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S Muller

Publications and source records attributed to S Muller.

At least 217 records · Page 12Linked to original sources
PubMed1995

Effect of histone and histone-RNA complexes on the disease process of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterised by the production of a variety of autoantibodies against cell surface, nuclear and cytoplasmic antigens. The antigen or antigens responsible for the induction of this disease is/are unknown. We have analysed the antigenicity and pathogenicity of free histones and histones complexed with RNA in Balb/c, B10 Br, C57BL/6 and MRL-lpr/lpr mice by giving 1 microgram and 25 micrograms of each antigen intraperitoneally in complete and incomplete Freund's adjuvant. The same number of control animals were injected with either adjuvant or PBS. In the initial experiment we gave three doses of antigen at three weekly intervals. B10 Brown and C57BL/6 mice had no response to the antigens. Balb/c mice developed a mild transient antibody response against H1 histone, branched peptide of ubiquitinated H2A (peptide T4) and also against ssDNA. However in repeated experiments when the histone-RNA complex was injected into young MRL-lpr/lpr animals at two weekly intervals, a significantly increased antibody response was detected against H1, peptide T4 and some histone peptide residues (204-218 of H1, 1-20 and 65-85 of H2A, 1-25 of H2B, 1-21 of H3 and 1-29 of H4) compared to the control groups. Moreover, this group also showed elevated serum anti-DNA antibody levels and early impairment of renal function assessed by the urine protein levels. These experiments have demonstrated that there is a genetic variation in antibody responses against histones and histone-RNA complexes and that histone-RNA complexes exaggerate the disease in young MRL-lpr/lpr mice by inducing antibodies to basic regions of histones and other autoantigens.

Animals↗
PubMed1995

Basaloid squamous cell carcinoma of the head and neck with a spindle cell component. An unusual histologic variant.

We describe two cases of basaloid squamous cell carcinoma of the head and neck with a spindle cell component. One tumor arose from the tonsil and the other in the larynx. Of the 30 cases of basaloid squamous cell carcinoma seen at this medical center, only 2 (6.6%) have demonstrated this histologic feature. To our knowledge, scant information exists with regards to a prominent spindle cell component occurring in basaloid squamous cell carcinoma, and none has been officially documented.

Aged↗
PubMed1994

Antigenic mimicry of natural L-peptides with retro-inverso-peptidomimetics.

Three analogues of the model peptide of sequence IRGERA corresponding to the COOH-terminal residues 130-135 of histone H3 were synthesized, and their antigenicity, immunogenicity, and resistance to trypsin were compared to those of the natural L-peptide. The three analogues correspond to the D-enantiomer, containing only D-residues, and two retro-peptides containing NH-CO bonds instead of natural peptide bonds. The chirality of each residue was maintained in the retro-peptide and inverted in the retro-inverso-peptide. Antibodies to the four peptide analogues were produced by injecting BALB/c mice with peptides covalently coupled to small unilamellar liposomes containing monophosphoryl lipid A. Each of the four peptide analogues induced IgG antibodies of various subclasses. The IgG3 antibodies reacted similarly with the four analogues, whereas antibodies of the IgG1, IgG2a, and IgG2b isotypes showed strong conformational preferences for certain peptides. The retro-inverso-peptide IRGERA mimicked the structure and antigenic activity of the natural L-peptide but not of the D- and retro-peptides, whereas the retro-peptide IRGERA mimicked the D-peptide but not the L- and retro-inverso-peptides. The equilibrium affinity constants (Ka) of three monoclonal antibodies generated against the L- and D-peptides with respect to the four peptide analogues were measured in a biosensor system. Large differences in Ka values were observed when each monoclonal antibody was tested with respect to the four peptides. The use of retro-inverso-peptides to replace natural L-peptides is likely to find many applications in immunodiagnosis and as potential synthetic vaccines.

Amino Acid Sequence↗
PubMed1994

Characterization of chromatin-condensing proteins during spermiogenesis in a neogastropod mollusc (Murex brandaris).

During the process of chromatin condensation in the spermiogenesis of the neogastropod mollusc Murex brandaris, the nuclear protein complement undergoes a complex series of changes. These changes lead to the appearance of three small protamines in the ripe sperm nuclei. We have characterized this system electrophoretically and at the compositional level, as well as through the analysis of crossreactions with antibodies elicited against a specific spermatozoan protamine. Our results indicate that the complex pattern of chromatin condensation during spermiogenesis in this species (M. brandaris) may be modulated by a series of post-translational (and intranuclear) modifications of DNA-interacting proteins, such as precursors to the sperm protamines. The amino acid composition of each sperm protamine is remarkably simple (lys + arg + gly > or = 96 mol%). This system of spermiogenic/spermatozoal proteins in the neogastropod M. brandaris clearly differs from that in patellogastropods and archaeogastropods, and it may be helpful in understanding evolutionary changes in the chromatin condensation pattern during the spermiogenesis of gastropod molluscs.

Animals↗
PubMed1994

Autoantibodies reacting with poly(ADP-ribose) and with a zinc-finger functional domain of poly(ADP-ribose) polymerase involved in the recognition of damaged DNA.

Poly(ADP-Ribose) polymerase (PARP) is a chromatin-associated enzyme that specifically binds to DNA strand breaks in a zinc-dependent manner. We describe here the presence of IgG antibodies reacting with recombinant human PARP in the serum of patients with systemic lupus erythematosus (SLE) and primary and secondary Sjögren's syndrome (pSS and sSS). The reactivity of patients' sera was further studied in ELISA with a synthetic peptide of 44 residues corresponding to the second zinc finger (F2) present in the DNA-binding domain of PARP and which was shown to effectively bind 65Zn. Thirty-five percent of SLE sera (n = 97), 42% of pSS sera (n = 67), and 56% of sSS sera (n = 16) were found to contain raised levels of IgG antibodies reacting with peptide F2 which corresponds to the domain in PARP that is directly involved in the specific recognition of single and double strand breaks in DNA. Antibodies reacting with the whole enzyme and/or peptide F2 occurred independently from antibodies reacting with poly(ADP-ribose) which is rapidly synthesized in vivo by PARP from NAD and then degraded in response to DNA strand breaks.

Amino Acid Sequence↗
PubMed1994

HLA association of anti-Ro60 and anti-Ro52 antibodies in Sjögren's syndrome.

The possible pathological role of antibody subsets specific for different regions of 60-KD and 52-KD Ro/SSA proteins (Ro60 and Ro52) and La protein is unclear. Previously, we have shown that in patients with Sjögren's syndrome, the fine specificity of Ro60 and Ro52 antibodies, as characterized with synthetic peptides, varied considerably according to the origin of sera. We therefore looked for possible associations of HLA class I and class II alleles with Ro and La IgG antibodies in patients with primary Sjögren's syndrome (n = 24) and secondary Sjögren's syndrome associated with systemic lupus erythematosus (n = 25). Ro60 and Ro52 antibodies were tested by ELISA with the complete parent proteins and with 10 to 24 residue-long peptides of these proteins. Anti-Ro60 antibodies were more frequent in DR3-positive patients and in DQ1-negative patients whereas the presence of Ro52 and La IgG antibodies was significantly increased in patients with A1/B8/DR3 haplotype. Certain HLA associations observed with antibodies reacting with the whole Ro52 protein were not found with antibodies reacting with certain Ro60 and Ro52 peptides and, reciprocally, certain anti-peptide antibodies were linked to particular haplotypes whereas antibodies to the respective parent proteins were not linked to these haplotypes. Thus the production of antibody subsets reacting with different parts or presentations of Ro proteins is, at least in part, influenced immunologically by different HLA haplotypes, and this predisposition may play a role in the pathological development of the disease.

Adult↗
PubMed1994

Increased erythrocyte aggregation in insulin-dependent diabetes mellitus and its relationship to plasma factors: a multivariate analysis.

Red blood cell aggregation in vitro (kinetics and shear resistance) was studied in 13 healthy controls and 13 type I (insulin-dependent) diabetic patients free of severe degenerative complications who were matched for age, sex, and body mass index. Measurements were performed with a device that analyzes the laser light backscattered by a blood suspension. Both the velocity of rouleau formation and the cohesion of the rouleau network were significantly increased in diabetic patients. Plasma viscosity and whole-blood viscosity measured at low shear rate (0.95 s-1) were also significantly elevated in the diabetic group. Multivariate analyses of the whole population sample and the diabetic patients confirmed the influence of plasma proteins on the kinetics of aggregation. Fibrinogen levels, which were close to normal, affected mainly the shear resistance of the aggregates. Triglyceride and apolipoprotein (apo) B levels and indexes of metabolic control or protein glycation (fasting blood glucose and fructosamine) also appeared to influence markedly both the kinetics of rouleau formation and the cohesion of the rouleau networks. These rheological abnormalities occurred in diabetic patients before the appearance of any severe degenerative complications. We suggest that these rheological abnormalities are linked to plasma or erythrocyte factors, and are not due to angiopathy.

Adult↗
PubMed1994

Mapping of linear epitopes of human histone H1 recognized by rabbit anti-H1/H5 antisera and antibodies from autoimmune patients.

Seventeen synthetic peptides of 15-16 residues, covering the complete sequence of the major human H1b variant, were tested for their capacity to bind serum IgG antibodies from 128 patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (pSS). One peptide (residues 111-127) of the human H1 degree variant and six synthetic and natural fragments of H5 were also tested. Results were compared to those obtained with antibodies from 11 rabbits immunized against chicken H1 and H5, and calf H1. The activity of peptides was tested in direct ELISA and in inhibition assays with free peptides in solution. A major epitope recognized by antibodies from SLE, RA and pSS patients as well as by rabbit antibodies was identified in the C-terminus of H1b (residues 204-218). Other peptides in the globular (residues 79-94) and C-terminal domains of H1b and peptide 111-127 of H1 degree were also recognized, albeit at a lower level and frequency, and some of them contain sequence homologies with peptide 204-218. Patients' antibodies and rabbit antisera were tested with complete H1 proteins from HeLa cells, calf thymus and chicken erythrocytes and with chicken H5. Less than 25% of autoimmune sera contained IgG antibodies reacting with H1/H5 in a direct ELISA. In dot-immunoassay, antigenic activity with intact H1/H5 proteins was detected in a larger number of sera. Using antibodies raised in rabbits against peptides 1-16 and 204-218 of H1b, we found no reaction with H1 immobilized on a solid-phase. In contrast, peptides 144-159, 170-185 and 204-218, which contain identical structural domains, compete with H1 in solution indicating that any of these three regions are accessible at the surface of free H1 and may be involved in the induction of specific antibodies in autoimmune patients.

Amino Acid Sequence↗
PubMed1994

Sequence analysis and fine specificity of two human monoclonal antibodies to histone H1.

Two human IgM lambda monoclonal antibodies (MAb) derived from the splenic lymphocytes of patients with idiopathic thrombocytopenia (Ben) and systemic lupus erythematosus (Wri) were studied. BEN-27 and WRI-170 hybridoma supernatants were screened for binding to ssDNA, dsDNA, poly (ADP-ribose), cardiolipin, histone subclasses and Klebsiella K30 cell wall antigen. Of this panel of antigens, BEN-27 and WRI-170 antibodies reacted only with histone H1. Their fine specificity was defined by direct and inhibition ELISA with synthetic peptides of the major human H1b variant. Antibody WRI-170 was shown to bind to both the N- and C-terminal peptides encompassing residues 1-16 and 204-218 of H1b whereas BEN-27 reacted only with peptide 204-218. To analyse the genetic origin of these autoantibodies, we determined the nucleotide sequence of the heavy (H) and light (L) chain variable regions of these two hybridomas. BEN-27 and WRI-170 MAbs were found to use VH1-DN1-JH4/V lambda 3-J lambda 2 and VH3-DIR2-D21/9-JH1/V lambda 2-J lambda 2 gene segment combinations respectively. Between 70 and 95% homology was demonstrated when the mRNA sequences for BEN-27 and WRI-170 were compared with published VH and V lambda germline sequences. This finding suggests that BEN-27 heavy and light chains and WRI-170 light chain use unidentified VH and V lambda germline gene segments whereas WRI-170 heavy chain derives from a VH gene segment recently identified. It is noteworthy that the CDRs of the two MAbs contain several negatively charged amino acids which are assumed to be of critical importance in antigen binding. Moreover, striking similarities are observed between BEN-27 heavy chain CDR2 and a previously described murine anti-H1 Ab heavy chain CDR2.

Amino Acid Sequence↗
PubMed1994

Selective induction of protection against influenza virus infection in mice by a lipid-peptide conjugate delivered in liposomes.

We have previously reported (Muller et al. Vaccine 1990, 8, 308) that two cyclic peptide analogues called D loop and K loop, corresponding to residues 139-147 in site A of the haemagglutinin (HA) of influenza A virus (strain X31), were both able to provide protective immunity to infected OF1 mice when administered in the form of peptide-ovalbumin conjugates. The predicted conformation of the D loop is nearly identical to that of the native loop known from the X-ray structure of HA, while the predicted conformation of the K loop differs significantly from the native one. In this study, the two peptides were conjugated to small unilamellar liposomes, thus creating a chemically defined immunogen, and OF1 mice were immunized with these liposomes containing monophosphoryl lipid A as adjuvant. Compared with protein carrier systems, the liposomal preparations are completely synthetic and avoid the use of Freund's adjuvant. By using liposomes associated with the D loop, we were able to achieve 70% protection of the mice against intranasal challenge with the influenza virus while no protection was obtained with the liposome-associated K loop. The difference in effect between the two liposome and ovalbumin carrier systems may result from the induction of different structures in the peptides when coupled to lipid anchors than when coupled to proteins.

Administration, Intranasal↗
PubMed1994

Hydrophobic Zn(II)-naphthalocyanines as photodynamic therapy agents for Lewis lung carcinoma.

Four Zn(II) 2,3-naphthalocyanines (unsubstituted ZnNc1, tetracetylamido substituted ZnNc2, tetramino substituted ZnNc3 and tetramethoxy substituted ZnNc4) incorporated into unilamellar liposomes of dipalmitoylphosphatidylcholine have been injected intra-peritoneally (i.p.) (0.25-0.3 mg kg-1) to male C57/Black mice bearing a transplanted Lewis lung carcinoma. The pharmacokinetic investigations show that three of the four studied ZnNcs, 1, 2 and 4, are good tumor-localizers in Lewis lung carcinoma. The highest concentration is detected after ZnNc1 administration. The lowest tumor concentration as well as the lowest phototherapeutic effect were established with ZnNc3. In previous work it was shown that this ZnNc did not differ from the other three studied ZnNcs regarding the quantum yield of 1O2-formation and the photoinduced electron transfer. Obviously not only the good photochemical properties but also the tumor drug uptake can be an important factor of effective PDT. The biodistribution investigations also show that 72 h after drug injection, the skin concentration of the studied ZnNcs returns to the original base line. Indeed, we can expect that the skin photosensitivity will last for no longer than three days after PDT. The established higher drug concentration in the tumor rather than in the liver tissue (20 h after injection) shows again the tumor targeting selectivity of the applied liposome-sensitiser delivered procedure. Evaluating the PDT effect as reflected in the dynamics of the mean tumor diameter, we obtained unambiguous data on the potential capacity of ZnNcs 1,2,4 as PDT-photosensitisers. The data obtained from the assessment of the cytotoxic effect of PDT on the basis of the degree of induced necrosis, gave an adequate characterization of the tumor tissue destruction.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Antibodies to DNA, chromatin core particles and histones in mice with graft-versus-host disease and their involvement in glomerular injury.

Chronic graft-versus-host disease (GVHD) was induced in female (C57 B10S/DBA/2)F1 hybrid mice with two successive injections of lymphoid cells from parental DBA/2 strain. Serial bleedings of 27 GVHD mice were screened with a panel of antigens including the five histones H1, H2A, H2B, H3 and H4, 15 histone peptides, core particles, dsDNA, heat-shock proteins hsp70 and ubiquitin, a branched peptide of ubiquitinated H2A (U-H2A), poly(ADP-ribose) and SSB/La protein. The predominant IgG response to histone peptides was directed against regions 204-218 of H1, 1-25 of H2B and 1-29 of H4. GVHD mice also produced IgG antibodies to dsDNA and chromatin core particles as reported previously. IgG antibodies reacting with dsDNA appeared before antibodies to core particles and histones. Raised levels of antibodies to U-H2A, but not to monomeric ubiquitin, were also found. While the level of antibodies to dsDNA, histones and core particles decreased significantly before the appearance of proteinuria, suggesting their involvement in glomerular injury, the longitudinal pattern of anti-U-H2A peptide response was apparently not linked to the manifestation of lupus nephritis in GVHD mice.

Animals↗
PubMed1994

Epitope mapping with synthetic peptides of 52-kD SSA/Ro protein reveals heterogeneous antibody profiles in human autoimmune sera.

The reactivity of autoantibodies present in the sera of 489 patients with Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and other autoimmune diseases was investigated by ELISA using recombinant 52-kD SSA/Ro protein (rRo52) and 39 overlapping synthetic peptides representing the entire sequence of Ro52. We report that IgG antibodies reacting with rRo52 were present in the sera of a large number of patients with SS (67% of patients with primary SS and 46% of patients with SS associated with SLE), whereas they were less frequent (10-25%) in SLE, rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and mixed connective tissue disease (MCTD), and absent in scleroderma. Among the 39 peptides tested, five were recognized by sera from 30-65% of patients with SS, namely peptides representing residues 2-11, 107-122, 107-126, 277-292 and 365-382. Patients with JCA had raised levels of IgG antibodies reacting with peptides 2-11 and 365-382, and 51% of patients with MCTD had raised levels of IgG antibodies reacting with peptide 365-382. None of the five peptides was recognized by more than 20% of sera from patients with SLE and RA. Interestingly, and of importance in the field of diagnostic tests based on peptides, the reactivity of antibodies to the Ro52 synthetic peptides varied greatly according to the origin of sera. Inhibition experiments using either patients' sera or antibodies induced in rabbits against Ro52 peptides showed that the four domains 2-11, 107-122, 277-292 and 365-382 are accessible on the surface of the Ro52 protein. These regions may thus be involved in the induction of specific antibodies in autoimmune patients.

Amino Acid Sequence↗
PubMed1994

A role for histones and ubiquitin in lupus nephritis?

Glomerulonephritis frequently develops in Systemic lupus erythematosus (SLE) but the pathogenesis is still poorly understood. Experimental evidence now suggests that histones can participate in immune complex formation in lupus nephritis. In a retrospective study, using samples from Northern and Southern Europe, Japan and South America, we searched for glomerular deposits of histones, both in native and ubiquitinated forms, in renal biopsy specimens from 48 patients with SLE and 70 cases of glomerulonephritis from patients without SLE. Positive glomerular immunofluorescent staining was revealed with rabbit antibodies to synthetic peptide 1-21 of histone H3, 22-45 of ubiquitin and to the branched region of ubiquitinated histone H2A (U-H2A) in 65% (31/48), 29% (14/48) and 54% (26/48) of the cases of SLE respectively. In total positive staining with at least one of the antibodies was seen in 36/48 (75%) cases. The staining was granular in nature and was present in capillary and mesangial areas. Only 3% (2/70) of non-SLE renal biopsies revealed positive staining with the above antibodies. None of the biopsy specimens from SLE patients were positive for ss- or ds-DNA, when tested with intercalating dyes. Serum samples were available from 15/48 SLE cases and were analysed with peptides and parent proteins by ELISA; epitopes in the N-terminal regions of core histones and in the C-terminus of histone H1 were often recognised by IgG antibodies in SLE sera, as was ubiquitin and the branched octapeptide of U-H2A. These results support the notion that the nuclear autoantigens histone and ubiquitin may be involved in the induction of glomerulonephritis in human SLE.

Animals↗
PubMed1994

Autoimmunity to histones, ubiquitin, and ubiquitinated histone H2A in NZB x NZW and MRL-lpr/lpr mice. Anti-histone antibodies are concentrated in glomerular eluates of lupus mice.

In lupus diseases products of chromatin catabolism released from dead cells might be involved in the induction of autoantibody and in the development of glomerulonephritis. While the pathogenic role of anti-DNA antibodies is recognized, the role of antibodies directed against structural proteins of chromatin is still questioned. IgG antibodies to histones, ubiquitin, and ubiquitinated histone H2A (UH2A) have been investigated both in plasma and in glomerular eluates of NZB x NZW and MRL-lpr/lpr mice. In NZB x NZW mice, anti-ubiquitin and anti-UH2A antibodies were detected at 8 weeks of age, simultaneously with anti-double-stranded DNA antibodies, whereas anti-histone antibodies appeared later. In MRL-lpr/lpr mice, anti-DNA antibodies were detected at 4 weeks, whereas anti-histone, anti-ubiquitin, and anti-UH2A antibodies were not detected at that age but appeared in plasma rapidly thereafter. In both strains, increased anti-histone activity was found in IgG eluted from glomeruli. These results support the suggestion that anti-histone antibodies are likely to play a pathogenic role in lupus nephritis. They also indicate that, like human lupus, murine lupus is characterized by the production of anti-ubiquitin and anti-UH2A antibodies.

Animals↗
PubMed1994

[Acute postoperative renal insufficiency in renal transplantation. Incidence and risk factors].

Delayed renal function (DFG) is known to influence both the short and long-term outcome of transplanted kidneys. Data collected retrospectively on all 129 cadaveric renal transplants performed between January 1991 and January 1993 within a single center were analyzed. 42 (32.55%) cases of acute renal failure (ARF) occurred during the immediate postoperative period and 28 patients required dialysis. When compared with immediate good allograft function, DGF was associated with previous failed transplant (7/15 vs 35/114, p = 0.01), donor age (39.2 +/- 13 vs 30.1 +/- 12 years, p = 0.01), and episodes of collapsus of the donor (11/25 vs 31/104, p < 0.01). The graft function of the recipient was not correlated with the serum creatinine of the donor. There was no apparent relationship between the cold ischemia or the anastomosis time and the occurrence of DGF. One-year patient and graft survival were similar in the two groups (respectively for the group ARF and without ARF: 96.4% and 96.5%; 88.8% and 89%), but patients with DGF had higher serum creatinine values at 12 months post DGF (185.6 +/- 44.8 mumol/l vs 157.5 +/- 30.8 mumol/l, p = 0.06). This study suggests that DGF is related to the characteristics of the donor graft and is more frequently encountered in previously transplanted recipients.

Acute Kidney Injury↗
PubMed1993

Antigenicity and immunogenicity of modified synthetic peptides containing D-amino acid residues. Antibodies to a D-enantiomer do recognize the parent L-hexapeptide and reciprocally.

The effect of introducing D-amino acid residues in an hexapeptide was examined both at the antigenic and immunogenic levels. A series of D-analogues of the model peptide of sequence IRGERA corresponding to the COOH-terminal residues 130-135 of histone H3 were produced. Four analogues contained a single change of an L-residue by the corresponding enantiomer, one peptide contained two D-residues and another one contained only D-residues (D-enantiomer). A peptide analogue was also synthesized in which the 2 Arg residues were replaced by Lys residues. The parent peptide and peptide analogues were injected into mice after covalent coupling to small unilamellar liposomes containing monophosphoryl lipid A as adjuvant. The substitution of L-Arg131 to Lys or D-Arg was found to change neither the antigenic nor immunogenic properties of the resulting peptides. In contrast, the substitution of Glu133, Arg134, and Ala135 by the respective enantiomers drastically altered the antigenicity of the modified peptides. Each of the six D-analogues induced an immune response with an unusually high level of IgG3 antibodies. The D-enantiomer produced IgG3 antibodies which reacted with the homologous peptide as well as with the all L-peptide and the parent protein H3 in solution but not with analogues containing one or two D-residues only. IgG3 antibodies produced against the all L-peptide reacted with the free all D-peptide but not with the other analogues containing D-residues in position 133, 134, and 135.

Amino Acid Sequence↗