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R Wank

Publications and source records attributed to R Wank.

At least 19 recordsLinked to original sources
PubMed2006

Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10.

Several microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n=72), random controls (n=225) and hospital-patient controls (n=36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.

Adult↗
PubMed2006

Do dogs harbour risk factors for human breast cancer?

We ask consulting patients regularly whether they keep pets in order to identify zoonotic factors. It became apparent that patients with breast carcinoma (N=69) owned significantly more often dogs but not cats compared to age matched female controls. We compared the frequencies of dog and pet ownership with data from public available statistics on women (N=1320) of the same age group in Bavaria. The most striking result was that more than twice the number of patients kept dogs permanently in the last 10 years and at the time of interrogation as compared to control individuals at the time of interrogation (p=0.0000003, relative risk 3.5). Further internet search on the morbidity of breast carcinoma showed in dogs a protracted course of disease and metastases into lung, liver and bones, resembling the course of disease in human breast cancer. In contrast with this, breast cancer presented in cats a dramatically short course and the main but unusual location of metastasis presents in the hind legs. A recent publication in Norway reported on a high frequency (53.3%) of breast carcinomas in 14,401 investigated dogs. Which transmissible factor or factors come into question? Variants of the mouse mammary tumor virus (MMTV) can productively replicate in human cells and in different animals, including dogs. Many investigators, but not all, could identify MMTV-like sequences in sporadic human breast cancer. MMTV or MMTV-like sequences have not been investigated in canine breast carcinomas until now. It is also conceivable that other microbes from the dog, for example bacteria, could participate in the first steps of carcinogenesis in human. It was recently shown that bartonella species promote vascularization and prevent apoptosis of infected cells with the same methods as helicobacter pylori. Our considerations require further research. Epidemiologic cohort studies and identification of potential carcinogenic microbial factors will prove or disprove our hypothesis that risk factors from dogs could contribute to the carcinogenesis of human breast cancer.

Animals↗
PubMed2001

Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells.

Chemokines and their receptors control the emigration of leukocytes during inflammation. The role of the RANTES (regulated on activation normal T-cell expressed and secreted) receptors CCR1 and CCR5 in the selective recruitment of monocytes, T(H)1-like T-cell clones, and peripheral T cells enriched for CD45RO(+) "memory" cells were tested in a system in which arrest under flow conditions is triggered by RANTES immobilized to activated endothelium. With the use of selective nonpeptide receptor antagonists or blocking antibodies, it was found that the RANTES-induced arrest of these cells was mediated predominantly by CCR1. In contrast, CCR5 mainly contributed to the spreading in shear flow, and both CCR1 and CCR5 supported transendothelial chemotaxis toward RANTES. The data in this study reveal specialized roles of apparently redundant receptors in distinct steps of leukocyte trafficking and suggest that not all receptors currently used to define mononuclear cell subsets are involved in their direct recruitment from the circulation.

Cell Adhesion↗
PubMed2001

Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II.

The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.

CCR5 Receptor Antagonists↗
PubMed2001

HLA-DR53 molecules restrict glutamic acid decarboxylase peptide presentation to T cells of a Type I diabetes patient: specification of the trimolecular HLA-peptide/T-cell receptor complex.

AIMS/HYPOTHESIS: Our aim was to define the molecular specificity of glutamic acid decarboxylase-specific T-cells isolated from a patient (patient 40) with recent onset Type I (insulin-depent) diabetes mellitus. METHODS: The peptide epitope was defined using synthetic peptides to identify the minimal sequence required for T-cell activation and to determine the amino acids that contribute either to MHC binding or T-cell receptor signaling. The MHC class II-restricted peptide presentation was determined using a panel of allogeneic antigen-presenting cells and murine fibroblast-cell lines transfected to express individual human class II alleles and by blocking studies with monoclonal antibodies. The T-cell receptor was also molecularly characterized. RESULTS: Despite that patient 40 carries high-risk alleles of the DRB1 and DQB1 loci, his T-cells recognize a glutamic acid decarboxylase-derived peptide in association with class II, DR53, molecules. Although anchor residues for DR53 molecules have not yet been determined, it was possible to model epitope binding based on sequence comparisons with other class II molecules associated with susceptibility or protection for Type I diabetes. CONCLUSION/INTERPRETATION: The complete molecular specification of the MHC-peptide ligand and the T-cell receptor complex of glutamic acid decarboxylase-specific T-cells will enable analysis of strategies designed to alter T-cell function. For example, the role of altered peptide ligands or T-cell receptor-specific peptides can be studied using a model whose components reflect the natural affinities of MHC-peptide and T-cell receptor-ligand interactions selected in response to this important autoantigen.

Amino Acid Sequence↗
PubMed1999

Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors.

Neurotrophins, such as neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), are potent regulators of neuronal functions. Here we show that human immune cells also produce NT-3 mRNA, secrete BDNF, and express their specific receptors trkB and trkC. The truncated trkB receptor, usually expressed in sensory neurons of the central nervous system, was also constitutively expressed in unstimulated Th cells. Full-length trkB was detectable in stimulated PBMC, B cell lines, and Th1, but not in Th2 and Th0 cell clones. Clonally restricted expression was also observed for trkC, until now not detected on blood cells. The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC, whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression. Microbial Ags, which influence the Th1/Th2 balance, could therefore modulate the neurotrophic system and thereby affect neuronal synaptic activity of the central nervous system.

Brain-Derived Neurotrophic Factor↗
PubMed1998

HIV-1-infected long-term slow progressors heterozygous for delta32-CCR5 show significantly lower plasma viral load than wild-type slow progressors.

OBJECTIVE: Patients heterozygous for delta32-CCR5 may have a delayed progression of HIV-1 disease. The aim of the present study was to investigate the influence of CCR5/delta32-CCR5 genotype in long-term slow progressors using plasma viral load as a marker of disease progression. DESIGN: We analyzed 70 long-term slow progressors (diagnosis > 8 years previously; CD4 count > 500/microl; asymptomatic, never received antiretroviral therapy) for CCR5 genotype, plasma viral load, and lymphocyte subsets. Distribution of CCR5 genotypes was compared with a cohort of 61 multiply exposed noninfected individuals and a group of 336 control subjects. All study participants were white. METHODS: CCR5 genotype was determined by polymerase chain reaction (PCR) amplification. Plasma viral load was quantified by branch DNA hybridization, lymphocyte subsets were determined by fluorescence-activated cell sorter (FACS) analysis. The Mann-Whitney-Wilcoxon test was used for statistical analyses. RESULTS: The frequency of the CCR5/delta32-CCR5 heterozygote genotype was higher in long-term slow progressors (37.1%) and multiply exposed noninfected individuals (26.2%), compared with the control group (15.8%). In addition, plasma viral load was found to be significantly lower in CCR5/delta32-CCR5 heterozygous long-term slow progressors (median < log10 2.70; 53.8% < log10 2.70; 0% > log10 4.0) relative to that seen in CCR5/CCR5 long-term slow progressors (median log10 3.64; 22.7% < log10 2.70; 22.7% > log10 4.0). CONCLUSIONS: These findings strengthen the hypothesis of a favorable influence of CCR5/delta32-CCR5 genotype on progression of HIV-1 infection. Therefore, evaluation of CCR5 genotype might influence antiretroviral therapy strategies in early stages of HIV-1 infection.

Cohort Studies↗
PubMed1998

Epstein-Barr virus-infected B cells of males with the X-linked lymphoproliferative syndrome stimulate and are susceptible to T-cell-mediated lysis.

Primary infection with the Epstein-Barr virus (EBV) results in fatal infectious mononucleosis in up to 70% of males affected by the X-linked lymphoproliferative syndrome (XLP). This rare disease is often associated with diverse natural killer (NK)-, B- and T-cell deficiencies. We describe experiments testing whether the B lymphocytes of affected males play a role in the pathogenesis of XLP due to a low susceptibility to T-cell-mediated immunity. Using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry we detected in these B cells the expression of viral proteins EBNA-1, EBNA-2, EBNA-3A, EBNA-3C, LMP-1 and LMP-2A, which provide targets for cytotoxic T cells. Major histocompatibility complex (MHC) class I, MHC class II and the B7 costimulatory molecule were present on the cell surface. Accordingly, the EBV-infected B cells were lysed in 51Cr-release assays by T lymphocytes sharing MHC determinants with the targets. This MHC-restricted and specific lysis was confirmed in competition experiments using MHC-specific monoclonal antibodies (MAbs) and synthetic peptides. XLP-derived LCLs could also induce MHC class I-restricted memory and cytotoxic T lymphocytes. Thus, these XLP-derived B cells resembled normal LCIs in vitro with respect to induction of EBV-specific cytotoxic T cells (CTL), the ability to present EB viral antigens and the susceptibility to EBV-specific and MHC-restricted CTL-mediated killing. The failure of the immune system to eliminate these virus-infected B cells in XLP is clearly not caused by a B-cell-specific defect.

Antigens, Viral↗
PubMed1998

Lack of protection from HIV infection by the mutant HIV coreceptor CCR5 in intravenously HIV infected hemophilia patients.

The CCR5 chemokine receptor is an important coreceptor for macrophage-tropic HIV strains. Homozygous carriers of the mutated CCR5 receptor with a 32 bp deletion (delta 32-CCR5) are highly protected against HIV infection. A protective effect has also been described for heterozygous individuals carrying both mutated and wildtype CCR5 receptors. We compared the frequency of the mutated delta 32-CCR5 HIV coreceptor in HIV positive patients infected by sexual contact (N = 160) with intravenously HIV infected hemophilic patients (N = 84) and HIV negative individuals (N = 421). We found no protective effect of delta 32-CCR5 HIV coreceptor in hemophilic patients (p = 0.0134). If proteins of plasma concentrates would be responsible for facilitating the entry of HIV macrophages by upregulation of the CCR5 wildtype receptor it would be of therapeutical interest to identify the responsible plasma proteins.

Female↗
PubMed1998

Recurrent herpes simplex virus-induced erythema multiforme: different HLA-DQB1 alleles associate with severe mucous membrane versus skin attacks.

In some individuals a local herpetic lesion precipitates a generalized inflammation of the skin, designated as erythema multiforme (EM). We determined the frequencies of the immune response genes of the HLA system by molecular HLA class II typing in 46 patients with EM and in many of their family members. Allele frequencies were correlated with disease form and disease-inducing factors. We found that specific complications of HSV infection occur preferentially in patients with certain HLA-DQB1 alleles. In 21 of the 46 patients EM was induced by recurrent HSV infection. Thirteen of these patients showing only minor or no involvement of mucous membranes had the HLA allele DQB1*0302 (phenotype frequency 61.9% versus 18.8% in controls, p corr = 0.0008) and all three patients with major involvement of mucous membranes had the rare HLA allele DQB1*0402 (phenotype frequency in controls 6,4%, p corr = 0.017).

Alleles↗
PubMed1997

Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients.

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.

Alleles↗
PubMed1993

The multifactorial nature of MHC-linked susceptibility to insulin-dependent diabetes.

Several lines of evidence suggest that major histocompatibility complex (MHC)-linked susceptibility to insulin-dependent diabetes mellitus (IDDM) is not restricted to the presence or absence of any single gene product. The existence of population-specific haplotypes associated with IDDM supports the concept that distinct combinations of MHC alleles interact synergistically to induce disease when other environmental and genetic factors are present. MHC-controlled peptide transport and binding to MHC molecules as well as the levels of MHC class I and class II expression in the thymus and pancreatic beta cells may also play significant roles in the outbreak of IDDM. These intrinsic factors shape the T-cell receptor (TCR) repertoire during T-cell ontogeny in the thymus and later influence the efficiency of potentially autoreactive T cells in the periphery. Several extrinsic factors, such as viruses or dietary proteins, may be directly involved in the TCR/MHC interaction at the cell surface; furthermore viruses can alter the regulatory mechanisms of peptide/MHC interaction and expression. We propose that these intrinsic and extrinsic factors need not be mutually exclusive and might even be interdependent: a given virus may act deleteriously only when certain autoreactive T cells and combinations of MHC alleles are present in the individual. IDDM would develop if pathogenic T-cells are activated and an appropriate target MHC/peptide is expressed in pancreatic beta cells. Future knowledge of the host-virus relationships influenced by the MHC genes, the function of their encoded proteins and the polymorphic gene structure of well-established susceptibility MHC haplotypes will help delineate an overall picture of this issue.

Animals↗