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Biomedical subjects

Reinhold E Schmidt

Publications and source records attributed to Reinhold E Schmidt.

At least 19 recordsLinked to original sources
PubMed2006

Gene and protein characteristics reflect functional diversity of CD56dim and CD56bright NK cells.

Recent findings underline the role of NK cell subsets in regulating adaptive immunity. To define characteristics of NK cell subpopulations, purified CD56(dim) and CD56(bright) NK cells were analyzed by using gene chip arrays covering more than 39,000 transcripts. Gene profiling revealed resting NK cells to differ in respect to 473 transcripts with 176 exclusively expressed in CD56(dim) and 130 solely in CD56(bright) NK cells. Results were compared with array analyses using mRNA obtained from activated CD56(dim) and CD56(bright) NK cells. In this approach, NK cell receptors, cytolytic molecules, adhesion structures, and chemokine ligands showed differential expression patterns in the two subpopulations. These data were validated using FACS, RT-qPCR, or cytokine bead array (CBA) techniques. Cytokines produced by CD56(dim) and CD56(bright) NK cells were determined using a protein array covering 79 different bioactive mediators. GDNF, IGFBP-1, EGF, and TIMP-2 were detected in both subsets. In contrast, IGFBP-3 and IGF-1 were mainly produced by CD56(dim), while GM-CSF, TARC, and TGFbeta3 were expressed by CD56(bright) NK cells. In summary, we report new characteristic features of CD56(dim) and CD56(bright) NK cells, further underscoring that they represent independent populations with functionally diverse capabilities. The information on NK cells generated in this study will help to define corresponding NK cell populations in other species that lack CD56 expression on NK cells, such as mice. This will subsequently lead to the establishment of suitable animal models for detailed analysis of NK cell populations in vivo.

Animals↗
PubMed2006

Host chemokine (C-C motif) ligand-2 (CCL2) is differentially regulated in HIV type 1 (HIV-1)-infected individuals.

Several cytokines and chemokines including chemokine (C-C motif) ligand-2 (CCL2) are induced in HIV-1 infection. However, the impact of HIV-1 viremia on CCL2 regulation is largely unknown. We utilized a DNA oligonucleotide microarray covering 110 inflammatory genes. Five genes were induced by at least 2-fold in PBMCs of HIV-1 viremic (>100,000 RNA copies ml(-1)) as compared with aviremic (<50 RNA copies ml(-1)) individuals. These genes were CCL2, CXC chemokine ligand-10, IFN-gamma, GTP-cyclohydrolase-1 and C-C chemokine receptor-1. In addition to microarray data verification by real-time PCR, analysis of independent patient samples revealed a similar expression pattern. CCL2 was the most strongly regulated gene at mRNA level and its serum concentration was significantly elevated in viremic compared with aviremic and HIV-1 seronegative controls, indicating a positive correlation between viremia and CCL2. Flow cytometric studies demonstrated a higher percentage of CCL2-expressing CD14(+) monocytes in viremic compared with aviremic individuals. These results suggest a highly restricted modulation of host inflammatory gene response by HIV. Genes up-regulated in the viremic state, in particular CCL2, presumably serve as potential enhancing factors in HIV-1 replication, represented by high viral load in HIV-1 viremic patients. Inhibition of increased CCL2 production could provide a new therapeutic intervention in HIV-1 infection.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype.

Gilbert's disease leads to intermittent non-hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV-treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (-66C) and UGT1A7 (-57G) promoter variants, and UGT1A7(129K/131K). ATV treatment increased median bilirubin levels from 10 to 41 micromol/L (P = .001) with hyperbilirubinemia exceeding 43 micromol/L in 37%. Hyperbilirubinemia over 43 micromol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3-66C, UGT1A7-57G, and UGT1A7(129K/131K), although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 micromol/L) to 41% to 46.1% (43 to >85 micromol/L), and 100% (>85 micromol/L). All six patients with hyperbilirubinemia greater than 85 micromol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion, the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy.

Adult↗
PubMed2006

Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice.

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody-induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a--produced by and acting on FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.

Anemia, Hemolytic, Autoimmune↗
PubMed2005

Fc receptors and their interaction with complement in autoimmunity.

Genetic studies in mice indicate a crucial role for Fc receptors (FcR) in antibody-mediated autoimmune diseases. Like other immune regulatory receptor pairs, the FcR system is constituted by activating and inhibitory receptors that bind the same ligand, the Fc portion of Ig. Analyses of animal models have shown that the inhibitory Fc receptor, FcgammaRIIB can suppress antibody-mediated autoimmunity, whereas activating-type FcR, such as FcgammaRIII promote disease development. This review summarizes recent advances of FcR, as obtained from gene deletion studies in mice, and highlights the importance of factors that interact with FcR in autoimmunity. There is emerging evidence for an indispensable role of the complement component C5a in the regulation of FcR and the sensing of FcR-dependent effector cell responses. On the other hand, FcR might be alternatives to serum complement in the generation of C5a at sites of inflammation. Thus, FcR and complement interact with each other at the level of C5a by linking regulatory events with effector cell activities in autoimmunity. This connecting pathway is now proposed to be a promising new therapeutic target for the treatment of inflammation and autoimmune disease in both mice and humans.

Animals↗
PubMed2005

Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia.

OBJECTIVE: To describe the efficacy and change in lipid profile in patients with severe hyperlipidemia after switch to an atazanavir-containing highly active antiretroviral therapy regimen. DESIGN AND METHODS: Open-field, 24-week, prospective observational cohort study including 33 HIV-infected, antiretroviral-experienced patients with hyperlipidemia. Changes in lipid profiles were evaluated by analyses of triglycerides, total cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, and efficacy by HIV RNA and CD4 cell changes, both from baseline to week 24. RESULTS: A rapid and significant decrease of 46% (5.81 +/- 4 mmol/L vs. 3.16 +/- 2.6 mmol/L, P = 0.002) in triglyceride levels was shown. Similarly, a sustained improvement of 18% was observed in total cholesterol levels during the first 24 weeks after switching to atazanavir (6.45 +/- 1.9 mmol/L vs. 5.3 +/- 1.3 mmol/L, P = 0.001). After 24 weeks of treatment there was a significant decrease of 22% in non-HDL cholesterol (5.76 +/- 1.9 mmol/L at baseline vs. 4.5 +/- 1.3 mmol/L at 24 weeks; P = 0.003). HDL and LDL cholesterol profiles did not change significantly as did the viral load or CD4 cell count. CONCLUSIONS: Switching to atazanavir results in a significant improvement in HIV therapy-induced hyperlipidemia. A switch to atazanavir is proposed as a valuable option to improve atherogenic lipid profiles while maintaining virologic control.

Adolescent↗
PubMed2005

Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation.

Complement and FcgammaR effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcgammaRIIB, increased levels of activating FcgammaRIII, and highly induced FcgammaR-mediated TNF-alpha and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of G(i)-type G protein signaling in C5aR-mediated control of the regulatory FcgammaR system in vitro, and analysis of the various C5aR-, FcgammaR-, and G(i)-deficient mice verifies the importance of Galpha(i2)-associated C5aR and the FcgammaRIII-FcgammaRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcgammaRIII-positive cells into C5aR- and FcgammaRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Galpha(i2)-dependent signal for modulating the two opposing FcgammaR, FcgammaRIIB and FcgammaRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.

Animals↗
PubMed2005

Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB x NZW)F1 mouse.

OBJECTIVE: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing pathogenic IgG anti-double-stranded DNA (anti-dsDNA) autoantibodies are deposited in renal capillaries and initiate glomerulonephritis (GN) by the activation of complement and effector cells. In contrast, it has been demonstrated that the presence of IgM anti-dsDNA antibodies correlates negatively with the development of GN in SLE. The aim of this study was to determine whether anti-dsDNA antibodies of the IgM isotype protect against IC-mediated organ damage in SLE. METHODS: Lupus-prone (NZB x NZW)F(1) mice (females) were treated with murine monoclonal IgM anti-dsDNA antibodies. Treatment was delivered by subcutaneous injection at a dosage of 100 mug/week starting at 16 weeks of age (prophylactic) or at 24 weeks of age (therapeutic). RESULTS: Mice treated with IgM anti-dsDNA exhibited a delayed onset of proteinuria and a reduced degree of renal pathology, which resulted in significantly improved survival as compared with control mice. Serum concentrations of IgG anti-dsDNA antibodies were not significantly modified. However, glomerular deposition of ICs was markedly reduced in both treatment protocol groups. In contrast, higher amounts of IgG and IgM and increased expression of Fcgamma receptor were demonstrated in liver sections from the treated mice compared with the untreated mice, suggesting an enhanced clearance of soluble ICs from phagocytic cells of the reticuloendothelial system. CONCLUSION: These data demonstrate the efficacy of IgM anti-dsDNA treatment in inhibiting the pathologic changes of lupus in (NZB x NZW)F(1) mice. Lower glomerular IC deposition is associated with a reduced inflammatory response and impaired organ damage. The reduced frequency of GN in SLE patients who have IgM anti-dsDNA antibodies may therefore reflect a disease-modifying effect of this class of autoantibodies that has potential therapeutic implications. Our findings should encourage the development of new therapeutic modalities using IgM anti-dsDNA antibodies in humans with SLE.

Animals↗
PubMed2005

The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis.

OBJECTIVE: Mannose-binding lectin (MBL) enhances opsonization and activates complement. Dysfunctional alleles of MBL have been associated with low plasma concentrations of MBL and increased risk of systemic lupus erythematosus (SLE), but genotyping studies have shown inconsistent results. We performed case-control studies of the MBL polymorphisms in 2 Caucasian cohorts and a meta-analysis incorporating all published results of MBL genotyping in SLE to explore whether the MBL functional variants are associated with SLE. METHODS: MBL genotypes at 7 single-nucleotide polymorphisms were sequenced in 96 European American patients with SLE and 96 age-, race-, and sex-matched controls. MBL codons 52, 54, and 57 were genotyped in 285 German patients with SLE and 200 race-matched controls. Allele frequencies of all known variants were tallied for meta-analysis. RESULTS: Although there was a trend toward association with MBL polymorphisms in both patient cohorts evaluated, none of them was significantly associated with SLE on its own. Seventeen comparisons from 15 studies were included in the meta-analysis. Publication bias was excluded by Egger's regression test (P = 0.14). The overall odds ratio for MBL codon 54 variant B was 1.406 (95% confidence interval 1.221-1.608; P < 0.001). Stratification by ethnicity showed significantly increased odds ratios for association of the MBL codon 54 B variant with SLE in African, Asian, and Caucasian cohorts. CONCLUSION: Meta-analysis of all available studies on MBL polymorphisms and SLE shows that MBL variant alleles such as MBL exon 1 codon 54 B, promoter -550 L, and promoter -221 X are SLE risk factors. This association is robust and persists after incorporation of data from our 2 cohorts in which the association failed to reach significance.

Adult↗
PubMed2005

Mutual interference of HIV and natural killer cell-mediated immune response.

Natural killer (NK) cells represent important early effector cells in innate immune defense as they exert their functions without prior sensitization. They participate in regulation of innate and adaptive immune responses and hematopoiesis by producing various cytokines and chemokines. In addition, NK cells lyse virally infected and malignant cells raising them to multifunctional members of the first line of defense. Unlike other lymphocytes they lack specific antigen receptors. They rather bind cells using ubiquitous molecules and communicate via a pattern of receptors specific for MHC-I molecules with their counterparts. In general, successful binding of the receptors delivers an inhibitory signal to NK cells thus sparing the target cell from lysis. In contrast, down-regulated or altered MHC-I expression as frequently observed during virus infection or on malignant cells prevents ligation of inhibitory receptors and MHC-I paralyzing inhibition and thus inducing lysis of the target cell. In human immunodeficiency virus (HIV) infection NK cells are of central importance since they can combat viral infection itself and opportunistic pathogens like fungi and protozoa that usually spread during the course of HIV infection. However, various studies have reported alterations in HIV patients affecting NK cell numbers and functions that might negatively influence course and severity of the disease. This review will focus on the mutual interference of NK cells and the HI virus.

Cytotoxicity, Immunologic↗
PubMed2004

Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects.

OBJECTIVE: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. METHODS: : HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add NVP and/or HU to the triple NRTI backbone of zidovudine plus lamivudine plus abacavir. Primary endpoint was treatment failure, defined as having plasma HIV RNA levels > 50 copies/ml after week 24, or discontinuation of randomized treatment. Follow-up was 72 weeks. RESULTS: For the 229 subjects, median plasma HIV-1 RNA was 4.61 log10 copies/ml and median CD4 cell count was 269 x 10 cells/l. NVP users reached plasma HIV-1 RNA < 50 copies/ml more rapidly than subjects using no NVP (log-rank test; P = 0.011). In the as-treated analysis, 21.6% of subjects using NVP versus 48.8% using no NVP reached the primary endpoint (P = 0.013). In the intent-to-treat analysis, 83.3% of subjects using HU versus 73.0% using no HU experienced treatment failure (P = 0.060), while no difference was observed in the as-treated analysis (34.5 versus 36.7%). Differences in the intent-to-treat analysis were accounted for by toxicity: 52.6% of subjects using HU experienced toxicity leading to discontinuation of randomized treatment versus 28.7% of subjects using no HU. CONCLUSION: The use of NVP in addition to a triple NRTI regimen improved both short- and long-term antiretroviral efficacy. The use of HU significantly contributed to treatment failure because of toxicity.

Adult↗
PubMed2004

Immune restoration inflammatory syndromes: apparently paradoxical clinical events after the initiation of HAART.

Immune reconstitution occurs after initiation of highly active antiretroviral therapy in immunodeficient HIV-positive individuals. Unexpected deterioration of inflammatory disease and atypical clinical features resembling symptoms of autoimmune disease may arise. These atypical inflammatory disorders, synonymously summarized as immune reconstitution syndrome, immune restoration disease, and immune restoration inflammatory syndrome (IRIS), are caused by augmentation of inflammation during immune reconstitution in an immunocompromised host. These disorders have to be distinguished from intercurrent infection and rheumatic disease, respectively. Treatment of IRIS consists of elements for both potential differential diagnoses (ie, anti-inflammatory and immunosuppressive drugs, such as in autoimmune disorders and antimicrobial chemotherapy, to decrease the burden of pathogen, such as in infectious disease). Therefore, awareness for IRIS is of increasing importance from a clinical point of view. However, diagnostic criteria and standards of treatment are still preliminary.

AIDS-Related Opportunistic Infections↗
PubMed2004

Adverse events of desirable gain in immunocompetence: the Immune Restoration Inflammatory Syndromes.

Augmentation of inflammation may occur during immune reconstitution in a immunocompromised host. This phenomenon is able to cause atypical inflammatory disorders, synonymously summarized as 'Immune Reconstitution Syndrome', 'Immune Restoration Disease' and 'Immune Restoration Inflammatory Syndrome' (IRIS). Immune reconstitution occurs, if temporarily use of immunosuppressive agents was terminated or if highly active antiretroviral therapy in human immunodeficiency virus positive individuals with secondary immunodeficiency was initiated. Unexpected deterioration of inflammatory disease and atypical clinical features, resembling symptoms of autoimmune disease may arise. They have to be distinguished from intercurrent infection and rheumatic disease, respectively. Treatment of IRIS would consist of both potential differential diagnoses: use of anti-inflammatory and immunosuppressive drugs like in autoimmune disorders as well as antimicrobial chemotherapy to decrease the burden of pathogen like in infectious disease. Therefore, awareness for IRIS is of increasing importance from a clinical point of view. However, diagnostic criteria and standards of treatment still have to be defined.

AIDS-Related Opportunistic Infections↗
PubMed2004

Altered coexpression of lectin-like receptors CD94 and CD161 on NK and T cells in HIV patients.

HIV patients either on highly active antiviral therapy (HAART) or therapy naive were analyzed for their CD56 phenotype and cytokine production in comparison to healthy controls (HC). Both NK cell populations (CD56(dim) and CD56(bright)) are found to be present in all groups with selectively decreased CD56(dim) NK cells in HAART naive patients. Patients on HAART exhibited significantly diminished numbers of CD161+CD56(dim) NK cells. CD56(dim) were equally potent in producing IFNgamma in all three groups. The number of TNFalpha+CD56(bright) NK cells from patients on HAART and TNFalpha+CD56(dim) NK cells from HAART naive patients was significantly reduced as compared to healthy controls. In summary our data revealed that functional capacities and coexpression patterns of lectin-like receptors on lymphocytes are differentially affected in HIV patients depending on the state of therapy (under HAART or HAART naive) or the cell type (NK or T cells), respectively.

Antigens, CD↗