bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Behcet's disease
Authors: Nagafuchi H , Takeno M , Yoshikawa H , Kurokawa M S , Nara K , Takada E , Masuda C , Mizoguchi M , Suzuki N 
Published: January 2005

SummaryExcessive Th1 cell function is importantly involved in the pathogenesis of Behcet's disease (BD). We previously found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell specific transcription factor. To investigate immune aberration in the pathogenesis of BD, we studied the expression of Txk and Th1 cytokines in peripheral blood lymphocytes (PBL) and skin lesions in patients with BD. Cytokine production by the lymphocytes was assessed using ELISA. PBL produced excessive Th1 associated cytokines including IFN-γ and IL-12 spontaneously and in response to exogenous HSP60-derived peptide stimulation, which was shown to induce proliferation of PBL, in patients with BD. Circulating CD4+ T cells expressed excessive Txk protein. A majority of cells infiltrating into skin lesions expressed IFN-γ in the BD specimens. IL-12 and IL-18 were also expressed in the mononuclear cell aggregates. Lymphocytes accumulating in the skin lesion expressed higher levels of Txk as compared with atopic dermatitis lesions, a typical Th2 disease. IFN-γ, IL-18 and Il-12 were detected in the BD skin lesions, which may induce preferential development of Th1 cells in patients with BD. The mononuclear cell aggregates contained Txk expressing cells in such skin lesions. Collectively, Txk expressing Th1 cells and the Th1 associated cytokines may play a critical role in the development of skin lesions in BD.
Interactions between the mannose receptor and thyroid autoantigens
Authors: Chazenbalk G D , Pichurin P N , Guo J , Rapoport B , McLachlan S M 
Published: January 2005

SummaryThyroid autoantigens require internalization and processing by antigen-presenting cells to induce immune responses. Besides pinocytosis, antigen uptake can be receptor-mediated. The mannose receptor (ManR) has a cysteine rich domain (CR) and eight carbohydrate recognition domains (CRD) that bind glycosylated proteins. The TSH receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) are glycoproteins. To investigate a role for the ManR in thyroid autoimmunity, we tested the interaction between these autoantigens and chimeric ManRs. Plasmids encoding the CR-domain linked to IgG-Fc (CR-Fc) and CDR domains 4–7 linked to IgG-Fc (CDR4-7-Fc) were expressed and purified with Protein A. Enzyme-linked immunosorbent assay (ELISA) plates were coated with human thyroid autoantigens and CR-Fc or CRD4-7-Fc binding detected with peroxidase-conjugated anti-IgG-Fc. CRD4-7-Fc binding was highest for the TSHR, followed by Tg and was minimal for TPO. CR-Fc bound to Tg but not to TSHR or TPO. The interaction between the TSHR and CRD-Fc was calcium-dependent; it was inhibited by mannose (not galactose), and required a glycosylated TSHR A-subunit. Moreover, precomplexing the TSHR A-subunit with CRD-Fc (but not CR-Fc), or adding mannose (but not galactose), decreased in vitro responses of splenocytes from TSHR-immunized mice. Our data indicate that the ManR may participate in autoimmune responses to Tg and the TSHR but not to TPO. Most important, ManR binding of heavily glycosylated TSHR A-subunits suggests a mechanism by which the minute amounts of A-subunit protein shed from the thyroid may be captured by antigen-presenting cells located in the gland or in draining lymph nodes.
Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship
Authors: Carlsson M , Sjöholm A G , Eriksson L , Thiel S , Jensenius J C , Segelmark M , Truedsson L 
Published: January 2005

SummaryIn cystic fibrosis (CF) prognosis concerning lung damage development is highly variable and difficult to predict. Mannan-binding lectin (MBL) deficiency has been reported to be associated with poor outcome in CF lung disease. MBL is a recognition molecule of the MBL pathway of the complement system and is encoded by a gene characterized by a high degree of polymorphism. Some genotypes result in low serum concentrations of MBL. MBL-associated serine protease 2 (MASP-2) is another protein belonging to the MBL pathway. A mutation resulting in low levels of MASP-2 in serum has been described recently. In the present study, 112 CF patients aged 4–54 years were investigated for MBL and MASP-2 genotypes, serum levels of MBL and MASP-2 and the MBL pathway function in serum. No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function. However, in the 27 patients colonized with Staphylococcus aureus, MBL-deficient genotypes were associated with decreased lung function. As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele. An unexpected finding was that CF patients had higher serum levels of MBL than healthy controls when corrected for MBL genotype. In conclusion, MBL pathway function was affected both by MBL and by MASP-2 genotypes. However, MBL or MASP-2 levels in serum did not affect the clinical outcome in the cohort of CF patients studied.
Correlation of disease evolution with progressive inflammatory cell activation and migration in the IL-4 transgenic mouse model of atopic dermatitis
Authors: Chen Lin , Martinez O , Venkataramani P , Lin S-X , Prabhakar B S , Chan L S 
Published: January 2005

SummaryAtopic dermatitis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration in the skin. In order to assess the roles of inflammatory cells in this disease, we analysed the activation status and surface markers of various leucocytes in the IL-4 transgenic mouse model of atopic dermatitis, by flow cytometry, immuofluorescence microscopy, and T cell proliferation assays. The studies were performed with a nontransgenic mouse control and transgenic mice at three disease stages: before disease onset, early skin disease, and late skin disease, so that we can delineate the immunological sequence of events. As the skin disease evolves, the skin draining lymph node cells from IL-4-Tg mice show a spontaneous proliferation and a progressively enhanced proliferative response to stimulants including anti-CD3, Con A, PHA, and Staphylococcus enterotoxins A and B. As the disease evolves, the percent of lymphoid organ T cells expressing activation molecules (CD44 and CD69) and costimulatory molecules (ICOS and PD-1) are progressively increased; the percent and total number of T cells are reduced in an incremental manner in the secondary lymphoid organs while the number of T cells infiltrating the skin increases in an incremental fashion; the total number of dendritic antigen presenting cells, macrophages, and NK cells gradually increases in the lymphoid organs. Collectively, our results suggest that there is a continued and progressive migration of activated inflammatory cells from the secondary lymphoid organs into the skin where they participate in immune responses resulting in the pathology associated with inflammation.
Alteration of newly induced endochondral bone formation in adult mice without tumour necrosis factor receptor 1
Authors: Lukić I K , Grčević D , Kovačić N , Katavić V , Ivčević S , Kalajzić I , Marušić A 
Published: January 2005

Summary
Tumour necrosis factor (TNF)-α, a major proinflammatory cytokine, exerts its role on bone cells through two receptors (TNFR1 and TNFR2). TNFR1, but not TNFR2, is expressed by osteoblasts and its function in bone formation in vivo is not fully understood. We compared in vivo new bone formation in TNFR1-deficient (TNFR1–/–) mice and wild-type mice, using two models of bone formation: intramembranous ossification following tibial marrow ablation and endochondral ossification induced by bone morphogenetic protein (BMP)-2. Intramembranous osteogenesis in TNFR1–/– mice did not differ from the wild-type mice either in histomorphometric parameters or mRNA expression of bone-related markers and inflammatory cytokines. During endochondral osteogenesis, TNFR1–/– mice formed more cartilage (at post-implantation day 9), followed by more bone and bone marrow (at day 12). mRNAs for BMP-2, -4 and -7 were increased during the endochondral differentiation sequence in TNFR1–/– mice. The expression of receptor activator of NF-κ B ligand (RANKL) and receptor activator of NF-κ B (RANK), as assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR), was also increased significantly during endochondral ossification in TNFR1–/– mice. In conclusion, signalling through the TNFR1 seems to be a negative regulator of new tissue formation during endochondral but not intramembranous osteogenesis in an adult organism. BMPs and RANKL and its receptor RANK may be involved in the change of local environment in the absence of TNFR1 signalling.
Identification of epithelial auto-antigens associated with periodontal disease
Authors: Ye P , Simonian M , Nadkarni M A , DeCarlo A A , Chapple C C , Hunter N 
Published: January 2005

SummaryWe previously reported evidence that patients with periodontitis have serum antibodies to oral Gram positive bacteria that are cross-reactive with epithelial antigens. In the present report cross-reactive epithelial antigens including CD24, lactate dehydrogenase A [LDM-A], antioxidant protein 2 [AOP 2] and nuclear factor of activated T cells 5 [NFAT 5], were identified by screening a cDNA expression library with pooled patient sera. Titres of antibodies to CD24 peptide correlated negatively with indices of periodontal disease severity. Strong expression of CD24 in the reactive periodontal epithelium and inflamed gingival attachment contrasted with low to undetectable expression in the external gingival epithelium. In periodontitis, a local action of these auto-reactive antibodies could modulate the regulatory potential associated with expression of CD24 in this epithelium.
Phenotypic perturbation of B cells in the Wiskott–Aldrich syndrome
Authors: Park J Y , Shcherbina A , Rosen F S , Prodeus A P , Remold-O’Donnell E 
Published: January 2005

SummaryWiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency/platelet disease due to mutations of WASP, a cytoskeletal regulatory protein of blood cells. Patients exhibit a range of immune defects generally attributed to defective T-cell function, including poor response to immunization, skewed immunoglobulin isotypes, eczema, recurrent infections, autoimmune disease and increased frequency of malignancies. Here we show a deficit of total B-cells in WAS patients of various ages and identify phenotypic perturbations involving complement receptors and CD27. Whereas B-cells of normal healthy donors are overwhelmingly CD21/CD35-positive, B-cells expressing these receptors are significantly reduced in number in WAS patients, and their paucity may cause suboptimal antigen capture and presentation. The frequencies of IgD– and IgG+ patient B-cells were not different from healthy donors (although absolute numbers were decreased), indicating that isotype switching is occurring. In contrast, the frequency of cells positive for CD27, the marker of post germinal centre B-cells, was significantly decreased even among isotype-switched cells, and B-cells resembling germinal centre progenitors (CD10+CD27–CD38bright) were more frequent in adult patients, suggesting impaired germinal centre maturation/differentiation. The documentation of these phenotypic perturbations and deficit of total cells suggest that defects intrinsic to B-cells contribute to the impaired humoral immunity that characterizes this disease.
Taurine attenuates CD3/interleukin-2-induced T cell apoptosis in anin vitromodel of activation-induced cell death (AICD)
Authors: Maher S G , Condron C E M , Bouchier-Hayes D J , Toomey D M 
Published: January 2005

SummaryInterleukin (IL)-2 immunotherapy is used for the treatment of metastatic melanoma and renal cell carcinoma and mediates its effects through the clonal expansion of lymphocytes. Although IL-2 remains the most effective form of therapy for these cancers, response rates are poor and dose escalation is hampered by side effects, which include vascular leak and lymphopenia. The mechanism underlying T cell loss is currently unidentified but could be the induction of activation-induced cell death (AICD) mediated by FasL. Our previous studies have shown that the amino acid taurine can attenuate apoptosis induced by a number of factors in different cell types. Here, we induced T cell AICD via CD3 and IL-2 stimulation and investigated the effect of taurine on lymphocyte apoptosis. Anti-CD3-activated Jurkat T cells treated with IL-2 significantly increased FasL expression, which was associated with increased apoptosis. Treatment with taurine prior to stimulation down-regulated FasL protein expression and partially inhibited apoptosis. Inhibition of FasL-signalling resulted in an identical reduction in apoptosis. As the kinetics of AICD are completely different in circulating T cells, we repeated these experiments in such cells to confirm our finding. Stimulation of CD4+ circulating T cells induced apoptosis in sensitized, but not freshly isolated T cells, which was abrogated partially by taurine. In Jurkat cells it was determined that taurine-mediated down-regulation of FasL protein expression was associated with decreased FasL mRNA expression and reduced NFκB activation. These results reveal one possible mechanism underlying the lymphopenia observed with IL-2 immunotherapy, involving increased FasL expression leading to apoptosis. Taurine may be of use in reversing the lymphopenia associated with IL-2, thereby augmenting its immunotherapeutic potential.
Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent
Authors: Islander U , Erlandsson M C , Chavoshi T , Jochems C , Movérare S , Nilsson S , Ohlsson C , Gustafsson J-Å , Carlsten H 
Published: January 2005

Summary
Estrogen has extensive effects on the immune system. The aim of the present experiments was to compare the effects of 17β-estradiol (E2) and 4-estren-3α,17β-diol (estren) on T lymphopoiesis and T cell-dependent inflammation. In order to investigate the role of estrogen receptors (ER) in the effects of E2 and estren on the immune system, ER knock-out mice lacking both ERα and ERβ (DERKO) were used. T lymphopoiesis and T cell-dependent inflammation were studied by investigating thymus cellularity, the delayed-type hypersensitivity (DTH) reaction, CD4+ T cells in spleen and serum levels of interleukin (IL)-6. As expected, the presence of ERs was mandatory for all the effects of E2. In contrast, treatment with estren reduced thymus cellularity in ER knock-out mice, indicating an effect through ER-independent pathways. Interestingly, estren suppressed only DTH, the frequency of CD4+ T cells in spleen and serum levels of IL-6 in wild-type (WT) mice, but not in mice lacking ERs. Thus, our study is the first to show that estren inhibits T lymphopoiesis via ER-independent pathways, whereas its suppressive effects on inflammation are ER-dependent.
Autoantibodies directed against the protease inhibitor calpastatin in psoriasis
Authors: Matsushita Y , Shimada Y , Kawara S , Takehara K , Sato S 
Published: January 2005

Summary
Psoriasis is believed to be a T cell-mediated autoimmune disease, but also exhibits autoantibody production. Calpastatin is an endogenous inhibitor of calpain, a ubiquitous protease that regulates inflammatory processes. Anti-calpastatin autoantibody was first identified as an autoantibody specific to rheumatoid arthritis, but has been also detected in other autoimmune diseases. In this study, we examined the presence and levels of anti-calpastatin antibody in 77 psoriasis patients by enzyme-linked immunosorbent assay. Compared with normal controls, psoriasis patients exhibited significantly elevated IgG anti-calpastatin antibody levels that were similar to those found in rheumatoid arthritis patients. Remarkably, IgG anti-calpastatin autoantibody in sera from psoriasis patients inhibited calpastatin activity. Calpain II expression was up-regulated in psoriasis skin lesions compared with normal skin while calpastatin expression was normal. The results of this study reveal the presence of anti-calpastatin autoantibody in psoriasis.
Impaired interleukin (IL)-4-associated generation of CCR4-expressing T cells in neonates with hereditary allergy risk
Authors: Haddeland U , Sletten G B , Brandtzaeg P , Nakstad B 
Published: January 2005

SummaryReduced microbial exposure in early life may contribute to the increase of atopic diseases in ‘westernized’ societies but the underlying mechanisms remain elusive. The objective of this study was to examine how exposure to bacterial lipopolysaccharide (LPS) during early antigen encounter might influence the maturation of neonatal lymphoid cells, and to define possible differences in this respect between neonates with high risk of allergy due to a family history (FH+) and controls with no apparent hereditary risk (FH–). Cord blood mononuclear cells from the FH+ or FH– group were stimulated with pure LPS or β-lactoglobulin (β-LG) in the presence of LPS. T cell expression of chemokine receptors CCR4 and CXCR3 was determined by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). Cellular expression of interleukin (IL)-4 was analysed by quantitative RT-PCR, whereas interferon (IFN)-γ was analysed by both quantitative RT-PCR and immunoassay. Stimulation with LPS, or β-LG together with LPS, induced up-regulation of CCR4 (P &lt; 0·05) and CXCR3 (P &lt; 0·05). For CCR4, such up-regulation was related to the level of IL-4 produced by the same T cells (rS = 0·49, P = 0·03), while CXCR3 expression was negatively correlated with the IL-4 levels (rS = −0·56, P = 0·02). Compared with the FH– group, the FH+ group showed a significantly lower capacity for generation of CCR4+ T cells (mean percentage of total T cells: FH+, 2·42%versus FH–, 5·74%; P &lt; 0·01), whereas induction of CXCR3 and IFN-γ did not differ significantly between the two groups. When the immune system in early life encounters antigen together with LPS, the T cell potential for compartmentalized interaction with other immune cells might be increased by elevated CCR4- and CXCR3-expression levels. In neonates at hereditary allergy risk, this putative homeostatic mechanism could theoretically be jeopardized due to decreased up-regulation of CCR4. Conversely, Th1 responses to antigen in the presence of LPS did not appear to be reduced compared with controls.
Exploiting T cell receptor genes for cancer immunotherapy
Authors: Xue S , Gillmore R , Downs A , Tsallios A , Holler A , Gao L , Wong V , Morris E , Stauss H J 
Published: January 2005

SummaryAdoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, ‘conventional’ adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for ‘unconventional’ antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8+ and CD4+ lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.
Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome
Authors: TRUJILLO M. E. , SCHERER P. E. 
Published: January 2005

Abstract.Adiponectin is an adipocyte‐derived hormone that was discovered in 1995. Unlike leptin, which was identified around the same time, the clinical relevance of adiponectin remained obscure for a number of years. However, starting in 2001, several studies were published from different laboratories that highlighted the potential antidiabetic, antiatherosclerotic and anti‐inflammatory properties of this protein complex. Methods to measure the protein with high throughput assays in clinical samples were developed shortly thereafter, and as a result hundreds of clinical studies have been published over the past 3 years describing the role of adiponectin in endocrine and metabolic dysfunction. Furthermore, adiponectin research has expanded to include a role for adiponectin in cancer and other disease areas. Although it is an impossible task to summarize the findings from all these studies in a single review, we aim to demonstrate the utility of circulating adiponectin as a biomarker of the metabolic syndrome. Evidence for this relationship will include how decreased levels of plasma adiponectin (‘hypoadiponectinaemia’) are associated with increased body mass index (BMI), decreased insulin sensitivity, less favourable plasma lipid profiles, increased levels of inflammatory markers and increased risk for the development of cardiovascular disease. Therefore, adiponectin levels hold great promise for use in clinical application serving as a potent indicator of underlying metabolic complications.
Favourable association of leg fat with cardiovascular risk factors
Authors: SAKAI Y. , ITO H. , EGAMI Y. , OHOTO N. , HIJII C. , YANAGAWA M. , SATOH S. , JINGU S. 
Published: January 2005

Abstract.Objectives.  To assess the association of trunk and leg fat mass (FM) and leg lean tissue mass (LTM) with conventional cardiovascular risk factors.Design. Cross‐sectional study.Setting and subjects.  We studied 1249 men and 3007 women (age 20–79 years) who attended a research institute for a health checkup between October 1995 and February 2004.Main outcome measures.  Body mass index, waist circumference (WC), hip circumference (HC), systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, triglycerides, glucose and haemoglobin A1C were measured. Trunk FM, leg FM and leg LTM were obtained by dual‐energy X‐ray absorptiometry. We evaluated the associations between the indices for regional body composition and cardiovascular risk factors, which included hypertension, hypercholesterolaemia, hypo‐HDL cholesterolaemia, hypertriglyceridaemia, dyslipidaemia and diabetes mellitus.Results.  Increase in WC and HC respectively showed increase and decrease in odds ratios of cardiovascular risk factors. Increase in trunk FM by 1 kg significantly increased the risk of the cardiovascular risk factors with the odds ratios ranging between 1.11 and 1.45. Increase in leg FM by 1 kg significantly decreased the risk with the odds ratios ranging between 0.52 and 0.90, except for the nonsignificant results for hypercholesterolaemia and hypo‐HDL cholestero‐laemia in men. Odds ratios of 1 kg increase in leg LTM were only significant for dyslipidaemia in men and hypercholesterolaemia in women (both 0.93).Conclusions.  WC and HC showed opposite and independent associations with cardiovascular risk factors. The favourable association of HC was mainly attributable to that of leg FM.