bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept
Authors: ARKWRIGHT P D , MCDERMOTT M F , HOUTEN S M , FRENKEL J , WATERHAM H R , AGANNA E , HAMMOND L J , MIRAKIAN R M , TOMLIN P I , VIJAYDURAI P I , CANT A J 
Published: March 2003

Summary
Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.
Induction of IL-15 by TCR/CD3 aggregation depends on IFN-γand protects against apoptosis of immature thymocytesin vivo
Authors: Matthys P , DOOMS H , ROTTIERS P , MITERA T , OVERGERGH L , LECLERCQ G , BILLIAU A , GROOTEN J 
Published: March 2003

SummaryTCR/CD3 aggregation by injection of anti-CD3 Ab produces T cell activation, release of cytokines such as IFN-γ, and apoptosis in the cortical region of the thymus. We show that anti-CD3 Ab induces IL-15 mRNA in spleens of wild-type but not IFN-γ receptor-knock-out (IFN-γR KO) mice. The loss of IL-15 mRNA induction in IFN-γR KO mice was associated with increased thymocyte apoptosis. Pretreatment of wild-type mice with neutralizing anti-IL-15 Ab increased the anti-CD3-triggered thymocyte apoptosis, thus mimicking the sensitive phenotype of IFN-γR KO mice. Inversely, anti-CD3-induced apoptosis in IFN-γR KO mice was suppressed by administration of recombinant IL-15. In IFN-γR KO mice and in wild-type mice that were treated with anti-IL-15, augmented apoptosis affected mainly CD4+CD8+ immature thymocytes. IL-15 as well as IL-15Rα mRNA expression in thymocytes was not increased by anti-CD3. These data demonstrate that systemic IL-15 exerts anti-apoptotic activity on immature T cells and establish a regulatory mechanism whereby TCR/CD3 engagement induces IL-15 expression via an IFN-γ-dependent pathway. The self-amplifying nature of this IFN-γ/IL-15 connection may constitute a regulatory pathway in central tolerance to self.
Detection and identification of a soy protein component that cross-reacts with caseins from cow's milk
Authors: ROZENFELD P , DOCENA G H , AÑÓN M C , FOSSATI C A 
Published: March 2003

SUMMARYSoy-based formulas are the most employed cow's milk substitutes in the treatment of cow's milk allergy in our country. Since adverse reactions have been reported in allergic patients as a consequence of exposure to soy proteins, we have investigated the possible cross-reactivity between components from soybean and cow's milk. A cow's milk specific polyclonal antiserum and casein specific monoclonal antibodies were used in immunoblotting and competitive ELISA studies to identify a 30-kD component from soybean that cross-reacts with cow's milk caseins. Its IgE binding capacity was tested by EAST, employing sera from cow's milk allergic patients, not previously exposed to soy proteins. The 30 kD protein was isolated and partially sequenced. It is constituted by two polypeptides (A5 and B3) linked by a disulphide bond. The protein's capacity to bind to the different antibodies relies on the B3 poly-peptide. These results indicate that soy-based formula, which contains the A5-B3 glycinin molecule, could be involved in allergic reactions observed in cow's milk allergic patients exposed to soy-containing foods.
Development of CD4+ T cell lines that suppress an antigen-specific immune responsein vivo
Authors: VIEIRA DE MORAES L , SUN B , RIZZO L V 
Published: March 2003

SUMMARYIt has been suggested for many years that the regulation of the immune system for the maintenance of peripheral tolerance may involve regulatory/supressor T cells. In the past few years, several investigators have demonstrated that these cells can be generated in vitro. It has also been shown that they can inhibit the progression of various autoimmune disease models when infused into susceptible mice. We have generated two murine T cell lines in the presence of KLH-specific T cell clones from BALB/c or DBA2 mice. The lines are characterized by a low proliferative response to mitogens, the capacity to secrete high amounts of IL-10 and TGF-β, and small amounts of IFN-γ. Interestingly, these cells are unable to produce IL-2, IL-4 or IL-5. The study of the surface phenotype of both lines revealed CD4+, CD25high, CD44low and CTLA-4– cells. When injected intravenously in (CBy.D2) F1 mice, these cells were able to inhibit 50–100% of the TNP-specific antibody production, when the hapten was coupled to KLH. In the present study we offer another evidence for the existence of regulatory T cells in the T lymphocyte repertoire, suggesting that they can also regulate immune responses to foreign antigens. Furthermore, we demonstrate an alternative pathway to generate these cells different from approaches used thus far.
After chemotherapy, functional humoral response capacity is restored before complete restoration of lymphoid compartments
Authors: ZANDVOORT A , LODEWIJK M E , KLOK P A , BREUKELS M A , RIJKERS G T , TIMENS W 
Published: March 2003

SUMMARYChemotherapy has, besides the beneficial effects, several adverse effects. Suppression of the immune system is one of the most important problems. Infections caused by encapsulated bacteria like Streptococcus pneumoniae are responsible for a major part of infectious problems during and after treatment. The splenic marginal zone is essential in the initiation of an immune response to encapsulated bacteria. In this study, we analysed the effects of three different cytostatic agents on humoral immune responses. We found a reduced, but detectable immune response capacity at two days after treatment although the marginal zone B cell population is severely reduced at this time point. Twenty-four days after cessation of treatment, the immune response capacity was largely restored although lymphoid compartments were still not completely restored at that time point. Apparently, the presence of only few marginal zone B cells is sufficient to evoke a rise in antibody titres and although antibody titre increases are low, even small rises are most likely clinically relevant.
Regulation of the interleukin-5 receptorα-subunit on peripheral blood eosinophils from healthy subjects
Authors: HELLMAN C , HALLDÉN G , HYLANDER B , LUNDAHL J 
Published: March 2003

SUMMARYThe aim was to study in vitro regulation of the IL-5 receptor α (IL-5Rα) on purified peripheral blood eosinophils from healthy subjects. The IL-5Rα was down-regulated, in a dose-dependent manner, by recombinant IL-5 and GM-CSF, with IL-5 being most potent. This down-regulation was not induced by autocrine release of GM-CSF or IL-5, respectively. Incubation of eosinophils with cell-free peritoneal dialysis fluid (PF) collected from a patient with peritoneal fluid eosinophilia (PFE), induced up-regulation of the proportion of CD69 positive eosinophils, in parallel with down-regulation of the proportion of IL-5Rα positive eosinophils. Experiments with neutralizing antibodies against IL-5 and GM-CSF, revealed that IL-5 was the principal cytokine responsible for the down-regulation of the IL-5Rα. When eosinophils were incubated with PF collected from the same patient in remission or with PF collected from a newly started patient or a patient with bacterial peritonitis, less down-regulation of the IL-5Rα was observed.In conclusion our data indicate that IL-5, as opposed to its proposed action on eosinophil progenitors, down-regulates the IL-5Rα chain on mature eosinophils. We therefore suggest that an IL-5 driven inflammation generates an eosinophil tissue phenotype that is characterized by a low IL-5Rα expression. These aspects of IL-5 action on IL-5Rα expression could gain new insights into the mechanisms of specific immuno-modulatory therapies, such as anti-IL-5.
Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies
Authors: STHOEGER Z M , DAYAN M , TCHERNIACK A , GREEN L , TOLEDO S , SEGAL R , ELKAYAM O , MOZES E 
Published: March 2003

SUMMARYTwo peptides, based on the sequences of the complementarity-determining regions (CDR) 1 and 3 of a pathogenic murine monoclonal anti-DNA autoatibody that bears the 16/6 idiotype (Id), were shown to either prevent or treat an already established systemic lupus erythematosus (SLE) in two murine models of lupus. Two additional peptides based on the human monoclonal anti-DNA, 16/6 Id were synthesized. This study was undertaken in order to investigate the ability of the CDR-based peptides to immunomodulate SLE-associated responses of peripheral blood lymphocytes (PBL) of SLE patients. PBL of 24 of the 62 SLE patients tested proliferated in vitro following stimulation with the human 16/6 Id. Peptides based on the CDRs of both the human and murine anti-DNA autoantibodies inhibited efficiently and specifically the 16/6 Id-induced proliferation and IL-2 production. The latter inhibitions correlated with an up-regulated production (by 2·5–3·5-fold) of the immunosuppressive cytokine, TGF-β. Overall, the results of our study demonstrate that the CDR-based peptides are capable of down-regulating in vitro autoreactive T cell responses of PBL of SLE patients. Thus, these peptides are potential candidates for a novel specific treatment of SLE patients.
Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes
Authors: KRYWORUCHKO M , PASQUIER V , THèZE J 
Published: March 2003

SummaryHuman immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (α, β, γ) in vitro. We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV.
Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid
Authors: DONIN N , JURIANZ K , ZIPOREN L , SCHULTZ S , KIRSCHFINK M , FISHELSON Z 
Published: March 2003

SUMMARYNucleated cells employ several strategies to evade killing by homologous complement. We studied complement resistance in the human carcinoma cell lines (CA) T47D (mammary), SKOV3 (ovarian), and PC-3 (prostate) with emphasis on the following mechanisms of defense: 1. Expression and shedding of the membrane complement regulatory proteins (mCRP) CD46, CD55 and CD59; 2. Resistance based on protein phosphorylation; 3. Cell surface expression of sialic acid residues; 4. Desensitization to complement upon exposure to sublytic complement doses. Anti-mCRP antibody blocking experiments demonstrated that CD59 is the main mCRP protecting these CA from complement. Soluble CD59 was also found in supernates of PC-3&gt; SKOV3 &gt; T47D cells. Second, inhibitors of PKC, PKA and MEK sensitized the CA to lysis, thus implicating these protein kinases in CA complement resistance. Third, removal of sialic acid residues with neuraminidase also sensitized CA to lysis. Finally, exposure of CA to sublytic doses of complement conferred on them enhanced resistance to lytic complement doses in a PKC-dependent process. Combined treatment of CA with anti-CD59 antibodies, PD98059 (a MEK inhibitor) and neuraminidase produced a large enhancement in CA sensitivity to complement. Our results show that CD59 and sialic acid residues present on the cell surface, and intracellular processes involving protein phosphorylation act additively to secure CA resistance to complement-mediated lysis. Therefore, the effectiveness of antibody- and complement-based cancer immunotherapy will markedly improve by suppression of the various complement resistance mechanisms.
Signal transducer and activator of transcription 6 geneG2964Apolymorphism and inflammatory bowel disease
Authors: XIA B , CRUSIUS J B A , WU J , ZWIERS A , VAN BODEGRAVEN A A , PEñA A S 
Published: March 2003

SummarySignal transducer and activator of transcription 6 (STAT6) is a key transcription factor involved in interleukin 4 (IL-4) and IL-13-mediated Th2 response. The STAT6 gene is located on chromosome 12q13.3–14·1 (IBD2 region) and is therefore a positional and functional candidate gene for study in inflammatory bowel disease. We investigated the G2964A polymorphism in the 3′ untranslated region of the STAT6 gene in Dutch patients with inflammatory bowel disease and healthy controls. The G2964A polymorphism in the STAT6 gene was genotyped in 141 unrelated Dutch Caucasian patients with ulcerative colitis, 183 patients with Crohn's disease and 173 healthy individuals by PCR and the amplification-created restriction site method. Patients with Crohn's disease were classified according to the Vienna classification and the patients with ulcerative colitis were classified with the age at onset, extent of disease and colectomy. We did not find significant differences in genotype and allele frequencies of the G2964A polymorphism in the STAT6 gene between ulcerative colitis, Crohn's disease and healthy controls. Subgroups of the patients with Crohn's disease classified according to the Vienna classification and those with ulcerative colitis classified according to age of onset, disease extension and colectomy did not differ in the distribution of this polymorphism. The STAT6 G2964A gene polymorphism is not involved in the overall susceptibility or in determining the phenotype of IBD.
Familial isolated primary hyperparathyroidism with parathyroid carcinomas: clinical and molecular features
Authors: Yoshimoto Katsuhiko , Endo Hideko , Tsuyuguchi Masaru , Tanaka Chisato , Kimura Takehiko , Iwahana Hiroyuki , Kato Genichi , Sano Toshiaki , Itakura Mitsuo 
Published: March 2003

OBJECTIVEFamilial isolated primary hyperparathyroidism (FIHP) is a rare hereditary disorder. We present four patients from a single family with FIHP, and genetic analysis of their parathyroid adenomas and parathyroid carcinoma.DESIGNDNA was extracted from tumours resected at surgery. Tumours were examined for loss of heterozygosity (LOH) with microsatellite polymorhpic markers.PATIENTSThe 27‐year‐old proband (Patient 1) died of parathyroid carcinoma with metastases to the lungs and chest wall. Sixteen years later, his 34‐year‐old sister (Patient 2) presented with a neck tumour and primary hyperparathyroidism. Family screening revealed parathyroid tumours in his 36‐year‐old sister (Patient 3) and 29‐year‐old cousin (Patient 4). Histological examination of resected tumours showed parathyroid carcinoma and adenoma in Patient 2, a parathyroid adenoma in Patient 3, and an atypical parathyroid adenoma in Patient 4. Autopsy of the proband ruled out multiple endocrine neoplasia (MEN) type 1, and the three patients who underwent parathyroidectomy did not exhibit any abnormalities in the pancreas or the pituitary gland.RESULTSAnalysis of tumour DNA from one parathyroid carcinoma (Patient 2), the atypical parathyroid adenoma (Patient 4), and two parathyroid adenomas (Patients 2 and 3) showed limited LOH on chromosomes 13q12.3–q32 in an adenoma of Patient 2 and 9p21–p22 and 13q12.3–q32 in an adenoma of Patient 3.CONCLUSIONThese results suggest the possible contribution of tumour suppressor genes including the retinoblastoma gene and the hereditary breast cancer susceptibility gene (BRCA2) on 13q to parathyroid tumours in this family.
Evidence for a role of intracellular stored parathyroid hormone in producing hysteresis of the PTH–calcium relationship in normal humans
Authors: Schwarz Peter , Madsen Jesper C. , Rasmussen Anne Q. , Transbøl Lb , Brown Edward M. 
Published: March 2003

OBJECTIVEDespite the clear recognition that extracellular ionized calcium controls PTH secretion, there have been suggestions of hysteresis in the relationship between extracellular ionized calcium and PTH during recovery from induced hypo‐ and hypercalcaemia in vivo in humans. In this study, we examined the possibility that release of intracellular stored PTH during induced hypocalcaemia may explain hysteresis.VOLUNTEERSEleven volunteers, five women and six men, were recruited to participate in the study.DESIGNA series of three protocols of repeated induction of hypocalcaemia or sequential induction of hypo‐ and hypercalcaemia.RESULTSWe observed in a total of 13 trials that a drastic lowering of blood ionized calcium by 0.20 mmol/l within 30 min elicited an immediate large, transient peak release of PTH amounting to 6–16 times the baseline concen_tration. However, following a steady‐state period of hypocalcaemia, a subsequent lowering of blood ionized calcium either following a brief return to normocalcaemia (protocol 1), from the initial hypocalcaemic level of blood ionized calcium (protocol 2) or after a brief period of induced hypercalcaemia (protocol 3) gave either no peak release of PTH or a markedly blunted peak. Thus, the PTH response during the initial induction of and the first recovery from hypocalcaemia in our protocol 3 showed significant hysteresis in the relationship between blood ionized calcium and PTH (P < 0.001), whereas, no hysteretic relationship could be shown during the second recovery from induced hypocalcaemia in four of five cases (NS). Moreover, no hysteretic relationship was observed during induction, recovery and re‐induction of hypercalcaemia in protocol 3 (NS).CONCLUSIONWe believe that the release of what might be preformed, intracellular stored depot PTH can explain, at least in part, the observed hysteretic PTH–calcium relationship in normal humans.
In old age the majority of thyroid peroxidase autoantibodies are directed to a single TPO domain irrespective of thyroid function and iodine intake
Authors: Czarnocka Barbara , Szabolcs István , Pastuszko Danuta , Feldkamp Joachim , Dohán Orsolya , Podoba Jan , Wenzel Bjorn 
Published: March 2003

OBJECTIVEWe have examined (1) which epitopes on thyroid peroxidase (TPO) are recognized by TPO autoantibodies (TPO‐Aab) in old age and to what extent? (2) Does the TPO‐Aab pattern differ in euthyroid and hypothyroid elderly subjects or does it depend on their iodine intake?DESIGNTPO‐Aab positive sera obtained from a screening study of nursing‐home residents living in areas of varying iodine intake were tested by competition studies with monoclonal antibodies (mAbs) recognizing different epitopes on TPO.SUBJECTSThe nursing‐home residents with TPO‐Aab positivity were from (A) an iodine abundant area (Eastern Hungary, median iodine excretion ‐MIE‐: 0.462 μmol/mmol creatinine, N = 13); (B) an area of obligatory iodinated salt prophylaxis since the 1950s (Slovakia, MIE: 0.090 μmol/mmol creatinine, N = 11); (C) a moderately iodine‐deficient area (Northern Hungary, MIE: 0.065 μmol/mmol creatinine, N = 13).MEASUREMENTSThirteen murine TPO antibodies generated against several epitopes of the four (A, B, C, D) antigenic domains on the TPO were co‐incubated with the TPO‐Aab positive sera on TPO coated microtitre plates. The amount of mAb bound was estimated after further incubation with goat anti‐mouse antibodies, conjugated with horseradish peroxidase and tetramethylbenzidine as chromogen. The TPO‐Aab positive sera were characterized by the pattern of percen_tage of inhibition of mAb binding caused by the TPO‐Aabs.RESULTSTPO‐Aabs inhibited only the binding of mAbs raised against the antigenic domains A (mAb9, mAb2, mAb60) and B (mAb64, mAb59, mAb18, mAb15). The extent of inhibition depended upon the TPO‐Aab titre but in all cases the binding of mAb9 was inhibited to the highest degree. The percen_tage inhibition of mAb9 was (a) 34 ± 17% (M ± SD) caused by sera (N = 8) with TPO‐Aab titre 1/100–1/200 (higher than that of all mAbs recognizing domain B, P < 0.01–P < 0.001), (b) 76 ± 18% caused by sera (N = 14) with TPO‐Aab titre 1/1000 (higher than that of all other mAbs −P < 0.01–P < 0.001, except mAb64), (c) 99 ± 4% caused by sera (N = 15) with TPO‐Aab titre 1/4000–1/16 000 (higher than that of all other mAbs, P < 0.01–P < 0.001). Thus, only mAb9 was inhibited completely by high titres of TPO‐Aabs. The qualitative and quantitative distribution pattern of mAb inhibition was similar in the subgroups of elderly hypothyroid and euthyroid subjects with comparable TPO‐Aab levels, as well as in the subgroups with varying iodine intake.CONCLUSIONS(1) In old age, there is a polyclonal TPO autoantibody response but the majority of the autoantibodies are directed to the TPO region mapped by or close to mAb9 (domain A); (2) the autoantibody response does not differ in elderly subjects with or without the clinical manifestations of autoimmune thyroid disease and does not depend on the iodine supply of the elderly subjects.