bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clustering of distinct autoimmune diseases associated with functional abnormalities of T cell survival in children
Authors: Pignata C , Alessio M , Ramenghi U , Bonissoni S , Difranco D , Brusco A , Matrecano E , Franzese A , Dianzani I , Dianzani U 
Published: March 2003

SUMMARYTo ascertain whether alterations of lymphocyte switching off may be associated with clustering of autoimmune diseases in children, Fas- and C2-ceramide-induced cell death was evaluated on T cell lines derived from three patients affected by clustering of autoimmune disorders. Three patterns were found: patient 3 was resistant to Fas- and C2-ceramide, patient 1 was resistant to Fas, but sensitive to C2-ceramide, patient 2 was resistant to C2-ceramide, but sensitive to Fas. By contrast, Fas- and C2-ceramide-induced cell death was normal in five children with systemic juvenile rheumatoid arthritis, five children with insulin-dependent diabetes and 10 age-matched healthy controls. Surface expression of Fas was low in patient 1, but normal in patients 2 and 3. Together with normal Fas transcripts, patients 2 and 3 displayed a transcript 152 bp longer than the normal one retaining intron 5. Our data indicate that polyreactive autoimmune syndromes may be associated with heterogeneous alteration of the immune response switching-off system.
Evidence for recognition of novel islet T cell antigens by granule-specific T cell lines from new onset type 1 diabetic patients
Authors: Tree T I M , O'Byrne D , Tremble J M , Macfarlane W M , Haskins K , James R F L , Docherty K , Hutton J C , Banga J P 
Published: March 2003

SUMMARYType 1 diabetes is a T cell-mediated autoimmune disease where a number of islet β-cell target autoantigens have been characterized on the basis of reactivity with autoantibodies. Nevertheless, there remains uncertainty of the nature of another group of autoantigens associated with the secretory granule fraction of islet β-cells that appear to be targeted predominantly by autoreactive T cells. We have previously characterized CD4+, HLA-DR-restricted T cell lines from new onset type 1 diabetic patients that are specific for the secretory granule fraction of rat tumour insulinoma, RIN. The T cell line from the first patient, HS, proliferates in response to crude microsomal membranes prepared from a recently established, pure human islet β-cell line NES2Y. In addition, the HS line also responds to secretory granule fractions prepared from a murine tumour insulinoma grown in RIP-Tag mice, showing the recognition of species-conserved antigen(s) in β-cells. Using partially matched antigen-presenting cells, the HS T cells and another line derived from a second patient, MR, were shown to be restricted by disease-associated DRB1*0101 and DRB1*0404 alleles, respectively. Neither the HS or MR T cell lines proliferate in response to a large panel of candidate islet cell antigens, including insulin, proinsulin, glutamic acid decarboxylase, the protein tyrosine phosphatase IA-2/phogrin, imogen-38, ICA69 or hsp60. Our data provide compelling evidence of the presence of a group of antigens associated with the secretory granule fraction of islet β-cells recognized by the T cell lines, whose definition may contribute to our knowledge of disease induction as well as to diagnosis.
Enhancement of natural killer (NK) cell cytotoxicity and induction of NK cell-derived interferon-gamma (IFN-γ) display different kinetics during experimental infection withTrypanosoma cruzi
Authors: Une C , Andersson J , Eloranta M-L , Sunnemark D , Harris R A , Örn A 
Published: March 2003

SUMMARYEarly immunological activation involves an initial phase of cytokine activity and involvement of cell types such as NK cells. Such early immune responses are often decisive in resolution of microbial infection. NK cells reduce parasitaemia and enhance survival in experimental Trypanosoma cruzi infection, although the nature of these protective effects is not well understood. In this study, a detailed analysis of innate cytokine induction in the absence and presence of NK cells during the first 8 days of infection was performed. Following intraperitoneal infection with a high dose of parasites, reverse transcriptase-polymerase chain reaction showed that splenic mRNA for IFN-γ appeared as a peak 24 h after infection and then reappeared 2–3 days later. In NK-depleted animals the first peak of IFN-γ was absent and the second wave was slightly delayed. mRNA for IL-12 and tumour necrosis factor-alpha (TNF-α) as well as IFN-α protein in serum was only recorded 24 h after infection, at the same time as the IFN-γ peak. NK depletion resulted in a small decrease of IL-12 mRNA levels, whereas TNF-α and IFN-α were not affected. NK cytotoxicity remained elevated throughout the 8 days and thus did not parallel the expression of IFN-γ production by NK cells. We conclude that NK cell cytokine production and cytolytic activity play different roles in response to challenge with T. cruzi.
Influence of age and HLA type on interferon-gamma (IFN-γ) responses to a naturally occurring polymorphic epitope ofPlasmodium falciparumliver stage antigen-1 (LSA-1)
Authors: Bucci K , Kastens W , Hollingdale M R , Shankar A , Alpers M P , King C L , Kazura J W 
Published: March 2003

SUMMARYAntigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-γ responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84–92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-γ ELISPOT responses increased with age in malaria-exposed subjects: 14–16% and 30–36% of 2–5- and 6–54-year-olds, respectively, had ≥ 10 IFN-γ-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P &lt; 0·05). IFN-γ responses to all three peptides were also greater for older than younger individuals. No children &lt; 3 years old had lymphocytes that responded to all three 84–92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-γ responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-γ responses to polymorphic epitopes of liver-stage antigens such as LSA-1.
A single measurement of CD38CD8 cells in HIV+, long-term surviving injecting drug users distinguishes those who will progress to AIDS from those who will remain stable
Authors: Froebel K S , Raab G M , D'alessandro C , Armitage M P , Mackenzie K M , Struthers M , Whitelaw J M , Yang S 
Published: March 2003

SUMMARYThis study compares the predictive power of a single measurement of CD8+CD38+, CD8+CD45RO+ or CD8+CD38+CD45RO+ subpopulations in predicting progression to AIDS in a cohort of HIV+ long-term surviving injecting drug users. The results showed that both the total CD8+ percentage, and the CD8+CD38+ and CD8+CD38+CD45RO+ subpopulations of cells all individually predicted progression to AIDS. In combination with CD4, only the CD8+CD38+ subpopulation enhanced the predictive power of the CD4 percentage alone. The CD8+ percentage correlated negatively with the CD4 percentage and the CD8+CD45RO+ subpopulation did not predict disease progression. The proportion of CD8+CD38+ cells identified which patients with a moderate CD4 level were more likely to progress to AIDS, and conversely, which patients with a low CD4 count were likely to remain clinically stable. The results were consistent irrespective of whether time was measured from the date of seroconversion, or from the date of the test. This study is the first to measure these markers in HIV-infected injecting drug users, and in long-term survivors. The results demonstrate the considerable added value of the CD8+CD38+ cell percentage over the CD4 count alone, in predicting HIV clinical progression.
MHC class I pathway is not required for the development of crescentic glomerulonephritis in mice
Authors: Li S , Holdsworth S R , Tipping P G 
Published: March 2003

SUMMARYMHC II and CD4+ T cells are required for anti-glomerular basement membrane (GBM) globulin-initiated crescentic glomerulonephritis (GN) in mice, but the role of MHC I and CD8+ T cells is unclear. The cytolytic function of CD8+ T cells requires recognition of peptide antigens presented on MHC I. CD8+ T cells can also perform helper functions via cytokine production. The contribution of MHC I to crescentic GN was investigated using TAP-1 gene knock out (TAP-1−/−) mice, which have deficient MHC I antigen presentation. Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 ± 4% of glomeruli (normal 0%), proteinuria (9·1 ± 1·6 mg/20 h, normal 1·5 ± 0·3 mg/20 h) and impaired renal function (creatinine clearance 110 ± 8 μl/min, normal 193 ± 10 μl/min) following administration of sheep anti-mouse GBM globulin. TAP-1−/− mice, which have extremely low MHC I expression and reduced CD8+ T cells, developed similar GN with 39 ± 3% crescents, proteinuria (12·7 ± 4·3 mg/20 h) and impaired renal function (creatinine clearance 123 ± 20 μl/min). In vivo antibody-induced CD8 depletion did not attenuate crescent formation or protect renal function in C57Bl/6 mice developing GN, although significant reduction in proteinuria (5·3 ± 1·2 mg/20 h, P = 0·012) and glomerular recruitment of CD4+ T cells and macrophages were observed compared with control treated mice with GN. These data demonstrate that MHC I is not required for development of crescentic GN in mice. The MHC I-independent contribution of CD8+ T cells to proteinuria and inflammatory cell recruitment suggests that they may serve a ‘helper’ rather than cytolytic role in this disease.
Coxsackievirus B3 infection induces anti-flavoprotein antibodies in mice
Authors: Cicek G , Vuorinen T , Stähle I , Stepanek P , Freudenberg N , Brandsch R 
Published: March 2003

SUMMARYEnteroviruses, the most common cause of acute myocarditis, are also supposed aetiological agents of dilated cardiomyopathy. Autoantibodies (anti-M7; Klein & Berg, Clin Exp Immunol 1990; 58:283–92) directed against flavoproteins with covalently bound flavin (αFp-Ab; Otto et al., Clin Exp Immunol 1998; 111:541–2) are detected in up to 30% of sera of patients with myocarditis and idiopathic dilated cardiomyopathy (IDCM). Mice inoculated with a myocarditic variant of coxsackievirus B3 (CVB3) were employed to study the occurrence of serum αFp-Ab following viral infection. The presence of αFp-Ab was analysed by Western blotting with the flavoprotein antigens 6-hydroxy-d-nicotine oxidase (6HDNO) and sarcosine oxidase (SaO). Of 10 sera from CVB3-infected mice, five showed a strong reaction with both antigens. The sera were reactive also to the mitochondrial covalently flavinylated proteins dimethylglycine dehydrogenase and sarcosine dehydrogenase. Sera of non-infected mice did not react with these antigens. A 6HDNO mutant protein with non-covalently bound FAD no longer reacted on Western blots with sera of CVB3-infected mice. Preincubation with FAD abolished or reduced the reaction of the sera with the 6HDNO antigen. At 2 weeks p.i. the αFp-Ab were of the IgM and IgG isotypes, at 7 and 9 weeks p.i. of the IgG isotype. The sera of CVB3-infected mice reproduced closely the antigenic specificity of the anti-M7 sera of patients, lending further support to the role of coxsackieviruses in the pathogenesis of IDCM.
Patients with inflammatory bowel disease (IBD) reveal increased induction capacity of intracellular interferon-gamma (IFN-γ) in peripheral CD8+ lymphocytes co-cultured with intestinal epithelial cells
Authors: Bisping G , Lügering N , Lütke-Brintrup S , Pauels H-G , Schürmann G , Domschke W , Kucharzik T 
Published: March 2003

SUMMARYIntestinal epithelial cells seem to play a key role during IBD. The network of cellular interactions between epithelial cells and lamina propria mononuclear cells is still incompletely understood. In the following co-culture model we investigated the influence of intestinal epithelial cells on cytokine expression of T cytotoxic and T helper cells from patients with IBD and healthy controls. Peripheral blood mononuclear cells (PBMC) were purified by a Ficoll–Hypaque gradient followed by co-incubation with epithelial cells in multiwell cell culture insert plates in direct contact as well as separated by transwell filters. We used Caco-2 cells as well as freshly isolated colonic epithelia obtained from surgical specimens. Three-colour immunofluorescence flow cytometry was performed after collection, stimulation and staining of PBMC with anti-CD4, anti-CD8, anti-IFN-γ and anti-IL-4. Patients with IBD (Crohn's disease (CD), n = 12; ulcerative colitis (UC), n = 16) and healthy controls (n = 10) were included in the study. After 24 h of co-incubation with Caco-2 cells we found a significant increase of IFN-γ-producing CD8+ lymphocytes in patients with IBD. In contrast, healthy controls did not respond to the epithelial stimulus. No significant differences could be found between CD and UC or active and inactive disease. A significant increase of IFN-γ+/CD8+ lymphocytes in patients with UC was also seen after direct co-incubation with primary cultures of colonic crypt cells. The observed epithelial–lymphocyte interaction seems to be MHC I-restricted. No significant epithelial cell-mediated effects on cytokine expression were detected in the PBMC CD4+ subsets. Patients with IBD—even in an inactive state of disease—exert an increased capacity for IFN-γ induction in CD8+ lymphocytes mediated by intestinal epithelial cells. This mechanism may be important during chronic intestinal inflammation, as in the case of altered mucosal barrier function epithelial cells may become targets for IFN-γ-producing CD8+ lymphocytes.
Adrenalectomy enhances response of tumour necrosis factor-alpha (TNF-α) to haemorrhage in the conscious rat
Authors: Yamashita M , Yamashita M 
Published: March 2003

SUMMARYSeveral factors have been implicated in TNF-α induction after haemorrhage, but the precise mechanism is unknown. To assess a possible role of adrenal glands on TNF-α induction after haemorrhage, adrenalectomized (ADX) and sham-adrenalectomized (Sham) rats were subjected to 20 ml/kg haemorrhage (approximately 30% of the total blood volume) over 5 min in the conscious state, and changes in serum TNF and hepatic TNF-α mRNA were analysed by cytotoxicity against L929 cells and by semiquantitative reverse transcription-polymerase chain reaction, respectively. Changes in plasma corticosterone (CS) and mean arterial blood pressure (MABP) were also detected. Plasma CS levels showed a rapid increase after haemorrhage in Sham rats, whereas there was no response in ADX rats. Responses of MABP were comparable in the two groups. Both serum TNF and hepatic TNF-α mRNA showed rapid increases after haemorrhage in the Sham group, and these increases were significantly augmented in the ADX group. Pretreatment with CS (100 μg/h) negated these augmentations in ADX rats. These results show that adrenalectomy enhances the response of TNF-α to 20 ml/kg haemorrhage in the conscious rat, and suggest that endogenous glucocorticoids may play an inhibitory role in the induction of TNF-α after haemorrhage.
Quantitative analysis of inflammatory cells infiltrating the cystic fibrosis airway mucosa
Authors: Hubeau C , Lorenzato M , Couetil J P , Hubert D , Dusser D , Puchelle E , Gaillard D 
Published: March 2003

SUMMARYAirway inflammation represents a hallmark of the cystic fibrosis (CF) disease. However, the mucosal distribution of immune cells along the CF airways has not been clearly defined, particularly in intermediate bronchi and distal bronchioles. We analysed lung tissues collected at the time of transplantation from homozygous ΔF508+/+CF patients versus non-CF donors. Using immunohistochemistry, the distribution of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, polymorphonuclear neutrophils (PMN), mast cells, CD3+ T cells, including the CD4+ and CD8+ subsets, CD20+ B cells, CD38+ plasma cells and CD68+ macrophages, was analysed at lobar, segmental and distal levels of the bronchial tree. Using image cytometry, the number of cells per mm2 was assessed in the depth of the bronchial wall. In CF airways, alterations mainly consisted in lesions of the surface epithelium. Numerous immune cells were heterogeneously distributed all along the bronchial tree and mainly located in the mucosa, beneath the surface epithelium. Compared to non-CF donors, the lymphoid aggregates formed by B cells were significantly larger all along the CF airways (P = 0·001). The number of T lymphocytes was higher at the CF distal level (P = 0·035), where we observed an intense tissue damage. PMN preferentially accumulated (P = 0·033) in the CF surface epithelium, which overexpressed ICAM-1 but not VCAM-1 and E-selectin. These results highlight the nature of the inflammatory infiltrate in the CF airway mucosa and emphasize a prominent implication of PMN, B and T lymphocytes in the CF disease.
Non FcR-binding murine antihuman CD3 monoclonal antibody is capable of productive TCR signalling and induces proliferation in the presence of costimulation
Authors: Meijer R T , Yong S L , Ten Berge I J M , Van Lier R A W , Schellekens P T A 
Published: March 2003

SummaryCLB T3/4.A is a non FcR-binding CD3 mAb of the murine IgA isotype, which may be used as an alternative for the mitogenic OKT3 mAb in the treatment of acute cellular rejection after organ transplantation. We studied TCR signalling and T cell activation in response to T3/4.A in normal human PBMC in vitro. T3/4.A induced a rapid rise in free cytoplasmic Ca2+, not different from the response to mitogenic CD3 mAb. However, protein tyrosine phosphorylation and, particularly, MAPK activation, were reduced as compared to mitogenic CD3 mAb. T3/4.A enhanced expression of both CD69 and CD25, but proliferation and detectable cytokine production did not occur. Addition of either CD28 mAb or IL-2 induced a strong proliferative response, which was accompanied by cytokine production. At higher mAb concentrations, T cell activation decreased, which correlated with TCR downmodulation. To exclude the possibility that activation by T3/4.A depends on interaction of murine IgA Fc with as yet unknown FcR, we showed that also with CD3 mAb F(ab′)2 fragments upregulation of activation molecules occurred, as well as proliferation in the presence of costimulation. We conclude that the non FcR-binding murine IgA mAb T3/4.A acts as a partial agonist and leads to proliferation and cytokine production only in the presence of appropriate costimuli. These findings may explain the mitigated cytokine release syndrome observed in vivo with some nonmitogenic CD3 mAbs.
The effect of interleukin-10 and of interleukin-12 on the in vitro production of anti-double-stranded DNA antibodies from patients with systemic lupus erythematosus
Authors: Tyrrell-Price J , Lydyard P M , Isenberg D A 
Published: March 2003

SUMMARY
IL-10 and IL-12 are cytokines which are important in regulating immune responses. Plasma levels of IL-10 and autoantibodies against double-stranded DNA (dsDNA) often mirror disease activity in patients with SLE. IL-12 secretion from SLE patients' blood mononuclear cells also correlates with disease activity, but has an inverse relationship. The aim of this study was to measure the effect of IL-10 and of IL-12 on the production of IgG autoantibodies from patients with SLE, both cross-sectionally and longitudinally.
Peripheral blood mononuclear cells (PBMC) were cultured with IL-10 (at 20 ng/ml or 2 ng/ml) or IL-12 (at 2 ng/ml or 0·2 ng/ml) or without cytokine and the supernatanants tested for the production of double-stranded DNA antibodies (dsDNA abs), single-stranded DNA antibodies (ssDNA abs) and total IgG antibodies (IgG abs) by ELISA. The BILAG disease activity index was recorded at each patient visit (a global score of six or more is regarded as active disease).
In general, treatment with IL-10 caused PBMCs from patients with inactive disease to increase their antissDNA and dsDNA ab production (by upto 354% and 186%, respectively) while patients with active disease decreased their antibody production (by upto 91% and 97%, respectively). Overall there was a correlation between disease activity and change in antissDNA and dsDNA ab production (r = − 0·51; P = 0·03 and r = − 0·48; P = 0·042, respectively). Treatment with IL-12 at 0·2 ng/ml inhibited antissDNA and dsDNA antibody production, having the greatest effect on patients with active disease (decreasing antissDNA and dsDNA antibody production by upto 75% and 73%, respectively). This resulted in a significant correlation between disease activity and change in antissDNA antibody production (r = − 0·76; P = 0·03), but significance was not reached with antidsDNA antibody production (P = 0·06). Together these data suggest that the effect of these cytokines on antibody production by SLE PBMCs involves several factors; one of which is disease activity.
T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity
Authors: Giovannetti A , Pierdominici M , Mazzetta F , Salemi S , Marziali M , Kuonen D , Iebba F , Lusi E A , Cossarizza A , Aiuti F 
Published: March 2003

SUMMARYThe immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated.20 HIV-1-infected patients with mean CD4+ T cell count of 298/µl, plasma viral load of 4·7 log10 copies/ml and naive for protease inhibitors (PI) were studied during12 months of HAART. An increased number of both CD4+ and CD8+ naive T cells and a normalization of the frequency of CCR5- and CXCR4-expressing CD4+ T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IL-4- and (IFN)-γ-, producing T cells and a decreased percentage of CD8+ IFN-γ + cells. A correlation between the frequency of IFN-γ-producing T cells and that of memory, CCR5+ and CD95+ T cells was demonstrated in both CD4+ and CD8+ subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4+ but not the CD8+ T cell subset. However, the level of perturbation of the third complementarity-determining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN-γ response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease.