CRId) were characterized on anti-laminin antibodies. They were expressed on the three anti-laminin mAb, on kidney-eluted and circulating anti-laminin antibodies. CRId-bearing immunoglobulins were detected transiently in the circulation and paralleled the anti-laminin antibody activity. By immunofluorescence studies on kidney cryostat sections two different CRId were defined. One was localized close to the antigen-combining site since it was not revealed on kidney-bound antibodies, in contrast with the second CRId. This latter CRId was also found deposited in a typical linear pattern in the early phase of the disease and in a granular pattern in the late phase, demonstrating that these CRId are components of immune deposits. Taken together, these results suggest that in this model of T-dependent polyclonal B cell activation, restricted sets of V genes encode for at least a part of the anti-GBM autoantibodies.

Animals↗
PubMed1990

Class II genes of miniature swine. II. Molecular identification and characterization of B (beta) genes from the SLAc haplotype.

Genomic clones corresponding to class II beta genes of the SLAc haplotype of miniature swine have been isolated and characterized. These genes have been grouped into seven non-overlapping clusters on the basis of restriction mapping. Ordering of exons within each cluster was accomplished by hybridization of Southern blots of restriction fragments with exon-specific probes. The two clusters (clusters 2 and 3) encoding the DRB and DQB genes were identified on the basis of hybridization with locus-specific 3' untranslated cDNA probes. Cluster 4 contained exons of both DOB and DQB genes, the basis for which remains to be determined. The remaining four clusters (1, 5, 6, 7) were identified as containing DP, DR, and DO coding sequences, respectively, on the basis of sequence analysis. The porcine class II region appears very similar to that of man in number and nature of the class II genes identified and in the intron/exon organization of corresponding genes.

Animals↗
PubMed1990

Structure of miniature swine class II DRB genes: conservation of hypervariable amino acid residues between distantly related mammalian species.

As part of our studies of the class II genes of miniature swine, we have isolated and characterized cDNA clones corresponding to DRB genes from two major histocompatibility complex homozygous strains. Comparison of the sequences of these clones to those of human DRB genes revealed a striking amino acid homology between the hypervariable residues of SLA-DRBc and the human DRB1-0101 allele. The percentage of differences in these residues between the pig DRBc allele and the human DRB1-0101 allele was significantly lower (29%) than that between the DRB1-0101 allele and all other human alleles (average, 66.2%). This similarity was not seen in a comparison of the number of silent substitutions, by which the swine DRBc and the human DRB-0101 differed. Since phenotypic selection operates at the level of protein products rather than nucleotide sequences, these data suggest the existence of selective mechanisms that have resulted in similar hypervariable regions in certain alleles even in these widely disparate species. Consistent with this hypothesis, an examination of available murine and bovine class II sequences revealed a homology in hypervariable residues between the human DRB1-1401 allele and the mouse E beta s allele as well as a cow DRB allele. Consideration of these data along with intraspecies allelic sequence comparisons suggests that at least some of the interspecies similarities have emerged as the result of convergent evolution, possibly as the result of a need to react to common pathogens.

Amino Acid Sequence↗
PubMed1988

[Systemic necrotizing vasculitis with bronchial asthma and eosinophilia: Churg-Strauss syndrome].

Two cases of the Churg-Strauss syndrome are reported, seen within the past year. The first concerned a 31-year-old woman with a rapidly progressive illness characterized by bronchial asthma, leukocytosis and eosinophilia, abdominal pain, diarrhoea and purpura. In the second case, a 47-year-old man had granulomatous epididymitis and interstitial nephritis before the asthma and eosinophilia developed. In both the diagnosis was confirmed by lung biopsy. Immunosuppressive treatment achieved rapid regression of all symptoms and of the eosinophilia, without recurrence so far.

Adult↗
PubMed1988

Class II genes of miniature swine. I. Class II gene characterization by RFLP and by isolation from a genomic library.

Class II genes of miniature swine have been characterized by restriction fragment length polymorphism (RFLP) analysis and by analysis of a series of clones isolated from a lymphocyte genomic library. For RFLP analysis, DNA samples from three independent major histocompatibility complex homozygous lines and three intra-MHC recombinant lines were digested with a variety of restriction enzymes and analyzed in Southern blots using human cDNA probes for DP, DQ, DR, and DZ alpha genes, and DP, DQ, DR, and DO beta genes. One, or at most two, unique fragments were detected by hybridization with each of the human alpha probes tested. In contrast, multiple bands (five to six for most enzymes examined) were detected by each of the human beta probes tested, the majority of which were found to cross-react with at least three of these probes under conditions of moderate stringency. Genomic DNA from the SLAc haplotype was cloned into an EMBL-3 bacteriophage vector, and the corresponding genomic library was screened with each of these human cDNA probes. The class II genes thereby isolated from this library showed characteristics consistent with those anticipated from the RFLP analysis. Thus, unique alpha genes were obtained which showed no evidence of cross-hybridization, while beta genes showed extensive cross-hybridization and were frequently detected in the library by more than one human beta gene probe. These data are consistent with early evolutionary divergence of alpha genes, prior to mammalian speciation, and with continuing evolution of beta genes, with possible shared usage of these genes by different alpha loci. The data also imply that alpha genes can readily be assigned to loci homologous to their human counterparts, but that beta genes will require further mapping and/or sequence analysis to confirm assignments.

Animals↗
PubMed1988

Characterization of a latent protein encoded by the large internal repeats and the BamHI Y fragment of the Epstein-Barr virus (EBV) genome.

Analysis of EBV nuclear antigen 1 (EBNA 1) encoding transcripts by cDNA characterization revealed a potentially polycistronic message generated by long-range splicing of several exons (Speck, S., and Strominger, J., Proc. Natl. Acad. Sci. USA 82, 8305-8309, 1985). Besides the open reading frame encoding EBNA 1, two other open reading frames are found in the EBNA 1-specific cDNA. The first reading frame consists of several exons from BamHI W and Y viral genome fragments (W1, W2, Y1, and Y2). In our experiments, the W1 exon was expressed in the tryptophan-regulated expression vector pATH11. Rabbit sera, raised against the bacterial fusion protein, recognized one or two proteins of molecular weights between 30,000 and 100,000 in several EBV genome harboring Burkitt lymphoma and EBV immortalized peripheral blood cell lines. Although, in a few cell lines from both groups no specific protein could be detected. Immunofluorescence analysis and characterization of subcellular distribution demonstrated that this W/Y fragment encoded latent protein is located, in part, in the cytoskeleton fraction, and in the chromatin. In addition, 2-D immunoblot analysis revealed post-translational modifications of this latent protein, probably due to phosphorylation. In DNA-binding studies on DNA cellulose columns, this W/Y encoded latent protein exhibited specific DNA binding activities.

Amino Acid Sequence↗
PubMed1988

[Effect of intravenous diltiazem on stress-induced myocardial ischemia (study of hemodynamics and reproducibility of repeated studies].

UNLABELLED: To obtain data about (a) the reproducibility of repeated standardized exercise tests, under blank and placebo conditions and (b) the improvement of ischaemic symptoms and of haemodynamics after intravenous application of diltiazem (0.3 mg/kg body weight), 20 patients with angina pectoris and angiographically proven coronary heart disease were analysed in a randomized double-blind study. RESULTS: a) A control exercise test 1 h after the first blank test showed no significant changes of the following parameters neither at rest nor during exercise: heart rate, systolic and diastolic blood pressure, double product, pulmonary capillary wedge pressure, cardiac output, peripheral vascular resistance, stroke volume, ST-segment depression, symptoms of angina pectoris, and maximal work tolerance (steady state, supine position). b) After intravenous application of diltiazem, at rest, both systolic blood pressure (-13 mm Hg, p less than 0.03); diastolic blood pressure (-10 mm Hg, p less than 0.01) and peripheral vascular resistance (-189 dyn x s x cm-5, p less than 0.02) decreased. During exercise testing, diastolic blood pressure (-9 mm Hg, p less than 0.02), pulmonary capillary wedge pressure (-13 mm Hg, p less than 0.01) and peripheral vascular resistance (-152 dyn x s x cm-5, p less than 0.02) were reduced, and angina pectoris was less severe (p less than 0.01): in comparison to placebo the onset of anginal symptoms occurred later (24 vs 49 W, p less than 0.01). Maximal exercise tolerance and maximal cardiac output were improved, and ST-segment depression was less pronounced. The study shows that haemodynamic data and ischaemic parameters are well reproducible in repeated exercise tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Neonatal IgE injections do not modify Nippostrongylus brasiliensis-induced and mercuric chloride-induced IgE increase in the rat.

The effect of neonatal IgE injections on total IgE responses was studied in two rat models. After Nippostrongylus brasiliensis infection, no differences in serum IgE level and surface or cytoplasmic IgE expression were observed between IgE-treated and control LOU/C rats. Likewise, after HgCl2 injection, IgE-treated Brown-Norway rats and controls showed no difference in serum IgE level or in the development of autoimmune glomerulonephritis and proteinuria. It has been concluded that IgE-class-restricted tolerance, induced by neonatal injections of IgE, cannot be observed in rats after strong IgE stimulation.

Animals↗
PubMed1986

Autoreactive T cells in mercury-induced autoimmune disease: in vitro demonstration.

Mercuric chloride induces in Brown-Norway rats an autoimmune disease due to a T dependent polyclonal activation of B cells. Various autoantibodies and a striking increase in total serum IgE level are observed as consequences of this polyclonal activation. The aim of this study was to investigate the in vitro response of autologous syngeneic normal lymphocytes to lymphocytes exposed in vivo or in vitro to HgCL2. Helper/inducer T cells (W3/25 +) exposed to HgCl2 were found to stimulate normal T lymphocytes in the presence of normal Ia (+) cells. The proliferating T cells also had the helper/inducer phenotype. To demonstrate the potential relevance of this in vitro phenomenon to the autoimmune disease, HgCl2-pretreated T cells were injected into the footpads of normal syngeneic recipients. Draining popliteal lymph nodes contained a highly significant number of both surface IgE positive and IgE containing cells. These experiments demonstrate that HgCl2 induces autoreactive T cells and suggest that these cells may be responsible for the autoimmune disease.

Animals↗
PubMed1986

Autoimmunity induced by HgCl2 in Brown-Norway rats. I. Production of monoclonal antibodies.

Mercuric chloride (HgCl2) induces in Brown-Norway rats (BN) a B cell polyclonal activation resulting in autoimmune disease. Spleen cells from BN rats injected with HgCl2 were fused with IR983F, a nonsecreting rat myeloma cell line, in order to obtain monoclonal antibodies reacting with autoantigens or IgE-producing hybridomas. After screening for immunoglobulin-producing clones, we found 5% clones with anti-tissue activity, 8% with anti-TNP activity, and 41% secreting IgE. Among the anti-tissue monoclonal antibodies, one recognizes both TNP and mesangial structures of rat normal glomeruli, which could be an as yet unrecognized mechanism of nephrotoxicity. These experiments 1) confirm that HgCl2 induces polyclonal activation, 2) show that the mercury model is of interest to obtain monoclonal IgE and various autoantibodies, and 3) suggest a new possible mechanism of antibody-mediated renal injury.

Animals↗
PubMed1986

Autoimmunity induced by HgCl2 in Brown-Norway rats. II. Monoclonal antibodies sharing specificities and idiotypes with mouse natural monoclonal antibodies.

Spleen cells derived from BN rats receiving HgCl2 were fused with the nonsecreting rat myeloma cell line IR983F. We screened 59 supernatants from immunoglobulin-secreting hybrids for antibody activity against actin, tubulin, autologous and heterologous myosin, myoglobin, dsDNA, peroxidase, and the haptens TNP, NIP, NNP, and NBrP. Six monoclonal antibodies (mAb) were found to react with antigen(s) of the panel. At least three groups of antibody specificities were identified: clones reacting with TNP (1 IgM, 1 IgE); clones reacting with horseradish peroxidase (1 IgM); and clones possessing widespread reactivity for several antigens as found for mouse natural autoantibodies (2 IgM, 1 IgE). We also analyzed the idiotypic (Id) determinants of the 59 mAb by using anti-Id antibodies described elsewhere prepared in rabbits against the BALB/c D23 natural monoclonal autoantibody and recognizing a BALB/c recurrent Id (Id D23) of natural polyspecific autoantibodies. We found that all rat mAb that possessed widespread reactivities bore this Id. We performed similar studies in sera from normal and mercury-stimulated rats. The results indicate a role for HgCl2 in the stimulation of natural antibodies producing cells and the existence of interspecies cross-reactive Id among mouse and rat natural antibodies.

Animals↗