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Biomedical subjects

H H Peter

Publications and source records attributed to H H Peter.

At least 109 records · Page 6Linked to original sources
PubMed1996

Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings.

Peripheral blood lymphocytes (PBL) and alloreactive T cell lines of two male infants born to consanguinous parents and presenting with severe combined immunodeficiency (SCID) showed a pronounced deficiency in T cell activation. Although phenotypically normal, the proliferative response of the childrens' T cells was strongly reduced but could be improved by the addition of interleukin-2 (IL-2). Furthermore both childrens' T cells were unable to produce the cytokines IL-2, interferon-gamma (IFN-gamma), IL-4 and tumor necrosis factor-alpha (TNF-alpha). This multiple cytokine production deficiency could not be restored by IL-2 or co-stimulatory signals provided by antigen-presenting cells (APC). Moreover, mRNA for IL-2 and IFN-gamma could not be detected. In contrast, expression of the activation-dependent cell surface markers CD25 and CD69 was within normal limits. To determine whether the functional defect of the patients' T cells was due to the absence or abnormal binding of transcription factors involved in cytokine gene expression, electrophoretic mobility shift assays were used to examine the DNA binding of AP-1, Oct, CREB, SP1, NF-kappa B and the nuclear factor of activated T cells (NF-AT) to their respective response elements in the promoter of the IL-2 gene. Whereas AP-1, NF-kappa B, Oct, CREB and SP1 displayed normal binding activities in nuclear extracts, the binding of NF-AT to its IL-2 promoter response element was barely detectable both before and after T cell stimulation. Our results strongly suggest that this NF-AT/DNA binding defect is responsible for the multiple cytokine deficiency and the SCID phenotype observed in the two infant brothers.

Antigen-Presenting Cells↗
PubMed1996

Antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis: a prospective study.

To investigate a possible relationship between the presence of antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), antinuclear antibodies (ANA), complement, disease activity and disease severity, 111 clinically well-documented RA patients were studied prospectively for ANCA, RF, ANA, C-reactive protein (CRP), total haemolytic complement (CH50) and complement split product C3d. Disease activity and severity were also assessed clinically, as well as anamnestically, using the Hannover Activity of Daily Living Questionnaire, the functional Steinbrocker grades, and numeric and verbal rating scales. At a serum dilution of 1:50, 20% of the 111 sera showed predominantly an atypical perinuclear staining pattern. There was no correlation between ANCA positivity and serological markers, disease activity and disease severity. Regarding previous therapies with disease-modifying antirheumatic drugs, ANCA+ patients took sulphasalazine significantly more often than ANCA- patients.

Activities of Daily Living↗
PubMed1996

Complement activation by C-reactive protein on the HEp-2 cell substrate.

The complement (C) activation by C-reactive protein (CRP) in acute-phase sera is routinely tested in our laboratory by means of an indirect immunofluorescence method (C3-IFT) on rat kidney sections. This C3-IFT assay is based on the binding of CRP to the renal tissue followed by the fixation of C4 and C3 components to distinct vessel-associated medullary structures as a result of CRP-mediated C activation in vitro. While the activation cascade leading to the deposition of C4 and C3 could previously be deduced experimentally, we were unable as yet to visualize CRP and the components of the C1 complex on kidney sections when testing patients' sera by indirect immunofluorescence. In an attempt to analyze the mechanisms of unexpectedly negative C3-IFT results (e.g. bacterial endocarditis) we employed monolayers of fixed HEp-2 cells which have previously been shown to be a suitable substrate for CRP binding. By incubating purified native CRP supplemented with normal human serum as a source of C we detected the C components Clq, Clr, Cls, C4 and C3 in the same speckled immunofluorescent pattern on HEp-2 cell nuclei as described characteristically for CRP binding. The serial activation steps from CRP up to C3 could also be followed on HEp-2 cells using C3-IFT-positive acute-phase sera. However, certain C3-IFT-negative acute-phase sera showed an arrest between Cls and C4 of the CRP-mediated C activation cascade. HEp-2 cells can thus be used to monitor the process of autologous C activation initiated by endogeneous CRP in patients' sera. In contrast to native CRP, urea-modified CRP (mCRP) did not bind to HEp-2 cell nuclei, but was detected in association with distinct filamentous cytoplasmic structures. Unlike its native counterpart, binding of mCRP was not followed by a deposition of C components.

Animals↗
PubMed1996

Novel spirodihydrobenzofuranlactams as antagonists of endothelin and as inhibitors of HIV-1 protease produced by Stachybotrys Sp. I. Fermentation, isolation and biological activity.

Six novel spirodihydrobenzofuranlactams I - VI (1 - 6) and a related spirodihydrobenzofuranalcohol, the previously described natural compound L-671,776 (7), were isolated from cultures of two different Stachybotrys species. These secondary metabolites showed antagonistic effects in the endothelin receptor binding assay and inhibited HIV-1 protease. Both biological activities are novel for L-671,776 (7). The pseudosymmetric spirodihydrobenzofuranlactam VI (6) is the most potent representative of this class of compounds exhibiting IC50 values of 1.5 microM in the ET-A receptor binding assay and 11 microM in the HIV-1 protease inhibition assay.

Animals↗
PubMed1996

Further minor metabolites of staurosporine produced by a Streptomyces longisporoflavus strain.

From the staurosporine producing strain R-19 Streptomyces longisporoflavus various minor metabolites were isolated: They include new compounds with a keto function at carbon 4' of staurosporine and several metabolites related to TAN-1030A. The new structures were elucidated by spectroscopic methods, mainly 1H NMR and 13C NMR and by comparison with TAN-1030A. The new compounds inhibited protein kinase C with IC50 values in the micromolar range with the exception of those compounds that are alkylated at the lactam nitrogen.

Alkaloids↗
PubMed1996

Magnetic resonance imaging (MRI) for detection of active sacroiliitis--a prospective study comparing conventional radiography, scintigraphy, and contrast enhanced MRI.

OBJECTIVE: Sacroiliitis is often difficult to diagnose in the absence of radiographic alterations. For the diagnosis of active sacroiliitis, plain radiography, scintigraphy, and contrast enhanced magnetic resonance imaging (MRI) were evaluated in a prospective study. METHODS: In 44 consecutive patients with complete clinical and laboratory evaluation, plain radiographs, quantitative sacroiliac (SI) scintigraphy, and MRI were performed to evaluate the contribution of these imaging techniques to the diagnosis of active sacroiliitis. Scintiscanning and MRI were done in 20 control subjects to define the normal range of imaging findings. We determined the sensitivity and specificity for each imaging method using a reference standard based on clinical symptoms of inflammatory low back pain with or without laboratory signs, and on clinical and radiographic followup during 1.5-2.5 years to confirm diagnosis. RESULTS: MRI was most sensitive (95%) and superior to quantitative SI scintigraphy (48%) or conventional radiography (19%) for the detection and confirmation of active sacroiliitis. For the assessment of inflammatory signs, MRI had higher specificity (100%) than scintigraphy (97%) or plain radiography (47%). At repeat MRI after 2-30 months, there was persistent pathologic signal intensity in the subchondral bone area despite clinically successful antiinflammatory drug therapy. CONCLUSION: For the assessment of active changes in the synovial portion and the subchondral bone marrow, contrast enhanced MRI is superior to quantitative SI scintigraphy or conventional radiography. MRI picks up an additional 75% of early cases not diagnosed by plain radiography. Scintigraphy is only of limited value. Persistent pathologic signal intensity in the subchondral bone marrow seems to be closely associated with previous inflammatory episodes, thus limiting specificity of MRI for active sacroiliitis. Based on our findings we suggest an algorithm for the evaluation of patients with suspected active sacroiliitis.

Adolescent↗
PubMed1995

Human ribosomal protein L7 inhibits cell-free translation in reticulocyte lysates and affects the expression of nuclear proteins upon stable transfection into Jurkat T-lymphoma cells.

Eucaryotic ribosomal protein L7 carries a 'Basic-Region-Leucine-Zipper (BZIP)'-like region which mediates high-affinity binding to mRNA and 28S rRNA and formation of homodimers [P. Hemmerich et al. (1993) Nucleic Acids Res. 21, 223-231). Its biological function is unknown as yet and no direct L7-equivalent in procaryotes has been found. In this report we show that eucaryotic L7 specifically inhibits the cell-free translation of reporter mRNAs. The interaction of L7 with mRNA is an essential step in this reaction which is inhibitable by antibodies directed against the BZIP-like region of L7, and by competitors of mRNA binding. L7-mediated inhibition of cell-free translation of polyA+ RNA from Jurkat T-lymphoma cells is selective in that the synthesis of a major 46 kD protein is suppressed. Upon stable transfection of L7 cDNA into Jurkat lymphoma cells two major proteins disappear, namely one nuclear protein and one which associates with the nucleus. Our data suggest a regulatory role of protein L7 in the eucaryotic translation apparatus.

Amino Acid Sequence↗
PubMed1995

Activated CD4+ and CD8+ T-cell subsets in Wegener's granulomatosis.

Several lines of evidence argue in favour of an involvement of T cells in the pathogenesis of Wegener's granulomatosis (WG). These include the presence of highly specific IgG autoantibodies to proteinase 3, perivascular T-cell infiltrates and elevated amounts of soluble interleukin-2 (IL-2) receptors in patient's serum. In order to further address this question we evaluated by double immunofluorescence and flow cytometry the expression of several cell surface molecules associated with T-cell activation. As compared to healthy controls (n = 15), the CD4+ subset was significantly diminished, while the percentage of CD8+ T cells was elevated in WG patients (n = 24). Within the CD4+ T-cell subset we found a highly significant increase in activation/memory markers (CD25, CD29, HLA-DR). Within the CD8+ T-cell subset the expression of CD11b, CD29 and CD57 was significantly elevated, while the expression of VD28 was reduced. The use of 10 V beta-, 1 V alpha- and 1 V gamma-specific monoclonal reagents failed to reveal any significant bias in the peripheral T-cell receptor V-gene repertoire of WG patients. There was also no correlation between T-cell activation markers and laboratory parameters [C-reactive protein (CRP), ESR], disease duration or therapy. A significant correlation was found only for the degree of organ involvement and the increase in CD4+ T cells coexpressing HLA-DR, as well as the increase in CD57 expression on CD8+ T cells. In conclusion, both CD4+ and CD8+ T-cell subsets were activated in WG. Cytotoxic CD8+CD57+CD11b+CD28- T cells may directly contribute to damage of vascular endothelium.

Adult↗
PubMed1995

Significance of antibodies to cardiolipin in unselected patients with systemic lupus erythematosus: clinical and laboratory associations. The SLE Study Group.

In a multicentre study anticardiolipin antibodies of the IgG and IgM isotypes were measured by a solid phase enzyme immunoassay in 368 patients with systemic lupus erythematosus (SLE) who were not selected on the basis of features of antiphospholipid syndrome. Clinical and laboratory associations of increased levels of anticardiolipin antibodies were evaluated. IgG and IgM antibodies to cardiolipin were documented in 224 (60.9%) and 128 (34.8%) patients, respectively. Regarding the symptoms of antiphospholipid syndrome, elevated amounts of anticardiolipin IgG were significantly associated with spontaneous abortion (P < 0.001), thrombocytopenia (P < 0.01), livedo reticularis (P < 0.01) and a positive direct Coombs test (P < 0.05), but not with thrombosis or central nervous system diseases such as epilepsy and psychosis. IgM antibodies to cardiolipin were associated with a positive direct Coombs test (P < 0.01), but with no other symptom of antiphospholipid syndrome. The predictive values of anticardiolipin antibody determinations in unselected SLE patients were poor for all features of antiphospholipid syndrome because of high proportions of false-positive and false-negative results. As for other manifestations of SLE, positive correlations between raised antibodies to double-stranded DNA and the occurrence of anticardiolipin antibodies of the IgG isotype were observed, and anticardiolipin IgM was negatively associated with nephritis.

Adolescent↗
PubMed1995

Common variable immunodeficiency (CVID) and MxA-protein expression in blood leucocytes.

The underlying immunopathogenic mechanism of CVID has been suspected to involve a chronic viral infection or an autoimmune condition. However, formal proof of viral infection is lacking. Measurement of MxA-protein in leucocyte lysates is a sensitive test for evaluating the activation of the host's interferon system. Both viral infections and autoimmune diseases such as systemic lupus erythematosus (SLE) strongly induce MxA-protein in peripheral leucocytes. We therefore examined 15 patients with longlasting hypogammaglobulinaemia for MxA-protein induction in vivo: 13 patients suffered from CVID, one from hyper-IgM syndrome, and one patient had chronic B lymphocytic leukaemia associated with immunoglobulin deficiency and chronic papilloma virus infection (condylomata accuminata). Only the latter patient exhibited a strong MxA-protein expression; two CVID patients were borderline positive, and the remaining 12 patients including the hyper-IgM syndrome were MxA-protein-negative. There was no relationship between MxA expression and low CD4/CD8 ratios or increased CD8/CD57+ T cell counts, although both conditions are often observed in CVID as well as in chronic viral infections. When exposed in vitro to interferon-alpha (IFN-alpha), peripheral blood leucocytes of four MxA-negative patients were capable of producing normal amounts of MxA-protein. Taken together, these results argue against a viral or autoimmune pathogenesis of CVID.

Adult↗
PubMed1995

T cell lines recognizing the 70-kD protein of U1 small nuclear ribonucleoprotein (U1snRNP).

In sera of patients with mixed connective tissue disease (MCTD) high titres of IgG autoantibodies to U1snRNP-specific proteins (70 kD, A, C) are found, suggesting an antigen-driven and T-cell-dependent process. In order to establish U1snRNP-specific T cell lines we cultured under various culture conditions mononuclear cells from MCTD patients and healthy donors with a highly purified UsnRNP preparation from HeLa cells. Nine T cell lines were established by limiting dilution cloning from two MCTD patients and five T cell lines from a healthy individual. All T cell lines expressed the TCR alpha beta/CD3 complex. Surprisingly, most of the T cells lines exhibited the CD8 phenotype. Irrespective of this phenotype, all T cell lines showed a proliferative response to an N-terminal part (aa 51-195) of recombinant U1-specific 70-kD protein. One CD8+ T cell clone exhibited cytotoxic activity against an autologous B cell line pulsed with snRNP or recombinant fragments (aa 51-95 and aa 51-88). Interestingly, two T cell lines proliferated in response to four recombinant polypeptides representing different parts of the U1snRNP 70-kD protein. Since regions of sequence homology are distributed over the 70-kD molecule, it is suggested that conserved motifs may be recognized by the T cell lines.

Adult↗
PubMed1995

Autoantibodies against eukaryotic protein L7 in patients suffering from systemic lupus erythematosus and progressive systemic sclerosis: frequency and correlation with clinical, serological and genetic parameters. The SLE Study Group.

Recent studies have shown that sera of patients suffering from systemic autoimmune diseases contain autoantibodies directed against the eukaryotic ribosomal protein L7 [1]. In the present study we screened a large panel of sera from patients with systemic lupus erythematosus (SLE) for the presence of anti-L7 autoantibodies and their relationship to clinical, serological and genetic parameters of SLE. By means of an ELISA employing recombinant protein L7 as antigen we detected anti-L7 autoantobodies in 172 of 506 SLE sera (34%). Negative correlations were observed between the presence of anti-L7 autoantibodies, serum IgG levels and proteinuria; a potentially positive relationship existed with lung fibrosis. In order to analyse further this possibility we screened sera of 129 patients suffering from progressive systemic sclerosis (PSS) for anti-L7 reactivity; 45 of these patients had lung fibrosis. Of the PSS patients, 41% exhibited anti-L7 autoantibodies, but positive reactions were evenly distributed among patients with and without lung fibrosis. Protein L7 thus represents a major autoantigen of systemic autoimmune diseases, but does not so far define a distinct subpopulation of patients.

Autoantibodies↗
PubMed1995

Autoantigenic epitopes on eukaryotic L7.

Ribosomal protein L7 has been established recently as a novel autoantigen representing a frequent target for autoantibodies from patients with systemic autoimmune diseases. Up to 75% of systemic lupus erythematosus (SLE) patients and 50% of mixed connective tissue disease (MCTD) and progressive systemic sclerosis (PSS) patients produce antibodies in vitro translated L7 and form immunoprecipitable complexes. In this study the B cell response to protein L7 was investigated with respect to the immunogenic determinants recognized by autoantibodies. Eighteen truncated fragments of protein L7 were generated as recombinant fusions with glutathione-S-transferase and examined by immunoblotting for their reactivity with sera from patients suffering from systemic rheumatic diseases. Anti-L7 antibodies target three major nonoverlapping autoepitopes. Two epitopes reside in the highly conserved C-terminal part of the protein, whereas the N-terminal autoepitope is not conserved during evolution. The N-terminal epitope comprises 24 amino acid residues. Ten amino acid resides of this epitope are shared with the BZIP-like RNA binding domain of protein L7. Autoantibodies recognizing this epitope crossreact with the corresponding region of a L7 homologue, namely ribosomal protein L7 (RPL7) from Dictyostelium discoideum. This indicates that amino acid residues 14VPE...KKR22, which are conserved between humans and fungi, contribute essentially to the formation of autoantibody-autoantigen complexes.

Amino Acid Sequence↗
PubMed1995

Two novel cationic staphylococcal proteins induce IL-2 secretion, proliferation and immunoglobulin synthesis in peripheral blood mononuclear cells (PBMC) of both healthy controls and patients with common variable immunodeficiency (CVID).

Two cationic proteins, a neutral phosphatase (NP-tase) and a 70-kD protein (p70) were isolated from Staphylococcus aureus by ion exchange chromatography. We compared their properties to those of the well established B cell mitogen of whole, fixed Staph. aureus strain Cowan I cells (SAC). Both purified proteins were able to induce immunoglobulin synthesis in PBMC cultures of healthy donors. NP-tase and p70 also induced immunoglobulin synthesis of PBMC from those patients with CVID who were also responsive to SAC plus IL-2 stimulation. Immunoglobulin synthesis in response to NP-tase and to p70 was time- and dose-dependent and could be inhibited by addition of specific antibodies against the proteins. In contrast to SAC, no addition of exogenous IL-2 was necessary to obtain maximal immunoglobulin synthesis induced by NP-tase or p70. However, neither protein was able to induce immunoglobulin synthesis in B cell-enriched cultures. High amounts of IL-2 were found in supernatants of PBMC from healthy donors following stimulation with low concentrations of NP-tase or p70, and this was associated with vigorous lymphocyte proliferation. Both proteins behave like typical antigens, and not like lectins or superantigens, since an NP-tase-stimulated T cell line showed an antigen-specific, MHC-restricted secondary response. In addition, no preferential T cell receptor V beta chain usage was found with eight V beta-specific MoAb. It is likely that the two proteins induce antigen-specific T cell activation, which is then followed by polyclonal activation of B cells via CD40 receptors and cytokine release.

Adult↗