bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levels of soluble FcγRIII correlate with disease severity in sepsis
Authors: Muller Kobold A C , Zijlstra J G , Koene H R , DE Haas M , Kallenberg C G M , Cohen Tervaert J W 
Published: March 2003

SUMMARYNeutrophil activation is thought to play a crucial role in the pathogenesis of sepsis. During activation, neutrophils adhere to and migrate through the endothelium. Therefore, the amount of circulating neutrophils does not adequately reflect the total amount of neutrophils that are involved in the pathophysiologic process of this condition. In this study we test the hypothesis that the severity of sepsis is associated with the total body mass of neutrophils as reflected in the plasma concentration of soluble Fcγ receptor type III (sFcγRIII). Nineteen patients with sepsis (12 male, seven female, median age of 69 years, range 29–87 years) were included in this study. Ten healthy volunteers served as controls. Plasma sFcγRIII concentrations were measured by ELISA. Other parameters that were studied were leucocyte count, plasma concentrations of lactoferrin and soluble l-selectin, and surface expression of CD11b and CD66b on circulating neutrophils. Disease activity was measured using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Soluble FcγRIII levels were elevated in sepsis patients whereas soluble l-selectin levels were moderately decreased compared with healthy controls. Markers of cell activation were significantly increased in sepsis patients. Soluble FcγRIII correlated with disease severity as measured by the APACHE score (P &lt; 0.05, r = 0.53), whereas the other parameters did not correlate with the APACHE score. In conclusion, this study demonstrates that soluble FcγRIII is a useful marker for disease severity in patients with sepsis.
A mixed population of immature and mature leucocytes in umbilical cord blood results in a reduced expression and function of CR3 (CD11b/CD18)
Authors: Reddy R K , Xia Y , Hanikýřová M , Ross G D 
Published: March 2003

SUMMARYNeonatal neutrophils express less membrane and cytoplasmic CR3 (iC3b-receptor, Mac-1, αMβ2-integrin) than do adult neutrophils, and it has been suggested that this renders neonatal neutrophils deficient in diapedesis and bactericidal activity. The reason(s) for this deficiency are unknown. In this study, CR3 expression and the CR3-dependent respiratory burst activity of individual neonatal neutrophils are quantified in comparison with adult leucocytes using flow cytometry. Monocytes and neutrophils are defined as CD14highCD15low and CD14lowCD15high, respectively. Although neonatal neutrophils bore less CR3 on average than did adult neutrophils, neonatal neutrophils were more heterogeneous and many neonatal neutrophils expressed adult levels of CR3. Because of higher neutrophil concentrations in cord versus adult blood, the calculated number of neutrophils in cord blood expressing high amounts of CR3 was equivalent to that of adult blood. Similar findings were made with monocytes. The size of the CR3-dependent respiratory burst stimulated by particulate β-glucan correlated directly with the expression of CR3 by individual neutrophils. With neonatal and adult neutrophils having comparable CR3 densities, the respiratory burst activities were equivalent. Wright–Giemsa differential staining of the subset of neonatal neutrophils with low CR3 levels isolated by fluorescence-activated cell sorting showed a higher proportion of immature cells than the sorted population expressing high CR3 levels. Therefore, higher proportions of immature cells in cord blood probably explain previous reports of deficient CR3 expression and function. The typical neutrophilia of cord blood may compensate for this apparent deficiency by providing adult concentrations of mature neutrophils.
Reduced production of both Th1 and Tc1 lymphocyte subsets in atopic dermatitis (AD)
Authors: LONATI A , LICENZIATI S , CANARIS A D , FIORENTINI S , PASOLINI G , MARCELLI M , SEIDENARI S , CARUSO A , DE PANFILIS G 
Published: March 2003

SUMMARYAn imbalance of interferon-gamma (IFN-γ)-bearing CD4+ T (Th1) cells in the pathogenesis of AD is well recognized; however, a possible role in AD for CD8+ T cells secreting Th1-like cytokines (Tc1) has not been properly addressed. In this study, two- and three-colour FACS analysis allowed us to discriminate the Th1 from the Tc1 subset. AD patients had half the number of IFN-γ-producing circulating T cells (P &lt; 0.005; 13.6 ± 1.9% (mean ± s.d.)) compared with normal donors (25.0 ± 2.4%). Specifically, both Th1 (4.8 ± 0.7%) and Tc1 (8.1 ± 1.1%) cells in AD were decreased compared with Th1 (8.8 ± 0.8%) and Tc1 (15.0 ± 1.5%) cells in controls. Moreover, at the mRNA level, the ratios of IFN-γ/IL-4 and IFN-γ/IL-10 were lower in cells from AD patients compared with controls. In conclusion, the decrease of IFN-γ-producing T lymphocytes in AD is due to a reduction in both Th1 and Tc1 IFN-γ-secreting cells; this may not only contribute to the over-production of IgE, but also explain the high incidence of cutaneous infections observed in AD patients.
Antigenicity of theLeishmania infantumhistones H2B and H4 during canine viscerocutaneous leishmaniasis
Authors: SOTO M , REQUENA J M , QUIJADA L , PEREZ M J , NIETO C G , GUZMAN F , PATARROYO M E , ALONSO C 
Published: March 2003

SUMMARYIn this study we show that sera from dogs naturally infected with Leishmania infantum contain antibodies that specifically react against the parasite H2B and H4 histones. The Leishmania H2B and the amino-terminal region of the histone H4, expressed as fusion proteins, when confronted with sera from canine viscerocutaneous leishmaniasis (VCL) dogs, were recognized by 63% and 47%, respectively. No reactivity was detected when sera from dogs naturally infected with pathogens other than Leishmania were used. Using a collection of synthetic peptides covering the complete sequence of both proteins, we have determined that the main linear antigenic determinants are located in the amino-terminal domains of these histones. The humoral response against histones H2B and H4 induced during canine leishmaniasis was found to be specific for Leishmania histones, since no cross-reactivity of the VCL sera with mammal histones was observed. Also, a comparative study of the prevalence of antibodies among VCL sera against the four core histones of L. infantum was performed. Although a large heterogeneity of the humoral responses against these proteins was found, histones H2A and H3 seem to be more prevalent immunogens than histones H2B and H4 during canine natural leishmaniasis. The origin of the anti-histone humoral response and its possible implications in the pathogenesis of Leishmania infection are discussed.
HBV-specific immune defect in chronic hepatitis B (CHB) is correlated with a dysregulation of pro- and anti-inflammatory cytokines
Authors: SCHLAAK J F , TULLY G , LÖHR H F , GERKEN G , MEYER ZUM BÜSCHENFELDE K-H 
Published: March 2003

SUMMARY
The aim of this study was to examine the immunomodulating effects of rhIL-12 on the immune response induced by hepatitis B virus (HBV) antigens in clinical subgroups of patients with HBV infection. Peripheral blood mononuclear cells (PBMC) of 80 patients were stimulated with HBsAg, HBcAg, pre-S1Ag and tetanus toxoid in the absence or presence of IL-12 (0.01, 0.1 and 1 ng/ml). Stimulation by anti-CD3 + anti-CD28 and lipopolysaccharide (LPS) were used as controls. Proliferation and cytokine production were determined by 3H-thymidine uptake and ELISA after 72 h. After stimulation with HBV antigens only, production of tumour necrosis factor-alpha (TNF-α) or IL-10 was observed in all patients, while interferon-gamma (IFN-γ) was detectable in only 27 patients. After costimulation with IL-12 and HBV antigens, however, large amounts of IFN-γ were found in all patients, while HBV-induced IL-10 production remained mostly unchanged. When clinical subgroups including patients with compensated liver cirrhosis were compared, PBMC from patients with HBeAg+ hepatitis showed the lowest capacity to produce IFN-γ after HBV antigen-positive IL-12. These data suggest that the ability of IL-12 to enhance IFN-γ production against HBV antigens is correlated with the presence of HBeAg and is not impaired in patients with advanced liver disease. In addition, IL-12 and IL-10 production by antigen-presenting cells may be a critical factor that determines the efficacy of the immune response against the hepatitis B virus.
Anti-mitochondrial flavoprotein autoantibodies of patients with myocarditis and dilated cardiomyopathy (anti-M7): interaction with flavin-carrying proteins, effect of vitamin B2 and epitope mapping
Authors: STÄHLE I , BRIZZIO C , BARILE M , BRANDSCH R 
Published: March 2003

SUMMARYVitamin B2 and flavin cofactors are transported tightly bound to immunoglobulin in human serum. We reasoned that anti-mitochondrial flavoprotein autoantibodies (αFp-AB) present in the serum of patients with myocarditis and cardiomyopathy of unknown aetiology may form immunoglobulin aggregates with these serum proteins. However, immunodiffusion and Western blot assays demonstrated that the flavin-carrying proteins were not recognized by αFp-AB. Apparently the flavin moiety in the native protein conformation was inaccessible to αFp-AB. This conclusion was supported by the absence of an immunoreaction between the riboflavin-binding protein from egg white and αFP-AB. Intravenous application of vitamin B2 to rabbits immunized with 6-hydroxy- d-nicotine oxidase, a bacterial protein carrying covalently attached FAD, did not neutralize αFp-AB which had been raised in the serum of the animals. FAD-carrying peptides generated from 6-hydroxy-d-nicotine oxidase by trypsin and chymotrypsin treatment were not recognized by the αFp-AB, but those generated by endopeptidase Lys were. This demonstrates that the epitope recognized by αFp-AB comprises, besides the flavin moiety, protein secondary structure elements.
An IgG1 titre to the F1 and V antigens correlates with protection against plague in the mouse model
Authors: WILLIAMSON E D , VESEY P M , GILLHESPY K J , ELEY S M , GREEN M , TITBALL R W 
Published: March 2003

SUMMARY
The objective of this study was to identify an immunological correlate of protection for a two-component subunit vaccine for plague, using a mouse model. The components of the vaccine are the F1 and V antigens of the plague-causing organism, Yersinia pestis, which are coadsorbed to alhydrogel and administered intramuscularly. The optimum molar ratio of the subunits was determined by keeping the dose-level of either subunit constant whilst varying the other and observing the effect on specific antibody titre. A two-fold molar excess of F1 to V, achieved by immunizing with 10 μg of each antigen, resulted in optimum antibody titres. The dose of vaccine required to protect against an upper and lower subcutaneous challenge with Y. pestis was determined by administering doses in the range 10 μg F1 + 10 μg V to 0.01 μg F1 + 0.01 μg V in a two-dose regimen. For animals immunized at the 1-μg dose level or higher with F1 + V, an increase in specific IgG1 titre was observed over the 8 months post-boost and they were fully protected against a subcutaneous challenge with 105 colony-forming units (CFU) virulent Y. pestis at this time point. However, immunization with 5 μg or more of each subunit was required to achieve protection against challenge with 107 CFU Y. pestis. A new finding of this study is that the combined titre of the IgG1 subclass, developed to F1 plus V, correlated significantly (P &lt; 0.05) with protection. The titres of IgG1 in vaccinated mice which correlated with 90%, 50% and 10% protection have been determined and provide a useful model to predict vaccine efficacy in man.
Antibody-independent classical complement pathway activation and homologous C3 deposition in xeroderma pigmentosum cell lines
Authors: KURITA M , MATSUMOTO M , TSUJI S , KAWAKAMI M , SUZUKI Y , HAYASHI H , TOYOSHIMA K , SEYA T 
Published: March 2003

AbstractOf human malignantly transformed cell lines, xeroderma pigmentosum (XP) cell lines were found to be highly susceptible to homologous complement (C): cells were opsonized by C3 fragments on incubation with diluted normal human serum. C3 fragment deposition on XP cells was Ca2+-dependent and occurred on live cells but not UV-irradiated apoptotic cells. (Ca2+ is required for activation of the classical C pathway via C1q and the lactin pathway via mannose binding lectin (MBL), and the surface of apoptotic cells usually activates the alternative C pathway.) In this study we tested which of the pathways participates in XP cell C3 deposition. In seven cell lines that allowed C3 deposition (i), Clq was shown to be essential but MBL played no role in C activation, (ii) Cls but not MASP bound XP cells for activation, (iii) no antibodies recognizing XP cells were required for homologous C3 deposition, and (iv) the alternative pathway barely participated in C3 deposition. Furthermore, the levels of C-regulatory proteins for host cell protection against C, decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), were found to be relatively low in almost all XP cell lines compared with normal cells. These results indicate that XP cells activate the classical C pathway in an antibody-independent manner through the expression of a molecule which directly attracts C1q in a C-activating form, and that relatively low levels of DAF and MCP on XP cells facilitate effective C3 deposition. The possible relationship between the pathogenesis of XP and our findings is discussed.
Depletion of liver and splenic macrophages reduces the lethality of Shiga toxin-2 in a mouse model
Authors: PALERMO M S , ALVES ROSA M F , VAN ROOIJEN N , ISTURIZ M A 
Published: March 2003

AbstractThe haemolytic uraemic syndrome (HUS) is a clinical syndrome consisting of haemolytic anaemia, thrombocytopenia, and acute renal insufficiency. HUS is the most frequent cause of acute renal failure in childhood. It has been previously suggested that the presence of Shiga toxin (Stx) is necessary but not sufficient for HUS development, and cytokines such as tumour necrosis factor-alpha (TNF-α) and IL-1β appear to be necessary to develop the syndrome. Since the mononuclear phagocytic system (MPS) is the major source of these cytokines, macrophages might be one of the relevant targets for Stx action in the pathophysiology of HUS. In this study our objective was to examine the role of the hepatic and splenic macrophages in a mouse model of HUS induced by injection of Shiga toxin type-2 (Stx2) or Stx2 plus lipopolysaccharide (LPS). For this purpose, depletion of mice macrophages by liposome-encapsulated clodronate (lip-clod), followed by injection of STx2 or Stx2 plus LPS, was assayed. In this study we show that depletion of hepatic and splenic macrophages by clodronate treatment induces a survival of 50% in animals treated with Stx2 alone or in presence of LPS. This maximal effect was observed when lip-clod was injected 48–72 h before Stx2 injection. Biochemical and histological parameters show characteristics of the lesion produced by Stx2, discarding non-specific damage due to LPS or lip-clod. In addition, we determined that the toxic action of Stx2 is similar in BALB/c and N:NIH nude mice, indicating the T cell compartment is not involved in the Stx2 toxicity. Briefly, we demonstrate that macrophages play a central role in the pathophysiology of HUS, and that the systemic production of cytokines by liver and/or spleen is for Stx2 to manifest its full cytotoxic effect. In addition, the toxicity of Stx2 alone, or in presence of LPS, is independent of the T cell compartment.
Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients
Authors: SCHWABE R F , ENGELMANN H , HESS S , FRICKE H 
Published: March 2003

SUMMARYCD40 and its ligand CD40L are key players in T cell–B cell interaction and T cell–antigen-presenting cell (APC) interaction. Inhibition of CD40–CD40L interaction leads to severe humoral and cellular immunodeficiency. In this study we examined the presence of soluble CD40 (sCD40) in the serum of haemodialysis (HD) patients, CAPD patients, chronic renal failure (CRF) patients and healthy donors in order to evaluate the possible involvement of CD40 in uraemic immunodeficiency. Soluble CD40 was detected in the serum of healthy donors (n = 41) with a mean of 0.14 ± 0.12 ng/ml and in the urine of healthy donors with a mean of 1.80 ± 0.74 ng/ml. Soluble CD40 was highly elevated in all patients with impaired renal function. HD patients (n = 22) had up to 100-fold elevated sCD40 levels with a mean concentration of 8.32 ± 4.11 ng/ml, whereas CAPD patients (n = 10) had considerably lower levels of sCD40 with a mean of 3.58 ± 2.40 ng/ml. A strong correlation between sCD40 and serum creatinine levels was noted in CRF patients (n = 66). The highly elevated levels of sCD40 may point to the involvement of CD40 and its ligand CD40L in the clinical manifestation of uraemic immunodeficiency.
Increased activity of caspase 3 and caspase 8 in anti-Fas-induced apoptosis in lymphocytes from ageing humans
Authors: Aggarwal S , Gupta S 
Published: March 2003

SUMMARYWe have previously shown an increased susceptibility of T cell subsets to anti-Fas-induced apoptosis in human ageing [1]. In this study, we have examined the role of downstream mediators, including caspases, in Fas-mediated apoptosis in lymphocytes from ageing humans. The cleavage activity of caspase-8 and caspase-3 was compared between ageing and young subjects at different times following anti-Fas treatment, using colorimetric detection analysis. The expression of Fas-associated death domain (FADD), caspase-8, and caspase-3 in lymphocytes was compared at the protein level using Western blotting, and at the mRNA level by Northern blot analysis. In lymphocytes from ageing subjects, there was an early increase in the cleavage activity of caspase-8 and caspase-3 compared with young controls. Furthermore, increased protein expression of FADD, caspase-8 and caspase-3 at the basal level was observed in lymphocytes from ageing humans. Our results suggest that the altered expression and activity of molecules in the Fas/FasL signalling pathway may play a role in increased Fas-induced apoptosis and T cell deficiency in ageing humans.
Rheumatoid factors in primary Sjögren's syndrome (pSS) use diverse VH region genes, the majority of which show no evidence of somatic hypermutation
Authors: Elagib K E E , Børretzen M , Jonsson R , Haga H J , Thoen J , Thompson K M , Natvig J B 
Published: March 2003

SUMMARYRheumatoid factor (RF) is the most common autoantibody found in patients with Sjögren's syndrome (SS). To study the genetic origin and the mechanisms acting behind its generation we have characterized and sequenced the immunoglobulin VH genes used by 10 IgM RF MoAbs derived from peripheral blood of six female patients with pSS. We compared the structure of the RF immunoglobulin VH genes with those obtained previously from rheumatoid arthritis (RA) patients and healthy immunized donors (HID). VH1 and VH4 were each used by four RF clones, one clone was encoded by VH3 family gene and one by VH2 family gene. This distribution frequency was different from that observed in RA, where VH3 was the dominant family, followed by VH1. Eight different germ-line (GL) genes encoded the clones and all of these genes were seen previously in RA and/or HID RF. Five clones rearranged to JH6, four rearranged to JH4 and one to JH5, in contrast to RF from RA and HID, where JH4 was most frequently used. D segment use and CDR3 structure were diverse. Interestingly, three out of four VH4 clones used the GL gene DP-79 that was seen frequently in RA RF. The degree of somatic mutation in the pSS RF was very much lower than seen in RA and HID RF. All the pSS RF clones except three were in or very close to GL configuration. This indicates that there is little role for somatic hypermutation and a germinal centre reaction in the generation of RF from peripheral blood in pSS.
Antibody production in autoimmune BXSB mice. I. CD40L-expressing B cells need fewer signals for polyclonal antibody synthesis
Authors: Blossom S , Gilbert K M 
Published: March 2003

SUMMARYMale, but not female, BXSB mice develop severe lupus associated with multiple immune system defects. It was recently shown that one immunological abnormality found in male BXSB mice encompasses B cell expression of CD40 ligand (CD40L) by an expanded population of large B cells. The present study was undertaken to determine how the CD40L-expressing large B cells in male BXSB mice compared with size-matched B cells from female mice in terms of their ability to secrete antibody. It was shown that the large B cells from female mice, similar to the small B cells from either male or female mice, required CD40 signalling, immunoglobulin cross-linking and cytokines for optimal antibody synthesis. In contrast, large B cells from male BXSB mice produced high levels of antibody when stimulated with only two of the three signals, and made significantly more total IgM and IgG, and anti-ssDNA antibody than size-matched B cells from female mice when stimulated with IL-4/IL-5 alone, IL-4/IL-5 plus low levels of anti-IgD-dextran, or IL-4/IL-5 plus anti-CD40 MoAb. The ability of the large B cells from male mice to produce antibody under suboptimal stimulatory conditions correlated with their expression of CD40L, and was inhibited by CD40-immunoglobulin. Taken together, these findings suggested that large CD40L-expressing B cells from male BXSB mice may be able to bypass a need for CD40 signalling from T cells, thus contributing to autoimmune disease by promoting antibody production in the absence of cognate T cell help.
The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation
Authors: Radford D J , Lord J M , Savage C O S 
Published: March 2003

SUMMARYThe ability of antineutrophil cytoplasm autoantibodies (ANCA) from patients with systemic vasculitis to stimulate protein kinase C (PKC) and tyrosine kinases was examined in human neutrophils. Using the superoxide dismutase-inhibitable reduction of ferricytochrome C, the kinetics of ANCA-induced superoxide (O2−) production were characterized and subsequently manipulated by specific inhibitors of PKC and tyrosine kinases. With this approach, ANCA IgG, but not normal IgG or ANCA F(ab′)2 fragments caused a time and dose dependent release of O2− from TNF-α primed neutrophils. The kinetics of ANCA-induced O2− production showed an initial 10–15 min lag phase compared to the N-formyl-l-methionyl-l-leucyl-l-phenylalanine response, suggesting differences in the signalling pathways recruited by these two stimuli. Inhibitor studies revealed that ANCA-activation involved members of both the Ca2+-dependent and -independent PKC isoforms and also tyrosine kinases. ANCA IgG resulted in the translocation of the βII isoform of PKC at a time corresponding to the end of the lag phase of O2− production, suggesting that PKC activity may be instrumental in processes regulating the activity of the NADPH oxidase in response to ANCA. Tyrosine phosphorylation of numerous proteins also peaked 10–15 min after stimulation with ANCA but not normal IgG. These data suggest that PKC and tyrosine kinases regulate O2− production from neutrophils stimulated with autoantibodies from patients with systemic vasculitis.