bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Th1/Th2 commitment in human CD4+ T cells with ageing
Authors: Sakata-Kaneko S , Wakatsuki Y , Matsunaga Y , Usui T , Kita T 
Published: March 2003

SUMMARYThe human immune system undergoes continuous remodelling with the advancement of age. Since age-associated functional alterations in the immune system could be caused by a possible change in helper T cell regulation in elderly subjects, we comparatively studied the function of CD4+ T cells in peripheral blood obtained from both young and old healthy volunteers. Upon cell activation by phorbol myristate acetate and ionomycin, the proportion of CD4+ T cells containing interferon-gamma (IFN-γ) was found to be greater in the old subjects. Utilizing a co-culture system, which activated CD4+ T cells via the TCR/CD3 complex and CD28, we found that CD4+ T cells from the old subjects secreted more IFN-γ and IL-2, but less IL-4, than those from the young subjects. Upon cell activation by co-culture, CD4+ T cells from the old subjects expressed more CD26, CD40L, and LFA-1, but less CD30, than those from the young. These results together suggest that the microenvironment in which CD4+ T cells develop in older people may cause production of more cells committed to Th1 than that in younger subjects.
Suppression of ongoing experimental allergic encephalomyelitis (EAE)in Lewis rats: synergistic effects of myelin basic protein (MBP) peptide68–86 and IL-4
Authors: Xu L-Y , Huang Y-M , Yang J-S , Van Der Meide P H , Link H , Xiao B-G 
Published: March 2003

SUMMARYMucosal myelin autoantigen administration effectively prevented EAE, but mostly failed to treat ongoing EAE. Patients with multiple sclerosis (MS), for which EAE is considered an animal model, did not benefit from oral treatment with bovine myelin. We anticipated that autoantigen, administered together with a cytokine that counteracts Th1 cell responses, might ameliorate Th1-driven autoimmune disease, and that nasal administration might considerably reduce the amounts of antigen + cytokine needed for treatment purposes. Lewis rats with EAE actively induced with myelin basic protein peptide (MBP 68–86) and Freund's complete adjuvant (FCA), received from day 7 post-immunization, i.e. after T cell priming had occurred, 120 μg MBP 68–86 + 100 ng IL-4 per rat per day for 5 consecutive days. These rats showed later onset, lower clinical scores, less body weight loss and shorter EAE duration compared with rats receiving MBP 68–86 or IL-4 only, or PBS. EAE amelioration was associated with decreased infiltration of ED1+ macrophages and CD4+ T cells within the central nervous system, and with decreased interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) and enhanced IL-4, IL-10 and transforming growth factor-beta (TGF-β) responses by lymph node cells. Simultaneous administration of encephalitogenic peptide + IL-4 by the nasal route thus suppressed ongoing EAE and induced IL-4, IL-10 and TGF-β-related regulatory elements.
Neuroendocrine changes in colon of mice with a disrupted IL-2 gene
Authors: Qian B-F , El-Salhy M , Melgar S , Hammarström M-L , Danielsson Å 
Published: March 2003

SUMMARYNeuroendocrine peptides have a variety of physiological functions in the gastrointestinal tract. This study was carried out to investigate the impact of IL-2 deficiency on the neuroendocrine system in normal colon, and the neuroendocrine changes during colonic inflammation. Mice with homozygous disrupted IL-2 gene (IL-2−/–) spontaneously developed a bowel disease with similarities to human ulcerative colitis. Different types of colonic endocrine cells and myenteric nerves were analysed in the IL-2−/– mice using immunomorphometry. The neuropeptide contents in the colonic tissues were determined by radioimmunoassay. Age-matched healthy IL-2+/– and IL-2+/+ mice served as controls and the colonic IL-2 levels were compared between these two groups of mice by ELISA. Our data showed that less than half the amount of IL-2 was synthesized in the colon of IL-2+/– mice compared with the IL-2+/+ wild-type mice. Two major differences in the neuroendocrine colon were found between the mice with an intact and disrupted IL-2 gene. One was age-related. The frequencies of various endocrine cells and myenteric nerves increased with age in the IL-2+/+ mice. However, no such increases were seen in the mice with a disrupted IL-2 gene. Instead, the volume densities of enteroglucagon, serotonin cells and substance P (SP), vasoactive intestinal polypeptide (VIP) and total myenteric nerves were lower in the older IL-2+/– and IL-2−/– mice compared with the wild type. The other was disease-related. Polypeptide YY (PYY) cells and tissue levels of PYY, SP and VIP were significantly decreased in the IL-2−/– mice during the course of bowel inflammation compared with the healthy IL-2+/– and IL-2+/+ controls. These findings indicate that colonic neuroendocrine alterations did occur in the mice with a disrupted IL-2 gene and diminished local IL-2 level, suggesting a role of IL-2 in the regulation of the neuroendocrine system and a prevalent interaction between the immune and neuroendocrine systems in normal colon. On the other hand, there were some changes that seemed to correlate with the bowel inflammatory process. They might be associated with the impaired function in inflamed gut and contribute to the development and/or prolongation of disease.
Human mast cell tryptase stimulates the release of an IL-8-dependent neutrophil chemotactic activity from human umbilical vein endothelial cells (HUVEC)
Authors: Compton S J , Cairns J A , Holgate S T , Walls A F 
Published: March 2003

SUMMARYTryptase, the major product of human mast cell activation, is a potent stimulus of vascular leakage and neutrophil accumulation in vivo in animal studies, but the mechanisms of action remain unclear. Using HUVEC cultures we have sought to investigate the potential of tryptase to alter monolayer permeability or induce the release of neutrophil chemotactic activity. Tryptase (1–100 mU/ml) failed to alter the permeability of endothelial cell monolayers as assessed by albumin flux over 1 h. However, supernatants from endothelial cells treated with tryptase (1–50 mU/ml) for a 24-h period induced neutrophil migration across Transwell filters, with maximal migration observed at 10 mU/ml tryptase. Pretreatment of tryptase with the protease inhibitor leupeptin abolished the chemotactic activity, indicating a dependence on the catalytic site. Moreover, this effect was abolished by addition of an IL-8 neutralizing antibody, suggesting that IL-8 release makes an important contribution to the chemotactic activity. The interaction of mast cell tryptase with endothelial cells could be important in stimulating the ingress of neutrophils following mast cell activation in inflammatory disease.
High levels of IL-10 and determination of other cytokines and chemokines in HIV-associated haemophagocytic syndrome
Authors: Benveniste O , Dereuddre-Bosquet N , Clayette P , Leport C , Vildé J-L , Dormont D 
Published: March 2003

SUMMARY
Haemophagocytic syndrome (HPS) and HIV infection are both associated with cytokine network dysregulation. We therefore analysed plasma levels and mRNA synthesis in peripheral blood mononuclear cells (PBMC) of cytokines, chemokines and chemokine receptors in one HIV-infected patient with HPS. We compared the results with those for eight HIV-infected patients with similar CD4+ T cell counts (207/mm3versus controls: median 214/mm3) and plasma virus load (4·1 log copies/ml, versus controls: median 4·2 log copies/ml). The HPS patient had a lower viral DNA load in PBMC and higher plasma levels of interferon-gamma, IL-10, and macrophage inflammatory protein (MIP)-1β. No difference in plasma tumour necrosis factor-alpha (TNF-α), IL-6 and MIP-1α concentration was observed between the HPS patient and control patients. No difference was observed in TNF-α, IL-1β, IL-10, IL-4, MIP-1α, MIP-1β, RANTES, CXCR-4, and CCR-5 mRNA levels in PBMC, but IL-6 levels were higher in the HPS patient. Our results emphasize the role of IL-10 in the control of immune hyperactivation that is observed in HPS.
T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding toChlamydiaantigens
Authors: Curry A J , Portig I , Goodall J C , Kirkpatrick P J , Gaston J S H 
Published: March 2003

SUMMARYChlamydia pneumoniae infection is associated with atherosclerosis and the organism has been identified in arterial lesions. To determine whether T lymphocyte-mediated immune responses to Chlamydia antigens within plaque could contribute to pathogenesis, we have derived T cell lines from atherosclerotic plaques of 32 patients. Culture with IL-2 alone proved insufficient for cellular activation and expansion, but additional stimulation with phytohaemagglutinin (PHA) or recall antigens allowed consistent establishment of T cell lines. Furthermore, in cultures of approx. 500 tissue fragments, Chlamydia organisms proved as effective as other recall antigens in producing outgrowth of arterial T cells (20–25% wells produced T cell lines). Testing the antigen responsiveness of T cell lines showed that those derived using Chlamydia organisms were more likely to respond to Chlamydia (5/29+) than those isolated using other stimuli (6/69+ for PHA; 5/57+ for PPD and tetanus toxoid (TT)). However, lines responsive to each of the recall antigens were observed. Using recombinant Chlamydia antigens, some Chlamydia-specific T cell lines were shown to respond to OMP2 and/or hsp60. Those recognizing Chlamydia hsp60 did not cross-react with human hsp60, but human hsp60-responsive lines were also observed. Thus, atherosclerotic plaque tissue contains a variety of memory T lymphocytes, and amongst these are cells capable of recognizing Chlamydia antigens. In a C. pneumoniae-infected plaque, such T cells may be activated by local antigen and could contribute to the inflammatory process in the arterial wall through CD40 ligand expression and cytokine secretion.
Eosinophil granule-derived major basic protein induces IL-8 expression in human intestinal myofibroblasts
Authors: Furuta G T , Ackerman S J , Varga J , Spiess A M , Wang M Y , Wershil B K 
Published: March 2003

SUMMARYEosinophil infiltration occurs in a variety of allergic and inflammatory diseases. The release of preformed mediators from eosinophils may contribute to inflammatory responses. We investigated the ability of eosinophiL-derived major basic protein and eosinophiL-derived neurotoxin to stimulate production of IL-8 from intestinal myofibroblasts. Intestinal myofibroblasts (18-Co cells) were incubated with major basic protein, eosinophiL-derived neurotoxin, or a synthetic analogue of major basic protein, poly- L-arginine. Immunoreactive IL-8 was measured by ELISA and IL-8 mRNA levels were analysed by Northern blot or reverse transcription-polymerase chain assay. Major basic protein induced IL-8 mRNA production and release of significant levels of IL-8 immunoreactive protein. By contrast, eosinophiL-derived neurotoxin stimulated little IL-8 release. The induction of IL-8 mRNA by poly-L-arginine was significantly inhibited by actinomycin D. These findings demonstrate a novel interaction between eosinophils and intestinal fibroblasts that may be involved in the pathogenesis of diseases associated with tissue eosinophilia.
Tuberculosis (TB) and HIV infection are independently associated with elevated serum concentrations of tumour necrosis factor receptor type 1 andβ2-microglobulin, respectively
Authors: Lawn S D , Rudolph D , Wiktor S , Coulibaly D , Ackah A , Lal R B 
Published: March 2003

SUMMARYThe aim of this study was to identify immune markers that are independently associated with HIV infection or TB in vivo. Using commercially available assays, we measured concentrations of five immune markers in sera from 175 out-patients attending medical clinics in Cote D'Ivoire and Ghana, West Africa. Patients were categorized into groups with TB only (TB+HIV−, n = 55), TB and HIV co-infection (TB+HIV+, n = 50), HIV infection only (TB−HIV+, n = 35), or neither infection (TB−HIV−, n = 35). TB+HIV+ and TB−HIV+ groups were matched for blood CD4+ lymphocyte count. Mean ±  s.d. concentrations of β2-microglobulin were similarly increased in both the TB−HIV+ (5·3 ± 2·1 μg/ml, P &lt; 0·0001) and the TB+HIV+ (5·0 ± 1·5 μg/ml, P &lt; 0·0001) groups compared with the TB−HIV− group (2·2 ± 1·8 μg/ml), but were only slightly increased in the TB+HIV− group (3·2 ± 1·8 μg/ml, P = 0·01). In contrast, mean serum concentrations of soluble tumour necrosis factor receptor type I (sTNF-RI) were similarly elevated in the TB+HIV− (1873 ± 799 pg/ml, P &lt; 0·0001) and TB+HIV+ (1797 ± 571 pg/ml, P &lt; 0·0001) groups compared with uninfected subjects (906 ± 613 pg/ml), but there was only a small increase in sTNF-RI in the TB−HIV+ group (1231 ± 165 pg/ml, P = 0·03). Both TB and HIV infection were associated with substantial elevation of serum concentrations of soluble CD8, soluble CD54, and sTNF-R type II. Analysis of additional samples from groups of TB+HIV− and TB+HIV+ patients receiving anti-TB treatment showed significant and equal reductions in mean serum sTNF-RI concentrations, but no significant change in mean β2-microglobulin. Thus, serum β2-microglobulin and sTNF-RI serve as relatively independent markers of HIV infection and TB, respectively, in studies of co-infected persons.
Mapping of novel autoreactive epitopes of the diabetes-associated autoantigen IA-2
Authors: Seissler J , Schott M , Morgenthaler N G , Scherbaum W A 
Published: March 2003

SUMMARYIA-2, a member of the tyrosine phosphatase family, has been identified as a dominant autoantigen in type 1 diabetes. To define humoral IA-2 epitopes, we generated a panel of IA-2 deletion mutants and chimeric proteins using the highly homologous tyrosine phosphatase-like protein IA-2β. Analysis of autoantibody reactivity in 111 IA-2 antibody positive sera from patients with type 1 diabetes revealed that humoral epitopes cluster to several domains of the intracytoplasmic part of IA-2 [IA-2ic, amino acid (aa) 604–979]. Immunodominant epitopes were found in the first N-terminal 73 amino acids (56% positive), in the middle domain residing between residues 699–874 (45% positive) and the C-terminus depending on the presence of aa 931–979 (at least 37% positive). Competition experiments with overlapping peptides revealed that autoantibody binding towards the N-terminus was dependent on residues 621–628. In the C-terminal domain, two novel conformation-dependent epitopes were identified. The first epitope requires the presence of the C-terminal part of IA-2 (aa 933–979) and an IA-2-specific region between residues 771–932. Reactivity against the second epitope was dependent on intact C-terminal domains as well as residues in the middle (aa 887–932) and N-terminal regions (aa 604–771) which are conserved in IA-2 and IA-2β. We here defined novel autoantigenic determinants in the N-terminus of IA-2 and characterized conformational epitopes residing in the C-terminal region or spanning from C-terminal residues to the N-terminal domain of IA-2ic. The identification of dominant target regions of diabetes-specific autoantibodies may help to elucidate the molecular mechanisms involved in the autoimmunity towards IA-2.
Point mutations in the promoter region of the CYBB gene leading to mild chronic granulomatous disease
Authors: Weening R S , De Boer M , Kuijpers T W , Neefjes V M E , Hack W W M , Roos D 
Published: March 2003

SUMMARY
Chronic granulomatous disease (CGD) is a clinical syndrome of recurrent bacterial and fungal infections caused by a rare disorder of phagocytic cells. In CGD, the phagocytes are unable to generate oxygen radicals after stimulation of these cells, due to a defect in the NADPH oxidase system. This NADPH oxidase is a multicomponent enzyme of at least four subunits, of which the β-subunit of cytochrome b558, gp91-phox, is encoded by an X-linked gene (called CYBB). We report here five patients from two families; in each family we found a different mutation in the promoter region of CYBB. Both mutations prevented the expression of gp91-phox in the patients' neutrophils and thus caused inability of these cells to generate oxygen radicals. However, the mutations left the gp91-phox expression and the function of the NADPH oxidase in the patients' eosinophils intact. The relatively mild course of the CGD in these patients can probably be attributed to the fact that the eosinophils have retained their oxidative capacity. Furthermore, our results indicate that neutrophils and eosinophils differ in their regulation of gp91-phox expression.
Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies (ANCA) leads to enhanced uptake by macrophages and increased release of tumour necrosis factor-alpha (TNF-α)
Authors: Moosig F , Csernok E , Kumanovics G , Gross W L 
Published: March 2003

SUMMARYSince proteinase 3 (PR3)-ANCA interact with PR3 on the surface of apoptotic polymorphonuclear neutrophils (PMN) and ingestion of apoptotic PMN is known to modulate macrophage inflammatory reactions, we raised the question whether PR3-ANCA-opsonized apoptotic PMN influence the uptake by macrophages and their state of activation. We therefor analysed the effects of PR3-ANCA-opsonized apoptotic PMN on the uptake process by enzymatic assay. We further investigated the production of TNF-α, IL-10, IL-12 and the secretion of lipid inflammatory mediators (TxB2, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2)) by human monocyte-derived macrophages using FACS and ELISA methods. We show that PMN-opsonization by PR3-ANCA substantially enhances phagocytosis by macrophages and thereby triggers the production of TNF-α and TxB2. These in vitro findings indicate that PR3-ANCA opsonization of apoptotic PMN might be an important mechanism in the pathogenesis of Wegener's granulomatosis (WG), prompting macrophages to produce proinflammatory mediators. These mediators, mainly TNF-α, might prime further PMN leading to perpetuation of the known priming-dependent mechanisms of ANCA action.
Rearrangement of the human heavy chain variable region gene V3–23 in transgenic mice generates antibodies reactive with a range of antigens on the basis of VHCDR3 and residues intrinsic to the heavy chain variable region
Authors: Mageed R A , Harmer I J , Wynn S L , Moyes S P , Maziak B R , Brüggemann M , Mackworth-Young C G 
Published: March 2003

SUMMARYTo formulate a ‘logic’ for how a single immunoglobulin variable region gene generates antibodies with different antigen specificity and polyreactivity, we analysed chimeric antibodies produced in transgenic mice carrying the germ-line human V3–23 gene, multiple diversity (D) and joining (J) gene segments. Hybridomas producing antibodies encoded by the V3–23 gene in combination with different mouse Vκ genes were obtained by fusion of splenocytes from transgenic mice. All antibodies had human μ-chains and mouse light chains, were multimeric in structure and expressed the human V3–23 gene. Nucleotide sequence analyses of genes encoding the heavy and light chains of 12 antibodies in relation to antigen specificity highlighted the importance of heavy chain variable region CDR3 in determining reactivity with different antigens. However, the results also suggest that non-CDR3 sequences intrinsic to the V3–23 gene itself may be involved in, or determine, the binding of the chimeric antibodies to some of the antigens tested in the current study.
Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives
Authors: Mohan C , Liu F , Xie C , Williams Jr R C 
Published: March 2003

SUMMARYAntibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11·8% and 18·3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.
Haemodialysis monocytopenia: differential sequestration kinetics of CD14+CD16+ and CD14++ blood monocyte subsets
Authors: Nockher W A , Wiemer J , Scherberich J E 
Published: March 2003

SUMMARYIn peripheral blood the majority of circulating monocytes present a CD14highCD16− (CD14++) phenotype, while a subpopulation shows a CD14lowCD16+ (CD14+CD16+) surface expression. During haemodialysis (HD) using cellulosic membranes transient leukopenia occurs. In contrast, synthetic biocompatible membranes do not induce this effect. We compared the sequestration kinetics for the CD14+CD16+ and CD14++ monocyte subsets during haemodialysis using biocompatible dialysers. Significant monocytopenia, as measured by the leucocyte count, occurred only during the first 30 min. However, remarkable differences were observed between the different monocyte subsets. CD14++ monocyte numbers dropped to 77 ± 13% of the predialysis level after 15 min, increasing to ≥ 93% after 60 min. In contrast, the CD14+CD16+ subset decreased to 33 ± 15% at 30 min and remained suppressed for the course of dialysis (67 ± 11% at 240 min). Approximately 6 h after the end of HD the CD14+CD16+ cells returned to basal levels. Interestingly, the CD14+CD16+ monocytes did not show rebound monocytosis while a slight monocytosis of CD14++ monocytes was occasionally observed during HD. A decline in CD11c surface density paralleled the sequestration of CD14+CD16+ monocytes. Basal surface densities of important adhesion receptors differed significantly between the CD14+CD16+ and CD14++ subsets. In conclusion, during HD the CD14+CD16+ subset revealed different sequestration kinetics, with a more pronounced and longer disappearance from the blood circulation, compared with CD14++ monocytes. This sequestration kinetics may be due to a distinct surface expression of major adhesion receptors which facilitate leucocyte–leucocyte, as well as leucocyte–endothelial, interactions.
Immune complex processing in C1q-deficient mice
Authors: Nash J T , Taylor P R , Botto M , Norsworthy P J , Davies K A , Walport M J 
Published: March 2003

SUMMARYComplement and Fcγ receptors are known to mediate the processing of immune complexes (IC), and abnormalities in these mechanisms may predispose to the development of lupus. We explored the processing of IC in mice deficient in complement component C1q. 125I-labelled IC comprising Hepatitis B surface antigen (HBsAg)/human anti-HBsAg (HBsAg/Ab) were injected intravenously and the sites of IC clearance determined by direct counting of organ uptake at various time points. The liver and spleen were the main sites of IC uptake in all mice. The splenic uptake of IC was significantly reduced in the C1q-deficient mice compared with the control mice. C1q-deficient mice also exhibited an initial accelerated hepatic uptake of IC similar to that seen in human subjects with hypocomplementaemia. The hepatic localization of IC at later time points was similar in both groups of mice. These data in mice are consistent with previous observations in humans that confirm that the classical pathway of complement plays an important role in the appropriate processing of IC in vivo.