bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of mercury-induced immune activation in nonobese diabetic (NOD) mice
Authors: Brenden N , Rabbani H , Abedi-Valugerdi M 
Published: March 2003

SummaryIn susceptible mice, the heavy metal ion mercury is able to induce a strong immune activation, which resembles a T helper 2 (Th2) type of immune response and is characterized by a polyclonal B cell activation, formation of high levels of IgG1 and IgE antibodies, production of autoantibodies of different specificities and development of renal IgG deposits. In the present study, we analysed the in vivo effects of mercury in nonobese diabetic (NOD) mice, which is believed to develop a spontaneous Th1 cell-mediated autoimmune diabetes similar to type 1 diabetes in humans. Three weeks of treatment with mercury induced a strong Th2 like immune/autoimmune response in NOD mice. This response was characterized by an intensive increase in splenic IgG1 antibody secreting cells, a marked elevation in serum IgE levels, a substantial increase in splenic IL-4 mRNA, but a significant decrease in splenic IFN-γ mRNA. Mercury-induced IgG1 antibodies were mainly against ssDNA, TNP and thyroglobulin, but not against nucleolar antigen. Moreover, mercury-injected NOD mice developed high titres of IgG1 deposits in the kidney glomeruli. We further tested if the generated Th2 response could interfere with the development of insulitis and diabetes in NOD mice. We found that three weeks of treatment with mercury was also able to significantly suppress the development of insulitis and postpone the onset of diabetes in these mice. Thus, mercury-induced immune activation can counter-regulate the Th1 cell-mediated autoimmune responses and confer a partial protection against autoimmune diabetes in NOD mice.
MC1 receptors are constitutively expressed on leucocyte subpopulations with antigen presenting and cytotoxic functions
Authors: Neumann Andersen G , Nagaeva O , Mandrika I , Petrovska R , Muceniece R , Mincheva-Nilsson L , Wikberg J E S 
Published: March 2003

SummaryThe expression of melanocortin MC1 receptors on human peripheral lymphocyte subsets was analysed by flow cytometry using rabbit antibodies selective for the human MC1 receptor and a panel of monoclonal antibodies against lymphocyte differentiation markers. The MC1 receptor was found to be constitutively expressed on monocytes/macrophages, B-lymphocytes, natural killer (NK) cells and a subset of cytotoxic T-cells. Interestingly T-helper cells appeared to be essentially devoid of MC1 receptors. The results were confirmed by RT-PCR which indicated strong expression of MC1 receptor mRNA in CD14+, CD19+ and CD56+ cells. However, only a faint RT-PCR signal was seen in CD3+ cells, in line with the immuno-staining results that indicated that only part of the CD3+ cells (i.e. some of the CD8+ cells) expressed the MC1 receptor. The MC1 receptors' constitutive expression on immune cells with antigen-presenting and cytotoxic functions implies important roles for the melanocortic system in the modulation of immune responses.
Ex vivoanalysis of phenotype and TCR usage in relation to CD45 isoform expression on cytomegalovirus-specific CD8+ T lymphocytes
Authors: Vargas A L , Lechner F , Kantzanou M , Phillips R E , Klenerman P 
Published: March 2003

SummaryHuman cytomegalovirus (CMV) is a ubiquitous pathogen which sets up a lifelong persistent infection and which can lead to significant disease in the immunosuppressed. The immunological mechanisms controlling CMV in the long term are not defined completely, but CD8+ T lymphocytes are thought to play an important role. Antiviral CD8+ T lymphocytes may exist in very large pools in healthy individuals. Although the detailed composition of these pools is not completely understood, there is known to be heterogeneity, in particular of CD45 isoform expression. We have therefore investigated the CD8+ T-lymphocyte response against CMV directly ex vivo using Class I tetramers combined with stains for a range of phenotypic markers followed by four-colour flow cytometric analysis. In particular, we examined expression of these phenotypic markers in relation to the expression of CD45 isoforms. We found that a spectrum of phenotypes exists stably, from CD45R0high/RAlow through CD45RAhigh/R0low, and that expression of other surface markers such as CD28 and CD62L, and also TCR usage, may vary in parallel with CD45 isoform expression. In some individuals, expansions of antigen-specific CD8+ T lymphocytes bearing specific TCR Vβ chains were restricted to cells of particular CD45 isoforms. Immunity against CMV comprises a large population of CD8+ T lymphocytes with heterogeneous potential, a spectrum in which CD45 isoform expression may play a central role.
Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia
Authors: Racioppi L , Cancrini C , Romiti M L , Angelini F , Di Cesare S , Bertini E , Livadiotti S , Gambarara M G , Matarese G , Lago Paz F , Stefanini M , Rossi P 
Published: March 2003

SummaryWe report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repair (NER) and basal transcription. Our patient showed neurological and immune system abnormalities, including CD4 + lymphopenia never previously reported in TTD patients. In vitro immunological studies revealed a marked reduction in T-cell proliferation in response to mitogens and CD3 cross-linking which was partially recovered by the addition of anti-CD28 antibody or exogenous interleukin-2. The patient's T cells displayed alterations in T-cell receptor (TCR/CD3) proximal signalling characterized by marked reduction in Lck kinase activity coupled with a constitutive hyperactivation of Fyn kinase. Despite these alterations, normal levels of Lck and Fyn proteins were detected. The role of antigen-presenting cells (APCs) in the pathogenesis of the T-cell defect was investigated by analysing dendritic cells (DCs) generated from the patient's blood monocytes. In these cells, flow cytometry revealed significantly reduced expression of the CD86 co-stimulatory molecules and HLA glycoproteins. In addition, the patient's DCs showed a decreased ability to stimulate naive T lymphocytes. Overall, the results of our study suggest that a defective TFIIH complex might result in alterations in T cells and DC functions leading to a severe immunodeficiency.
Interferon-gamma administration after abdominal surgery rescues antigen-specific helper T cell immune reactivity
Authors: Rentenaar R J , De Metz J , Bunders M , Wertheim-Van Dillen P M E , Gouma D J , Romijn J A , Sauerwein H P , TEN BERGE I J M , Van Lier R A W 
Published: March 2003

SummaryAntigen-induced activation of T cells is determined by many factors. Among these factors are (i) the number of T-cell receptors (TCRs) triggered by TCR ligands on antigen-presenting cells (APCs), and (ii) the intrinsic cellular threshold for activation. T-cell receptor triggering is optimized by adhesion molecules that form the interaction site between T cells and APCs, i.e. the immunological synapse. In addition, signals through co-stimulatory molecules lower the intrinsic T-cell activation threshold. Immunosuppressive agents and traumatic events such as major operative procedures change physiological T-cell responses. Depressed immune functions after surgery are presumed to render patients more susceptible to pathogens. Interferon-gamma (IFNγ) is a type II homodimeric cytokine with multiple immunostimulatory properties. Several studies have been performed to assess the effects of IFNγ treatment in patients in need of increased immune reactivity. However, until now, the effect of IFNγ on human antigen specific CD4pos T-cell reactivity after surgically-induced immunosuppression has not been reported. Therefore, a comparative trial of recombinant human (rh) IFNγversus placebo in patients after abdominal surgery was initiated. Antigen-specific helper T cell immune reactivity was assessed by antigen-induced cytokine production, intracellular cytokine staining and flow cytometry. A single dose of rhIFNγ rescued down-modulation of antigen-specific CD4pos T-cell reactivity, concomitant with an up-regulation of TCR-ligands on antigen-presenting cells. Selected patients may benefit from the immunostimulatory properties of rhIFNγ administration in vivo.
Placental cytokine and chemokine production in HIV-1-infected women: trophoblast cells show a different pattern compared to cells from HIV-negative women
Authors: Moussa M , Roques P , Fievet N , Menu E , Maldonado-Estrada J G , Brunerie J , Frydman R , Fritel X , Herve F , Chaouat G 
Published: March 2003

SummaryIn utero transmission of HIV-1 has been demonstrated and may account for around 10–20% of all materno–fetal HIV-1 transmission. The possible routes for such transmission are transannexial or transplacental. In both cases, the microenvironment (cytokines and chemokines) at the placental interface could be an important regulatory factor in viral transmission.We therefore performed explant cultures of placental villi, and isolated purified trophoblasts, from term placentae obtained from HIV-1-seropositive and HIV-1-seronegative women in order to assess and compare the cytokine and chemokine secretion profiles using ELISA and semiquantitative RT-PCR.No major differences could be seen in the secretions of cytokines and chemokines at the level of whole placental tissue in HIV-1-positive and HIV-1-negative women. However, variations were observed in the expression of inflammatory cytokines and chemokines from trophoblastic cells, depending on the status of HIV-1 infection of the mothers but not the babies, all of which remained uninfected. The significance of these data is discussed.
Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains
Authors: Häggqvist B , Hultman P 
Published: March 2003

SummaryCytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H-2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34-kDa-protein fibrillarin, and systemic immune-complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H-2s) and resistant A.TL (H-2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL-2 and IFN-γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up-regulation of IL-2 and IFN-γ levels, followed by substantial expression of IL-4 mRNA, which was significant compared to control A.SW and Hg-treated A.TL mice. Hg-exposed A.TL mice exhibited unchanged IFN-γ, reduced IL-2 and greatly increased IL-10 mRNA expression. Ag-treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL-2 and IFN-γ mRNA, but only a small and delayed rise in IL-4 mRNA. In conclusion, H-2-linked resistance to Hg-induced AFA is characterized by low constitutive expression of IL-2 and IFN-γ mRNA, which is not increased by Hg, and a marked increase in IL-10 expression. Conversely, the key features of H-2-linked susceptibility to Hg- and Ag-induced AFA are up-regulation of IL-2, IFN-γ and IL-4 mRNA expression, and down-regulation of IL-10 expression.
RecombinantLactobacillus plantaruminhibits house dust mite-specific T-cell responses
Authors: Kruisselbrink A , Heijne Den Bak-Glashouwer M-J , Havenith C E G , Thole J E R , Janssen R 
Published: March 2003

SummaryRecent evidence suggests that chronic exposure to lactobacilli, which are part of the normal intestinal flora, inhibits the development of allergic disorders. Allergy is mediated by Th2 cells, which produce high levels of IL4 and IL5, and suppressive effects of lactic acid bacteria on the development of allergy have been attributed to their Th1-inducing properties. On the other hand, lactic acid bacteria have also been shown to suppress autoimmune disorders which are mediated by Th1 cells producing high levels of IFNγ. To study this apparent discrepancy, the immunomodulatory potential of lactobacilli was evaluated using recombinants that express an immunodominant T-cell epitope of Der p 1 of house dust mites. Mucosal immunization of C57BL/6 J mice with such recombinants resulted in the induction of T cells which produced low amounts of IFNγ. Immunization with the house dust mite peptide followed by treatment with recombinant Lactobacillus plantarum resulted in the inhibition of both IFNγ and IL5 production. The effect on IFNγ production was shown to be a non-specific effect of L. plantarum. The effect on IL5 production, however, was only observed when the recombinant expressing the Der p 1 peptide, but not the control recombinant, was used for treatment. Neither of the recombinants had an effect on the antibody response. Taken together, these data suggest that recombinant L. plantarum may be a suitable candidate for the treatment of allergic disorders.
Interleukin-1 β enhances and interferon-γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts
Authors: Abe M , Shintani Y , Eto Y , Harada K , Fujinaka Y , Kosaka M , Matsumoto T 
Published: March 2003

Summary
Activin A is a multi-functional cytokine with a potent stimulation on erythroid cell differentiation in the bone marrow. The actions of activin A are determined by a balance of the levels of activin A and its inhibitor, follistatin (FS). However, the regulation of its actions in the bone marrow has been unclear. Here we show that bone marrow-derived stromal fibroblasts are the major source of activin A and FS in the bone marrow, and that the production of activin A is enhanced by interleukin-1β (IL-1β) and lipopolysaccharide (LPS), whereas interferon-γ (IFN-γ) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL-1β as well as LPS inhibits and IFN-γ stimulates FS secretion from stromal fibroblasts. Thus, these cytokines potently regulate activin A actions by reciprocal modulation of activin A and FS secretion from stromal fibroblasts. Because activin A exhibits anti-inflammatory effects in various tissues, up-regulation of activin A actions by IL-1β and endotoxin in the bone marrow may play a protective role against inflammatory processes as well as anaemia. The present results also suggest that the inhibitory effect of IFN-γ on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.
IgG1 anti-P2 as a marker of response to interferon in patients with chronic hepatitis C
Authors: Hirayama M , Maruyama T , Mitsui H , Maekawa H , Yamada H , Hashimoto N , Koike K , Kimura S , Yasuda K , Iino S , Green J 
Published: March 2003

Summary
To study the relations of antibody production to long-term outcomes after interferon (IFN) treatment in patients with chronic hepatitis C (CH-C), we used ELISA to measure the levels of antibodies against HCV core protein and peptides. Samples from 21 complete responders and 36 non-responders were collected before IFN therapy, soon after the end of IFN therapy and 6 months later. Using a set of 19 synthesized HCV core peptide antigens, we found that anti-P2 (11–25a.a.) was the most prevalent of all IgG antibodies (93%: 39/42). Among complete responders, IgG1 anti-P2 levels had fallen by the end of IFN therapy (from 79·8 ± 60·4–46·1 ± 44·2: P &lt; 0·01), and were lower still 6 months after the end of IFN therapy (31·0 ± 35·2: P &lt; 0·001); this change was the greatest of all antibodies studied. Among the non-responders, there was no change within the follow-up period. Soon after the end of IFN therapy, IgG1 anti-P2 levels were more than 30% lower than the initial value in more than two-thirds of the complete responders, but in only one-third of the non-responders (14/20 vs. 8/25: P &lt; 0·05). Six months after the end of IFN therapy, IgG1 anti-P2 levels were more than 30% lower than the initial value in more than 85% of the complete responders, but in only 12% of the non-responders (17/20 vs. 3/25: P &lt; 0·001). In conclusion, the changes in levels of IgG1 anti-P2 paralleled the activity of chronic hepatitis C after IFN therapy, and IgG1 anti-P2 levels may be markers of the efficacy of IFN therapy.
Screening of a HUVEC cDNA library with transplant-associated coronary artery disease sera identifies RPL7 as a candidate autoantigen associated with this disease
Authors: Linke A T , Marchant B , Marsh P , Frampton G , Murphy J , Rose M L 
Published: March 2003

SummaryA HUVEC cDNA library was screened with sera from two patients who had developed transplant-associated coronary artery disease (TxCAD) following cardiac transplantation. A total of six positive clones were isolated from a primary screen of 40 000 genes. Subsequent DNA sequence analysis identified these to be lysyl tRNA synthetase, ribosomal protein L7, ribosomal protein L9, β transducin and TANK. Another gene whose product could not be identified showed homology to a human cDNA clone (DKFZp566M063) derived from fetal kidney. Full-length constructs of selected genes were expressed as his-tag recombinant fusion proteins and used to screen a wider patient base by ELISA to determine prevalence and association with TxCAD. Of these ribosomal protein L7 showed the highest prevalence (55·6%) with TxCAD sera compared to 10% non-CAD.
Increased secretion of IL-18in vitroby peripheral blood mononuclear cells of patients with bronchial asthma and atopic dermatitis
Authors: El-Mezzein R E H , Matsumoto T , Nomiyama H , Miike T 
Published: March 2003

SummaryThis study was performed to determine whether or not IL-18, formerly called IFN-γ-inducing factor, is involved in the pathogeneses of allergic disorders. Peripheral blood mononuclear cells (PBMC) were obtained from patients with allergic bronchial asthma (BA), patients with atopic dermatitis (AD) and controls who did not have any allergic disease, and then cultured with lipopolysaccharide (LPS) or phytohaemagglutinin (PHA). The concentrations of IL-18, IFN-γ and IL-13 in supernatant fluids were determined by enzymatic immunoassaying, and the expression of IFN-γ messenger (m) RNA in the cells was measured by colorimetric microplate assaying. IL-18 secretion in the BA patients (geometric mean (gm) = 189 pg/ml) and AD patients (gm = 172 pg/ml) was significantly higher than that in non-allergic controls (gm = 118 pg/ml). In contrast, IFN-γ secretion in the BA patients (gm = 7·3 IU/ml) and AD patients (gm = 6·8 IU/ml) was significantly lower than that in non-allergic controls (gm = 20·7 IU/ml). The amounts of IL-13 in supernatant fluids and IFN-γ mRNA in cells were not statistically different among the BA patients, AD patients and non-allergic controls. The possible involvement of IL-18 in allergic disorders is discussed.
Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS)
Authors: Katzav A , Kloog Y , Korczyn A D , Niv H , Karussis D M , Wang N , Rabinowitz R , Blank M , Shoenfeld Y , Chapman J 
Published: March 2003

SummaryActivation and proliferation of lymphocytes requires the active signal transducer Ras. Activation of lymphocytes, associated with autoimmunity, may therefore be modified by S-farnesylthiosalicylic acid (FTS), a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. The MRL/lpr mouse is a genetic model of a generalized autoimmune disease sharing many features and organ pathology with systemic lupus erythematosus (SLE) and the primary antiphospholipid syndrome (APS). The objective of the present study was to examine the effect of FTS on laboratory and clinical pathology in the MRL/lpr mouse. Female MRL/lpr (n = 50) and MRL/++ control (n = 35) mice were treated intraperitoneally with either FTS (5 mg/kg/day) or saline between 6 and 18 weeks of age. The mice were weighed, tested for proteinuria and lymphadenopathy, lymphocyte proliferation, antibodies, grip strength and behaviour in an open field. FTS treatment resulted in a 50% decrease in splenocyte proliferation to ConA, LPS and a disease specific antigen, β2-glycoprotein-I, and in a significant decrease in serum antibody levels against cardiolipin and dsDNA. Proteinuria and grip strength were normalized and lymphadenopathy and postmortem lymph node and spleen weights were significantly reduced in FTS treated MRL/lpr mice. These findings indicate that modulation of Ras activation has a significant impact on the MRL/lpr model and may represent a new therapeutic approach for the treatment of systemic autoimmune diseases such as SLE and APS.
Delayed apoptosis of circulating neutrophils in Kawasaki disease
Authors: Tsujimoto H , Takeshita S , Nakatani K , Kawamura Y , Tokutomi T , Sekine I 
Published: March 2003

SummaryCirculating polymorphonuclear neutrophils (PMNs) are known to increase in number and are functionally activated in the acute phase of Kawasaki disease (KD). In the present study, we investigated whether the apoptosis of PMNs is deregulated in KD. When the isolated PMNs were cultured in vitro, the proportions of spontaneous apoptotic PMNs (annexin V+ cells and cells with fragmented DNA) were found to be significantly lower (P &lt; 0·01) in the patients with KD (n = 25) than in the patients with a bacterial infection (n = 20) or a viral infection (n = 20), or in healthy children (n = 20). The proportion of circulating Fas-positive PMNs was also significantly lower (P &lt; 0·01) in the acute KD patients than in the other groups. In the acute phase of KD, the proportion of spontaneous apoptotic PMNs showed a significant positive correlation (P &lt; 0·01) with the proportions of circulating Fas-positive PMNs. Furthermore, the agonistic anti-Fas MoAb (CH-11) induced a significant increase in the proportion of apoptotic PMNs in the patients with a viral infection and healthy children, but not in either the patients with KD or the patients with a bacterial infection. In the intracellular expression of anti- and pro-apoptotic proteins, the A1/Bax ratio was significantly higher in acute KD than in the other groups. These findings indicate that PMN apoptosis is inhibited during the acute phase of KD and also suggest that both the resistance against the Fas-mediated death signal and the down-regulation of the mitochondrial apoptotic signalling pathway due to an altered balance of Bcl-2 protein expression are responsible for the delayed PMN apoptosis.