bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smoking and a complement gene polymorphism interact in promoting cardiovascular disease morbidity and mortality
Authors: Arason G J , Kramer J , Blaskó B , Kolka R , Thorbjornsdottir P , Einarsdóttir K , Sigfúsdóttir A , Sigurðarson S T , Sigurðsson G , Rónai Z , Prohászka Z , Sasvári-Székely M , Böðvarsson S , Thorgeirsson G , Füst G 
Published: August 2010

Summary
We have demonstrated previously that carriers of a genotype called C4B*Q0 (silent allele of the C4B gene) have a substantially increased risk to suffer from myocardial infarction or stroke, and are selected out from the healthy elderly population. Because smoking carries a major risk for cardiovascular disease (CVD), it seemed worthwhile to study if these two factors interact. Study 1 involved 74 patients with angina pectoris (AP), 85 patients with recent acute myocardial infarction (AMI) and 112 survivors of a previous AMI and 382 controls from Iceland. Study 2 involved 233 patients with severe CVD and 274 controls from Hungary. Smoking habits were registered for each subject. The number of C4A and C4B genes was determined by phenotyping or genotyping. Compared to controls, C4B*Q0 carrier frequency was significantly higher at diagnosis in Icelandic smokers with AP (P = 0·005) and AMI (P = 0·0003) and Hungarian smokers with severe coronary artery disease (P = 0·023), while no such difference was observed in non-smoking subjects. Age-associated decrease in C4B*Q0 observed previously in two remote Caucasian populations was found, in the present study, to be associated strongly with smoking, and to already occur in smokers after age 50 years both in Iceland and Hungary. Our findings indicate that the C4B*Q0 genotype can be considered as a major covariate of smoking in precipitating the risk for AMI and associated deaths.
Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa
Authors: Antonopoulou A , Raftogiannis M , Giamarellos-Bourboulis E J , Koutoukas P , Sabracos L , Mouktaroudi M , Adamis T , Tzepi Ira , Giamarellou H , Douzinas E E 
Published: August 2010

Summary
Apoptosis of blood monocytes was studied in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa. Thirty-six rabbits were used, divided into the following groups: A (n = 6), sham; B (n = 6), administered anaesthetics; and C (n = 24), acute pyelonephritis induced after inoculation of the test isolate in the renal pelvis. Blood was sampled at standard time intervals for estimation of tumour necrosis factor (TNF)-α and isolation of monocytes. Half the monocytes were incubated and the other half was lysed for estimation of the cytoplasmic activity of caspase-3 by a kinetic chromogenic assay. No animal in groups A and B died; those in group C were divided into two subgroups, CI (n = 8) with present activity of caspase-3 of blood monocytes at 3·5 h and CII (n = 16) with absent activity. Their median survival was 2·0 and 3·5 days, respectively (P = 0·0089). Ex vivo secretion of TNF-α from monocytes was higher by monocytes of subgroup CII than subgroup CI at 3·5 h (P = 0·039) and of group A than CII at 48 h (P = 0·010). Median change of caspase-3 activity between 3·5 and 24 h of sampling was 56·1 and −5·8 pmol/min per 104 cells for subgroups CI and CII (P = 0·040), respectively. Respective changes between 3·5 and 48 h were 28 981·0 and 0 pmol/min per 104 cells (P = 0·036). Early induction of apoptosis in blood monocytes is of prime importance for the survival of the septic host and might be connected to changes of monocyte potential for the secretion of TNF-α.
Association of −318 C/T and +49 A/G cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis
Authors: Balbi G , Ferrera F , Rizzi M , Piccioli P , Morabito A , Cardamone L , Ghio M , Palmisano G L , Carrara P , Pedemonte S , Sessarego M , De Angioletti M , Notaro R , Indiveri F , Pistillo M P 
Published: August 2010

Summary
Systemic sclerosis (SSc) is a complex and heterogeneous autoimmune disorder with a multi-factorial pathogenesis. Like other autoimmune disorders, the possible role of specific cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in predisposing to SSc has been hypothesized, but it remains controversial. CTLA-4 promoter (−318C/T) and exon 1 (+49 A/G) polymorphisms have been analysed in 43 Italian females with SSc and in 93 unrelated matched healthy controls by a newly designed tetra-primer amplification refractory mutation system–polymerase chain reaction (T-ARMS–PCR) method. No significant association has been found with either polymorphisms. Nevertheless, SSc patients without concomitant Hashimoto's thyroiditis (HT) were carrying both the −318T allele (P = 0·031) and the +49 G allele (P = 0·076) more frequently than SSc patients with HT [defined by positivity for anti-thyroperoxidase (TPO) and anti-thyroglobulin (TGA) autoantibodies] than controls. Haplotype analysis confirms this association (P = 0·028), and suggests the predominant role of the −318T, whereas that of the +49 G, if any, seems weak. Thus, in Italian SSc patients the CTLA-4 −318C/T promoter polymorphism appears to be associated with the susceptibility to develop SSc without thyroid involvement. Larger studies are needed to confirm these findings and to clarify whether the −318C/T polymorphism is the functional responsible or whether it reflects the presence of another linked genetic element in the same chromosomal region.
Increased expression of Toll-like receptor 4 in peripheral blood leucocytes and serum levels of some cytokines in patients with ankylosing spondylitis
Authors: Yang Z-X , Liang Y , Zhu Y , Li C , Zhang L-Z , Zeng X-M , Zhong R-Q 
Published: August 2010

Summary
Toll-like receptor 4 (TLR4) is a member of the Toll-like receptor family, which can bridge innate and adaptive immune responses. Activation of the TLR4 signalling pathway may induce the release of proinflammatory cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL)-12, which was considered to play an important role in pathogenesis of immune-mediated diseases. Ankylosing spondylitis (AS) is an immune-mediated disease whose aetiology remains unknown. The aim of the study was to investigate the expression of TLR4 and serum TNF-α, IL-12 and soluble tumour necrosis factor-related apoptosis-inducing ligand (sTRAIL) level in AS patients. The results indicated that TLR4 protein and mRNA levels were significantly higher in AS patients than in healthy controls; however, there was no significant difference between human leucocyte antigen (HLA)-B27-positive and -negative AS patients, as well as serum levels of TNF-α, IL-12 and sTRAIL. In addition, in HLA-B27-positive AS patients, TLR4 level showed close associations with the cytokines and laboratory parameters of disease activity [erythrocyte sedimentation rate (ESR) and plasma C-reactive protein (CRP)], respectively. Similarly, the strong associations between the cytokines or between IL-12 and ESR or CRP were observed in HLA-B27-positive AS patients. Interestingly, in HLA-B27-positive AS patients, TNF-α correlated significantly with ESR, but did not with CRP. In contrast, sTRAIL correlated with CRP, but did not with ESR. Among HLA-B27-negative patients, no close correlation was found. In our study, it was suggested that the abnormal activation of TLR4 signalling and serum TNF-α, IL-12 and sTRAIL may play a key role in the development and progression of AS, which may be dependent on the status of HLA-B27 antigen.
CXC chemokine ligand 16 in periodontal diseases: expression in diseased tissues and production by cytokine-stimulated human gingival fibroblasts
Authors: Hosokawa Y , Hosokawa I , Ozaki K , Nakae H , Matsuo T 
Published: August 2010

Summary
Periodontal disease is an inflammatory disorder characterized by the involvement of chemokines that are important for the recruitment of leucocytes. Several cytokines are involved in regulating levels of chemokines in periodontal disease. CXCL16 is a chemokine related to the migration of T helper 1 (Th1) cells and natural killer (NK) cells. In this study, we examined its expression in periodontal tissues. Moreover, we investigated the effects of cytokines on the production of CXCL16 by human gingival fibroblast (HGF). Reverse transcription–polymerase chain reaction (RT–PCR) analysis and immunohistochemistry revealed that CXCL16 and its receptor, CXCR6, were expressed at the mRNA and protein levels in diseased tissues. Proinflammatory cytokines [interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ] increased the mRNA expression and release of CXCL16 in a dose-dependent manner. Moreover, treatment of HGFs with IFN-γ in combination with IL-1β had a synergistic effect on the production of CXCL16. On the other hand, IL-4 and IL-13 inhibited the IL-1β-induced CXCL16 production by HGFs. Inhibitors of A disintegrin and metalloprotease (ADAM)10 and ADAM17, a recently identified protease of CXCL16, reduced the amount of CXCL16 released from HGFs. These results suggest that the CXCL16 produced by HGFs may be involved in the migration of leucocytes into inflamed tissues, and provide evidence that CXCL16 production is controlled by cytokines in periodontal disease.
Selective unresponsiveness to beta cell autoantigens after induction immunosuppression in pancreas transplantation with anti-interleukin-2 receptor antibody versus anti-thymocyte globulin
Authors: van de Linde P , vd Boog P J M , Tysma O M H , Elliott J F , Roelen D L , Claas F H J , de Fijter J W , Roep B O 
Published: August 2010

Summary
Pancreas transplantation in type 1 diabetes patients could result in (re)activation of allo- and autoreactive T lymphocytes. Anti-thymocyte globulin (ATG) induction treatment is a successful, but broadly reactive anti-lymphocyte therapy used in pancreas and islet transplantation. A more selective alternative is daclizumab, a monoclonal antibody directed against the interleukin-2 receptor (CD25) on activated lymphocytes. We tested the hypothesis that daclizumab is more selective and has less immunological side effects than ATG. Thirty-nine simultaneous pancreas–kidney transplantation patients with type 1 diabetes were randomized for induction therapy with ATG or daclizumab. Auto- and recall immunity was measured cross-sectionally by lymphocyte stimulation tests with a series of auto- and recall antigens in 35 successfully transplanted patients. T cell autoimmunity to islets was low in both groups, except for a marginal but significantly higher reactivity against glutamic acid decarboxylase (GAD)65 in daclizumab-treated patients. The memory responses to recall antigens were significantly higher in the daclizumab-treated group compared to ATG-treated patients, specifically against purified protein derivative (PPD) (anti-bacterial immunity), Haemophilus influenzae virus matrix protein-1 (anti-viral immunity) and p53 [anti-tumour (auto)immunity]. These data imply that daclizumab is more specifically affecting diabetes-related immune responses than ATG. The autoimmunity is affected effectively after daclizumab induction, while memory responses towards bacterial, viral and tumour antigens are preserved.
The activation state of human intrahepatic lymphocytes
Authors: Tu Z , Bozorgzadeh A , Crispe I N , Orloff M S 
Published: August 2010

SummaryThe immune tolerance induced by the liver as an allograft is difficult to reconcile with the evidence that the liver selectively accumulates activated T cells from the circulation. However, much of this information is based on murine liver lymphocytes that were isolated using enzymatic digestion. In the present study we made use of a novel resource, the lymphocytes isolated during the perfusion of living donor liver lobe prior to transplantation. These healthy human liver lymphocytes displayed surface markers indicating a high degree of activation of natural killer cells, CD56+ T cells, CD4+ T cells and CD8+ T cells. These properties were independent of enzymatic treatment or the details of cell isolation. We conclude that the healthy human liver is a site of intense immunological activity.
Reduced number and function of peripheral dendritic cells in coeliac disease
Authors: Ciccocioppo R , Ricci G , Rovati B , Pesce I , Mazzocchi S , Piancatelli D , Cagnoni A , Millimaggi D , Danova M , Corazza G R 
Published: August 2010

SummaryDendritic cells (DC) play a pivotal role in shaping the immune response in both physiological and pathological conditions. In peripheral blood at least two subsets, the myeloid and plasmacytoid, have been described as having different T stimulatory functions and a variable degree of maturation. Certainly, antigen presentation plays a crucial role in the pathogenesis of coeliac disease and circulating immune cells are thought to reflect the state of immune response within the gut. Therefore, we aimed to investigate the quantitative and phenotypical modifications of peripheral blood DC, together with their functional properties, in this pathological condition. Blood samples from 11 untreated patients before and after a course of gluten-free diet, 27 treated patients and 14 controls underwent flow-cytometric analysis, while immunomagnetically sorted DC from the CD patients and eight human leucocyte antigen (HLA)-DQ2/8+ bone marrow donors were used to evaluate maturation status through the CD83 expression, cytokine profile for interleukin (IL)-6, IL-10, IL-12 and interferon (IFN)-α by enzyme-linked immunosorbent assay (ELISA), and functional properties by mixed leucocyte reaction before and after pulsing with digested gliadin. We found that in both untreated and treated patients, a significant reduction of the entire DC population, mainly the plasmacytoid subset, in comparison to healthy controls was observed. In active disease, an impaired allogenic lymphocyte reaction and a significant reduction of IFN-α production, paralleled by the presence of a more immature status, were also demonstrated. All the latter modifications have been reverted by pulsing DC with digested gliadin.
Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients
Authors: Lorea Baroja M , Kirjavainen P V , Hekmat S , Reid G 
Published: August 2010

SummaryOur aim was to assess anti-inflammatory effects on the peripheral blood of subjects with inflammatory bowel disease (IBD) who consumed probiotic yogurt for 1 month. We studied 20 healthy controls and 20 subjects with IBD, 15 of whom had Crohn's disease and five with ulcerative colitis. All the subjects consumed Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 supplemented yogurt for 30 days. The presence of putative regulatory T (Treg) cells (CD4+ CD25high) and cytokines in T cells, monocytes and dendritic cells (DC) was determined by flow cytometry from peripheral blood before and after treatment, with or without ex vivo stimulation. Serum and faecal cytokine concentrations were determined by enzyme-linked immunosorbent assays. The proportion of CD4+ CD25high T cells increased significantly (P = 0·007) in IBD patients, mean (95% confidence interval: CI) 0·84% (95% CI 0·55–1·12) before and 1·25% (95% CI 0·97–1·54) after treatment, but non-significantly in controls. The basal proportion of tumour necrosis factor (TNF)-α+/interleukin (IL)-12+ monocytes and myeloid DC decreased in both subject groups, but of stimulated cells only in IBD patients. Also serum IL-12 concentrations and proportions of IL-2+ and CD69+ T cells from stimulated cells decreased in IBD patients. The increase in CD4+ CD25high T cells correlated with the decrease in the percentage of TNF-α- or IL-12-producing monocytes and DC. The effect of the probiotic yogurt was confirmed by a follow-up study in which subjects consumed the yogurt without the probiotic organisms. Probiotic yogurt intake was associated with significant anti-inflammatory effects that paralleled the expansion of peripheral pool of putative Treg cells in IBD patients and with few effects in controls.
Can interferon-γ and interleukin-10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?
Authors: Gomes-Silva A , de Cássia Bittar R , dos Santos Nogueira R , Amato V S , da Silva Mattos M , Oliveira-Neto M P , Coutinho S G , Da-Cruz A M 
Published: August 2010

Summary
Suitable levels of interferon (IFN)-γ and interleukin (IL)-10 seem to favour the outcome of cutaneous leishmaniasis (CL), while high IFN-γ and low IL-10 production are associated with severity of mucosal leishmaniasis (ML). Considering that cytokine balance is important for the maintenance of protective responses in leishmaniasis, our aim was to investigate leishmanial antigens-induced IFN-γ and IL-10 levels maintained in healed individuals who had different clinical outcomes of Leishmania infection. Thirty-three individuals who recovered from L. braziliensis infection were studied: cured CL (CCL), cured ML (CML), spontaneous healing of CL (SH) or asymptomatic individuals (ASY). Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in culture supernatants of L. braziliensis-stimulated peripheral blood mononuclear cells (PBMC). IFN-γ levels were higher in CML (7593 ±  5994 pg/ml) in comparison to SH (3163 ± 1526 pg/ml), ASY (1313 ±  1048 pg/ml) or CCL (1897 ± 2087 pg/ml). Moreover, cured ML cases maintained significantly lower production of IL-10 (127 ± 57·8 pg/ml) in comparison to SH (1373 ± 244 pg/ml), ASY (734 ± 233 pg/ml) or CCL (542 ±  375 pg/ml). Thus, a high IFN-γ/IL-10 ratio observed in CML can indicate unfavourable cytokine balance. On the other hand, no significant difference in the IFN-γ/IL-10 ratio was observed when CCL individuals were compared to SH or ASY subjects. In conclusion, even after clinical healing, ML patients maintained a high IFN-γ/IL-10 secretion profile in response to leishmanial antigens. This finding can explain a delayed down-modulation of exacerbated inflammatory responses, which can be related in turn to the necessity of prolonged therapy in ML management. Conversely, lower IFN-γ/IL-10 balance observed in CCL, SH and ASY individuals can represent a better-modulated immune response associated with a favourable prognosis.
IgM plays an important role in induction of collagen-induced arthritis
Authors: Zheng B , Zhang X , Guo L , Han S 
Published: August 2010

SummaryIgM is one major type of B cell receptor (BCR) expressed on most of the B cells from immature to mature stages. During normal B cell ontogeny, signals transduced through the IgM BCR play an important role in regulating B cell maturation and survival at multiple checkpoints. In addition, IgM BCR is also required for antigen-dependent differentiation and activation of B cells. However, whether IgM BCR-mediated signalling is important for the pathogenesis of autoimmune diseases remains elusive. Using IgM-deficient mice, we examined the effect of absence of IgM on the development of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis (RA). Compared to their wild-type littermates, IgM-deficient mice were either resistant to arthritis induction or developed significantly less severe arthritis. There was a significant decrease of autoantibody production in IgM-deficient mice, particularly IgG2a antibodies, which is believed to be pathogenic in CIA. Thus, although IgM–/– mice have relatively normal B cell development with IgD BCR replacing IgM BCR, the absence of IgM-mediated signals has a profound impact on the development of CIA, indicating that IgM plays an important role in the development and pathogenesis of autoimmune arthritis and IgM-mediated signalling is critical in the generation of pathogenic autoreactive antibodies.
Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction
Authors: Harashima S-I , Harashima C , Nishimura T , Hu Y , Notkins A L 
Published: August 2010

SummaryIA-2 is a major autoantigen in type 1 diabetes and autoantibodies to it have become important diagnostic and predictive markers. IA-2 also is an intrinsic transmembrane component of dense core secretory vesicles and knock-out studies showed that IA-2 is a regulator of insulin secretion. Here we show that overexpression of IA-2 puts mouse insulinoma MIN-6 beta cells into a pre-apoptotic state and that exposure to high glucose results in G2/M arrest and apoptosis. Molecular study revealed a decrease in phosphoinositide-dependent kinase (PDK)-1 and Akt/protein kinase B (PKB) phosphorylation. Treatment of IA-2-transfected cells with IA-2 siRNA prevented both G2/M arrest and apoptosis and increased Akt/PKB phosphorylation. A search for IA-2 interacting proteins revealed that IA-2 interacts with sorting nexin (SNX)19 and that SNX19, but not IA-2, inhibits the conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 and thereby suppresses the phosphorylation of proteins in the Akt signalling pathway resulting in apoptosis. We conclude that IA-2 acts through SNX19 to initiate the pre-apoptotic state. Our findings point to the possibility that in autoimmune diseases, tissue destruction may be autoantigen-induced, but not necessarily immunologically mediated.
Response to region of difference 1 (RD1) epitopes in human immunodeficiency virus (HIV)-infected individuals enrolled with suspected active tuberculosis: a pilot study
Authors: Vincenti D , Carrara S , Butera O , Bizzoni F , Casetti R , Girardi E , Goletti D 
Published: August 2010

Summary
Tuberculosis is the most frequent co-infection in human immunodeficiency virus (HIV)-infected individuals, and which still presents diagnostic difficulties. Recently we set up an assay based on interferon (IFN)-γ response to region of difference 1 (RD1) peptides selected by computational analysis which is associated with active Mycobacterium tuberculosis replication. The objective of this study was to investigate the response to RD1 selected peptides in HIV-1-infected individuals in a clinical setting. The mechanisms of this immune response and comparison with other immune assays were also investigated. A total of 111 HIV-infected individuals with symptoms and signs consistent with active tuberculosis were enrolled prospectively. Interferon (IFN)-γ responses to RD1 selected peptides and recall antigens were evaluated by enzyme-linked immunospot assay. Results were correlated with CD4+ T cell counts, individuals' characteristics, tuberculin skin test, QuantiFERON-TB Gold and T-SPOT.TB. Results from 21 (19%) individuals were indeterminate due to in vitro cell anergy. Among ‘non-anergic’ individuals, sensitivity for active tuberculosis of the assay based on RD1 selected peptides was 67% (24 of 36), specificity was 94% (three of 54). The assay also resulted positive in cases of extra-pulmonary and smear-negative pulmonary active tuberculosis. The response was mediated by CD4+ effector/memory T cells and correlated with CD4+ T cell counts, but not with plasma HIV-RNA load. Moreover, the RD1 selected peptides assay had the highest diagnostic odds ratio for active tuberculosis compared to tuberculin skin test (TST), QuantiFERON-TB Gold and T-SPOT.TB. RD1 selected peptides assay is associated with M. tuberculosis replication in HIV-infected individuals, although T cell anergy remains an important obstacle to be overcome before the test can be proposed as a diagnostic tool.