bluuebunny/crossref_metadata_2025_split huggingface dataset:
T lymphocyte phenotypic profile in lung segments affected by cavitary and non-cavitary tuberculosis
Authors: MAZZARELLA G , BIANCO A , PERNA F , D'AURIA D , GRELLA E , MOSCARIELLO E , SANDUZZI A 
Published: December 2004

SUMMARYClinical manifestations of pulmonary tuberculosis (TB) may depend on a complex interaction between the host and the pathogen. Clinical outcomes of pulmonary tuberculosis are variable, ranging from asymptomatic lifelong infection to parenchymal lung destruction, resulting in cavitary lesions. To investigate the hypothesis that local cellular immune response may affect presentation and outcome in tuberculosis, we performed bronchoalveolar lavage (BAL) in lung segments affected by cavitary and non-cavitary tuberculosis. We then correlated the type of cellular response at the level of the involved lung segments with clinical evolution in terms of cavity formation. We found alveolar lymphocytosis in patients with both cavitary and non-cavitary pulmonary tuberculosis, with increased CD4+ lymphocytes in patients with non-cavitary pulmonary tuberculosis. A predominant Th1 immune response has been observed in non-cavitary patients, while cavitary involved segments exhibit the presence of Th2 lymphocyte subsets. These data, while confirming the importance of Th1-type CD4+ cells and IFN-γ in effective cellular immunity in active pulmonary tuberculosis, also suggest that the presence of Th2 lymphocytes may contribute to tissue necrosis phenomena associated with cavitary evolution of pulmonary tuberculosis. Our observations indicate the importance of the type of local immune response at the site of disease in the development of different clinical characteristics and outcome in pulmonary tuberculosis.
Mannan-binding lectin and hepatitis C infection
Authors: KILPATRICK D C , DELAHOOKE T E S , KOCH C , TURNER M L , HAYES P C 
Published: December 2004

SUMMARY
Japanese patients with chronic hepatitis C infection unresponsive to treatment with interferon possessed genotypes disproportionately conferring low mannan-binding lectin (MBL) concentrations. Our aims were to confirm or refute this finding in European patients at the MBL protein level, and to investigate whether a low circulating concentration of MBL might influence susceptibility to, or disease progression from, hepatitis C viral infection. Serum samples obtained from 180 hepatitis C patients and 566 blood donors were assayed for MBL. MBL concentrations were related to disease characteristics retrieved from patients’ records. MBL concentrations were higher in hepatitis C patients (median 2·5 µg/ml versus 1·3; P &lt; 0·0001) and the proportion of patients with very low (MBL-deficient) concentrations was similar to that of the healthy controls. There were no significant associations between patients with low serum MBL and the disease features studied, including response to antiviral therapy. Therefore, low circulating MBL does not increase susceptibility to hepatitis C infection, and MBL concentration does not have a major influence on the course of the disease or the response to antiviral therapy. MBL replacement therapy would therefore not be indicated for chronic hepatitis C patients who failed to respond fully to treatment with interferon and ribavirin.
Immunological hurdles to lung gene therapy
Authors: FERRARI S , GRIESENBACH U , GEDDES D M , ALTON E 
Published: December 2004

SUMMARYGene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, α1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.
Regulation of CCR5 expression and MIP-1α production in CD4+ T cells from patients with rheumatoid arthritis
Authors: WANG C R , LIU M F 
Published: December 2004

SUMMARY
Production of CCR5 expression and MIP-1α, a ligand of CCR5, by CD4+ T cells from patients with rheumatoid arthritis (RA) were studied. We analysed further the influence of IL-15 stimulation, CD40/CD40 ligand (CD40L) interaction and CCR5 promotor polymorphism. One hundred and fifty-five RA patients and another 155 age- and sex-matched healthy individuals were enrolled. Peripheral CD4+ and double negative (DN) T cells from patients had lower portions of CCR5, whereas synovial CD4+ and DN T cells showed a much higher CCR5 expression. IL-15 significantly up-regulated the expression of CCR5 on purified CD4+ T cells. CD40L expression on synovial CD4+ T cells was increased greatly in CCR5+ portions by IL-15. MIP-1α production by synovial CD4+ T cells was also enhanced by IL-15. Co-culture of CD40 expressing synovial fibroblasts with IL-15-activated synovial CD4+ T cells significantly increased MIP-1α production. Expression of CCR5 on patients’ CD4+ T cells was not influenced by the promotor polymorphism of CCR5 gene. Taken together, these data suggest CCR5+CD4+ T cells infiltrate the inflamed synovium and IL-15 up-regulates CCR5 and CD40L expression further and enhance MIP-1α production in synovial CD4+ T cells. Production of MIP-1α by synovial fibroblasts is significantly increased by engagement of CD40 with CD40L. Synovial microenvironment plays a potential role in regulation of CCR5+CD4+ T cells in rheumatoid joints.
NF-κB activation in peripheral blood mononuclear cells in neonatal asphyxia
Authors: HASEGAWA K , ICHIYAMA T , ISUMI H , NAKATA M , SASE M , FURUKAWA S 
Published: December 2004

SUMMARYNeonatal asphyxia results in hypoxic–ischaemic encephalopathy. Previous studies have demonstrated that brain hypoxia and ischaemia lead to the production of proinflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6. Transcription factor NF-κB is essential for the expression of these cytokines. We examined whether or not NF-κB is activated in peripheral mononuclear cells (PBMC) in neonatal asphyxia by flow cytometry. In addition, we examined the relationship between NF-κB activation in PBMC and the neurological prognosis. Flow cytometry analysis demonstrated that the level of NF-κB activation in CD14+ monocytes/macrophages of the patients with asphyxia who had neurological sequelae was significantly higher than in the controls, and in the patients with asphyxia who survived (31·7 ± 7·2%versus 2·5 ± 0·9%, P = 0·008, and versus 1·6 ± 1·4%, P = 0·014, respectively). Our findings suggest that NF-κB activation in peripheral blood CD14+ monocytes/macrophages in neonatal asphyxia is important for predicting the subsequent neurological sequelae.
Differential regulation of Th1 responses and CD154 expression in human CD4+ T cells by IFN-α
Authors: SHIBUYA H , NAGAI T , ISHII A , YAMAMOTO K , HIROHATA S 
Published: December 2004

SUMMARYLike interleukin (IL)-12, interferon (IFN)-α has been shown to play an important role in inducing human Th1 responses. Recent studies have shown that human Th1 responses driven by IL-12 are associated with enhanced expression of CD154. The present study examined the effects of IFN-α on CD154 expression in human CD4+ T cells, with special attention to the relationship with Th1 responses. Highly purified CD4+ T cells from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-α and IL-12 in the complete absence of accessory cells. IFN-α suppressed CD154 protein and mRNA expression in CD4+ T cells at the initial phase of activation with immobilized anti-CD3, but enhanced it in the subsequent maturation phase irrespective of the presence of IL-12. By contrast, IFN-α by itself did not enhance IFN-γ production or mRNA expression in CD4+ T cells in the absence of IL-12 even in the presence of stimulation with anti-CD28, but enhanced it in the presence of IL-12. Accordingly, IFN-α enhanced IL-12Rβ2 mRNA expression in anti-CD3-stimulated CD4+ T cells. Neither IFN-α nor IL-12 influenced the stability of CD154 mRNA in anti-CD3-activated CD4+ T cells. These results indicate that IFN-α by itself enhances CD154 expression in CD4+ T cells independently of the induction of IFN-γ mRNA expression. The data also suggest that the optimal induction of human Th1 responses by IFN-α might require the presence of IL-12 and that the induction of Th1 responses and CD154 expression in human CD4+ T cells might be regulated through different mechanisms.
Biased T-cell receptor repertoires in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome)
Authors: PIERDOMINICI M , MAZZETTA F , CAPRINI E , MARZIALI M , DIGILIO M C , MARINO B , AIUTI A , AMATI F , RUSSO G , NOVELLI G , PANDOLFI F , LUZI G , GIOVANNETTI A 
Published: December 2004

SUMMARYChromosome 22q11.2 deletion (del22q11.2) syndrome (DiGeorge syndrome/velocardiofacial syndrome) is a common syndrome typically consisting of congenital heart disease, hypoparathyroidism, developmental delay and immunodeficiency. Although a broad range of immunologic defects have been described in these patients, limited information is currently available on the diversity of the T-cell receptor (TCR) variable β (BV) chain repertoire. The TCRBV repertoires of nine patients with del22q11.2 syndrome were determined by flow cytometry, fragment size analysis of the third complementarity determining region (CDR3 spectratyping) and sequencing of V(D)J regions. The rate of thymic output and the phenotype and function of peripheral T cells were also studied. Expanded TCRBV families were detected by flow cytometry in both CD4+ and CD8+ T cells. A decreased diversity of TCR repertoires was also demonstrated by CDR3 spectratyping, showing altered CDR3 profiles in the majority of TCRBV families investigated. The oligoclonal nature of abnormal peaks detected by CDR3 spectratyping was confirmed by the sequence analysis of the V(D)J regions. Thymic output, evaluated by measuring TCR rearrangement excision circles (TRECs), was significantly decreased in comparison with age-matched controls. Finally, a significant up-regulation in the percentage, but not in the absolute count, of activated CD4+ T cells (CD95+, CCR5+, HLA-DR+), IFN-γ - and IL-2-expressing T cells was detected. These findings suggest that the diversity of CD4 and CD8 TCRBV repertoires is decreased in patients with del22q11.2 syndrome, possibly as a result of either impaired thymic function and/or increased T-cell activation.
Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages
Authors: THERRIAULT M-J , PROULX L-I , CASTONGUAY A , BISSONNETTE É Y 
Published: December 2004

SUMMARY
Lung cancer is strongly associated with cigarette smoking. More than 20 lung carcinogens have been identified in cigarette smoke and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We hypothesized that NNK modulates alveolar macrophage (AM) mediator production, thus contributing to carcinogenesis. An AM cell line, NR8383, was treated with [3H]NNK and lipopolysaccharide (LPS), and NNK metabolites released in supernatants were analysed by high-performance liquid chromatography (HPLC). NNK was metabolized by carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol (NNAL) or activated by α-carbon hydroxylation. AMs were also treated with NNK (100–1000 µm), with and without LPS, for different periods of time (6–72 h), and mediators released in supernatants were quantified by enzyme-linked immunosorbent assay (ELISA) or the Griess reaction. NNK inhibited (in a concentration-dependent manner) AM production of tumour necrosis factor (TNF), macrophage inflammatory protein-1α (MIP-1α), interleukin (IL)-12 and nitric oxide (NO), whereas IL-10 production was increased. Cyclooxygenase inhibitors – NS-398 and indomethacin – and anti-prostaglandin E2 (anti-PGE2) antibody abrogated the NNK-inhibitory effect on MIP-1α production by AM. NNK stimulated the release of PGE2, and exogenous PGE2 inhibited AM MIP-1α production, suggesting that the NNK immunomodulatory effect may be mediated by PGE2 production. Thus, in addition to its carcinogenic effects, NNK may contribute to the lung immunosuppression observed in tobacco smokers.
IL-1β-induced Langerhans’ cell migration and TNF-αproduction in human skin: regulation by lactoferrin
Authors: CUMBERBATCH M , BHUSHAN M , DEARMAN R J , KIMBER I , GRIFFITHS C E M 
Published: December 2004

SUMMARYIn mice, the roles of cytokines in the initiation of epidermal Langerhans’ cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)-1β to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL-1β administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P &lt; 0·01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time-point of 4 h, injection of IL-1β was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P &lt; 0·01) tumour necrosis factor (TNF)-α production (2·99 ± 1·18 pg TNF-α/mg protein; mean ± s.d. of n = 10) in response to IL-1β treatment compared with saline control injections (0·90 ± 1·05 pg TNF-α/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron-binding protein found in exocrine secretions and skin, inhibited IL-1β-mediated LC migration and also compromised the production of TNF-α protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL-1β is associated with both the stimulation of human epidermal LC migration and local TNF-α production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF-α is an important mediator.
Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial
Authors:   THE FINNISH TRIGR STUDY GROUP, SADEHARJU K , HÄMÄLÄINEN A-M , KNIP M , LÖNNROT M , KOSKELA P , VIRTANEN S M , ILONEN J , ÅKERBLOM H K , HYÖTY H 
Published: December 2004

SUMMARYThis study evaluated the possible role of enterovirus infections in the pathogenesis of type I (insulin-dependent) diabetes in a prospective dietary intervention trial. Children participated in the second pilot of the Trial to Reduce IDDM in Genetically at Risk (TRIGR) project. They were randomized into two groups receiving either a casein hydrolysed formula (Nutramigen®) or a regular formula, whenever breast milk was not available over the first 6–8 months of life. Altogether 19 children who turned positive for autoantibodies associated with type I diabetes by 2 years of age and 84 matched control children were analysed for enterovirus antibodies and enterovirus RNA in serum. Enterovirus infections were common during the first 2 years of life and more frequent among boys than girls (P = 0·02). Autoantibody-positive children had more enterovirus infections than autoantibody-negative children before the appearance of autoantibodies (0·83 versus 0·29 infection per child, P = 0·01). The average levels of IgG antibodies to echovirus antigen were also higher in autoantibody-positive than in autoantibody-negative children (P = 0·0009). No difference was found in the frequency of enterovirus infections between children receiving the casein hydrolysed formula or regular formula. These results suggest that enterovirus infections are associated with the induction of β-cell autoimmunity in young children with increased genetic susceptibility to type I diabetes.
Low concentrations of cytokines produced by allergen-stimulated peripheral blood mononuclear cells have potent effects on nasal polyp-derived fibroblasts
Authors: OLSSON S , CAGNONI F , DIGNETTI P , MELIOLI G , CANONICA G W 
Published: December 2004

SUMMARYAccumulating data show that fibroblasts are important regulators in the development and maintenance of allergic airway inflammation. However, most studies so far have used individual recombinant cytokines in high concentrations, unlikely to be found in vivo. We aimed to investigate how cytokines produced by peripheral blood mononuclear cells (PBMC) affect fibroblast functions. Primary airway fibroblasts where incubated with allergen-stimulated or non-stimulated PBMC supernatants from allergic patients. The levels of cytokines in PBMC supernatants were measured and the expression of CD54, CD40 and CD106 as well as the production of eotaxin, interleukin (IL)-6 and IL-8 were assessed in fibroblasts. Although the levels of single cytokines measured in PBMC supernatants were low, a significant up-regulation of the surface molecules as well as of IL-6 and IL-8 production was found in fibroblasts cultured with allergen-stimulated PBMC supernatants as compared to non-stimulated, while the increase in eotaxin production was not significant. The evaluation of correlations between cytokines produced by PBMC and effects seen on fibroblasts did not indicate a crucial role for any single cytokine. Furthermore, the addition of comparably low concentrations of recombinant interferon (rIFN)-γ or recombinant tumour necrosis factor (rTNF)-α did not induce the same effects as PBMC supernatants, the only exception being TNF-α as a direct inducer of CD54 expression. Our results show that synergistic mechanisms has a more important role than single mediators, highlighting important differences between in vitro experiments, where effects of individual mediators are studied, versus the actual situation in vivo.
Role of gamma/delta T cell receptor-expressing lymphocytes in cutaneous infection caused byStaphylococcus aureus
Authors: MÖLNE L , CORTHAY A , HOLMDAHL R , TARKOWSKI A 
Published: December 2004

SUMMARYThe high number of γ/δ-expressing T cells found in the epithelial lining layer suggests that they form a first line of defence against invading pathogens. To evaluate the role of γ/δ T cell-receptor (TCR)-expressing cells in cutaneous infection caused by Staphylococcus aureus, mice lacking γ/δ-expressing T cells (TCRδ−/−) were inoculated intradermally with S. aureus, and compared with S. aureus-infected congeneic TCRδ+/− control mice. The number of bacteria recovered from the skin of TCRδ−/− mice was significantly higher (P = 0·0071) at early time-points after inoculation compared to the number of bacteria isolated from infected TCRδ+/− congeneic controls. Nevertheless, inflammatory responses measured as serum IL-6 levels, were significantly lower in TCRδ−/− mice than in the control group. A possible explanation for this discrepancy was the observation of significantly decreased overall numbers of infiltrating cutaneous T lymphocytes, which are important producers of IL-6. These results support the notion that the γ/δ-expressing T cells that reside at the epithelial lining layer of the skin is of importance for early containment of the bacteria, thereby limiting their replication and spread.
Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?
Authors: PURCELL A W , TODD A , KINOSHITA G , LYNCH T A , KEECH C L , GETHING M-J , GORDON T P 
Published: December 2004

SUMMARYPatterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.
Impaired CD40-signalling in Langerhans’ cells from murine neonatal draining lymph nodes: implications for neonatally induced cutaneous tolerance
Authors: SIMPSON C C , WOODS G M , MULLER H K 
Published: December 2004

SUMMARYCutaneous tolerance to antigens may be induced in mice through application of antigen during the first few days following birth. The mechanism governing this neonatally induced tolerance remains uncertain. We employed a contact hypersensitivity model to analyse dendritic cell (DC) function and the expression of classical and non-classical lymphocyte populations within the neonate. Examination of draining lymph node DC after antigenic challenge of the skin revealed these DC to be significantly deficient in their ability to stimulate antigen-specific T cell proliferation. Co-stimulatory molecule (CD40, CD80 and CD86) expression of these cells was deficient in comparison to adult DC, and functional tests revealed these cells to possess a critical absence of CD40 signalling. A numerical analysis of classical and non-classical lymphocyte expression demonstrated that while the neonatal spleen is devoid of T cells, the lymph nodes have a normal repertoire of T, B, γδ and CD4+CD25+ lymphocytes but an increased expression of natural killer (NK) cells. This study indicates that functionally deficient DC are likely contributors to neonatally induced cutaneous tolerance.