bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers
Authors: Fijen J W , Zijlstra J G , De Boer P , Spanjersberg R , Cohen Tervaert J W , Van Der Werf T S , Ligtenberg J J M , Tulleken J E 
Published: March 2003

SUMMARYSepsis resulting in multiorgan failure and death is still a major problem in intensive care medicine, despite extensive attempts to interfere in the supposed underlying mechanism of a deranged immune system. This is not only due to the persistent lacunae in knowledge about the immune system in sepsis but also due to the lack of sufficient instruments for intervention. Inhibitors of the p38 mitogen-activated protein kinase (p38MAPK) have been used to study the signalling pathway of the immune response. In vitro and animal studies have demonstrated that blocking p38MAPK could mitigate the pro-inflammatory response and improve survival after endotoxaemia.Using an endotoxaemia model in healthy human volunteers we evaluated the attenuation of clinical and cytokine response to endotoxin after inhibition of p38MAPK by an oral dose of RWJ-67657, a pyrindinyl imidazole. We measured the clinical parameters temperature, blood pressure and heart rate. The proinflammatory cytokines tumour necrosis factor-α, interleukin-6 and interleukin-8 were measured by ELISA at various points during a 24-h period. Drug toxicity was evaluated by routine clinical and laboratory examinations.After a single dose dose of RWJ-67657 the temperature and blood pressure response remained at the basal level. The inhibition of TNF-α, IL-6 and IL-8 response was a dose dependent. With the maximum dosage, reduction in peak serum levels of the proinflammatory cytokines was greater than 90%. There was no drug-related toxicity.Interpretation:We conclude that inhibition of p38MAPK by RWJ-67657 might be a tool to intervene in the deranged immune response in sepsis and other inflammatory diseases.
Oligoclonally expandingγδT lymphocytes induce IgA switching in IgA nephropathy
Authors: Toyabe S , Harada W , Uchiyama M 
Published: March 2003

SUMMARYThe aetiology of IgA nephropathy (IgAN) is closely related with abnormality of mucosal immunity. We investigated the roles of γδ T cells in the regulation of IgA production by B cells in IgAN patients. The proportion of γδ T cells in peripheral blood mononuclear cells (PBMNC) was higher in IgAN patients than in the controls and was found to be correlated with the proportion of surface IgA-positive (sIgA+) B cells, which are precursors of IgA-secreting plasma cells. After in vitro PWM stimulation, sIgA expression on B cells and IgA production were significantly enhanced in PBMNC obtained from IgAN patients, whereas the enhancements were abolished by removal of γδ T cells from the PBMNC. Purified γδ T cells from IgAN patients induced surface IgA expression on naïve sIgD+ B cells more effectively than did αβ T cells. Moreover, stimulated γδ T cells from IgAN patients produced a larger amount of TGF-β1, which is one of the main cytokines that induces IgA class switching on B cells, as compared with αβ T cells and control γδ T cells. The expanded γδ T cells from IgAN patients exclusively expressed Vγ9, and the nucleotide sequences of junctional regions of Vγ9 showed very limited TCR diversities. It was therefore concluded that γδ T cells, which are expanded in response to specific antigens, enhance IgA class switching on B cells in IgAN patients.
The GOR gene product cannot cross-react with hepatitis C virus in humans
Authors: Koike R , Iizuka T , Watanabe T , Miyasaka N 
Published: March 2003

SUMMARY
GOR (GOR47–1) is an epitope thought to be a host-derived antigen cross-reactive with hepatitis C virus (HCV) since it was isolated from a cDNA library of host animals reactive with sera of HCV-positive patients. An enzyme immunosorbent assay (ELISA) using this epitope as antigen is of sufficient sensitivity and specificity for screening patients with HCV. However, the relationship between GOR47–1 epitope and autoimmune phenomena associated with HCV infection or autoimmune hepatitis is controversial. Here we isolated the human GOR gene and found that the GOR47–1 epitope was not translated in humans due to a single base replacement from chimpanzee. Furthermore, we found some patients who had antibodies against another epitope, which is translated (GOR1–125) in humans, although there was no correlation between the existence of anti-GOR47–1 or anti-GOR1–125 Ab and autoimmune phenomena. Serum IgG levels did not influence the titres of these antibodies. Taken together with the results of several other studies, our finding that the GOR47–1 epitope cannot be translated into a protein suggests that there is little relationship between autoimmunity and the GOR gene product in human beings. We also discuss here the possible mechanism of cross-reactivity between HCV and the GOR gene product.
Selection of single chain variable fragments (scFv) against the glycoprotein antigen of the rabies virus from a human synthetic scFv phage display library and their fusion with the Fc region of human IgG1
Authors: Ray K , Embleton M J , Jailkhani B L , Bhan M K , Kumar R 
Published: March 2003

SummaryWe have prepared human recombinant antibody molecules against the glycoprotein antigen of the rabies virus (GPRV) based on the single chain variable fragment (scFv) format. Anti-GPRV scFvs were selected from a human synthetic scFv phage display library with a repertoire of approximately 109 specificities. After three rounds of selection against the PV11 strain of the virus, 40% of the clones tested recognized the rabies antigen. Of the 20 positive clones that were sequenced, five distinct sequences were identified. These distinct scFvs were cloned into a mammalian expression vector carrying the human IgG1 Fc region. The specificity of the resulting scFv-Fc molecules for GPRV was established by ELISA, dot blot and western blot analyses and membrane immunofluorescence. Two of the scFv-Fc fusion proteins neutralized the PV11 strain in a standard in vivo neutralization assay where the virus was incubated with the scFv-Fc molecules before intracranial inoculation in mice. These anti-GPRV scFv-Fc molecules have the potential to be used as an alternative to the presently available HRIG, for use in post-exposure preventive treatment.
Antilactoferrin antibodies in autoimmune liver disease
Authors: Muratori L , Muratori P , Zauli D , Grassi A , Pappas G , Rodrigo L , Cassani F , Lenzi M , Bianchi F B 
Published: March 2003

SUMMARY
Antilactoferrin antibodies have been reported in patients with several autoimmune disorders, including primary biliary cirrhosis, autoimmune hepatitis and autoimmune cholangitis. We investigated the prevalence and the clinical significance of such autoreactivity in patients with autoimmune and viral chronic liver disease. Sera from 39 patients with autoimmune hepatitis, 51 with primary biliary cirrhosis, 17 with autoimmune cholangitis, 24 with primary sclerosing cholangitis and 28 with HCV-related chronic hepatitis were studied. Positivity for antilactoferrin antibodies was evaluated by Western immunoblotting with purified human lactoferrin. Antilactoferrin antibodies were detected more often in autoimmune liver disorders (25% autoimmune hepatitis, 25% primary biliary cirrhosis, 35% autoimmune cholangitis, 29% primary sclerosing cholangitis) than in HCV-related chronic hepatitis (3·5%, P &lt; 0·02 versus all). Positivity for antilactoferrin antibodies was not associated with a particular clinical or biochemical profile of the underlying liver disease. No correlation was observed between antilactoferrin reactivity and perinuclear antineutrophil cytoplasmic antibodies. Antilactoferrin antibodies are present significantly more often in autoimmune than in viral liver disorders, but they cannot be considered the serological marker of a specific autoimmune liver disease.
Functional heterogeneity of anti-endothelial cell antibodies
Authors: Bordron A , Révélen R , D'Arbonneau F , Dueymes M , Renaudineau Y , Jamin C , Youinou P 
Published: March 2003

SUMMARYWhile it has been claimed that some anti-endothelial cell antibodies (AECA) activate EC, there is also evidence that others trigger apoptosis. To address the issue of whether activation is a prerequisite for AECA-mediated apoptosis of EC, 23 AECA-positive sera were evaluated for their ability to induce activation and/or apoptosis. Activation was defined as an over-expression of E-selectin and intercellular adhesion molecule 1. Optical microscopy, annexin V binding, hypoploid cell enumeration, and determination of poly (ADP-ribose) polymerase cleavage-related products were used to assess apoptosis. Four functional profiles were defined: 10 sera promoted activation and apoptosis (act+/apo+), one was act+/apo-, six act-/apo+, and the remaining six act-/apo-. The reduced membrane expression of thrombomodulin was associated with apoptosis, rather than activation. Caspase-3 was implicated in the two models of apoptosis, the ratios of several survival proteins to Bax decreased, regardless of the ability of apo+ AECA to activate the cells, while radical oxygen species did not appear to be involved. Furthermore, it occurred that macrophages engulfed EC treated with apoptosis-promoting AECA, but not those incubated with AECA that did not induce apoptosis. Hence, AECA represent an extremely heterogeneous family of autoantibodies, not only because of the variety of their target antigens, but also the subsequent diversity of their effects.
Functional T lymphocytes infiltrate implanted polyvinyl alcohol foams during surgical wound closure therapy
Authors: Gouttefangeas C , Eberle M , Ruck P , Stark M , Müller J E , Becker H-D , Rammensee H-G , Pinocy J 
Published: March 2003

SUMMARY
Vacuum-assisted closure involving the implantation of polyvinyl alcohol foam is a technique recently developed for the treatment of patients suffering from either wound infection or chronic wounds. This method has been shown to improve and accelerate wound healing. However, little is known about the cell populations that infiltrate the foam, and their potential role in resolving the infection and promoting granulation tissue formation. Our study demonstrates that wound-implanted foams are mainly infiltrated with granulocytes, but that mononuclear cells, including macrophages and minor populations of T, B and natural killer lymphocytes, are also present. We show that foam-infiltrating T cells, especially CD4+ T cells, constitute a phenotypically and functionally heterogeneous population influenced by wound-infecting bacteria. Thus, T lymphocytes could play a role in wound cleansing. In addition, our data indicate that implanted polyvinyl alcohol foams might be suitable microenvironments for manipulating T cell-mediated immune responses in patients.
L-tryptophan contaminant ‘peak E’ induces the release of IL-5 and IL-10 by peripheral blood mononuclear cells from patients with functional somatic syndromes
Authors: Barth H , Klein R , Berg P A 
Published: March 2003

SummaryIn 1989, the development of eosinophilia myalgia syndrome (EMS) was observed in some patients after the intake of l-tryptophan containing several contaminants, including 1,1′-ethylidenebis[l-tryptophan] (‘peak E’). Since l-tryptophan has been taken particularly by individuals suffering from functional somatic syndromes (FSS), such as fibromyalgia syndrome (FMS), we put forward the hypothesis that EMS may have developed preferentially in patients with FSS as an allergic reaction towards the contaminant peak E. We therefore studied the immunological reactivity towards l-tryptophan and peak E in these individuals (n = 12) and compared these data with those obtained in 12 healthy controls and 12 patients with other chronic disorders. Peripheral blood mononuclear cells (PBMC) were cultured for 7 days with pure l-tryptophan and peak E. Supernatant fluids were collected at day 7. The type 2 cytokines IL-4, IL-5 and IL-10, and the type 1 cytokines IL-2 and IFN-γ, were determined by a double sandwich ELISA. PBMC from seven of the 12 FSS patients, but only three of the 24 controls, produced cytokines after incubation with peak E (P &lt; 0·05). Interestingly, six of the seven FSS patients reacting with peak E produced IL-5 and/or IL-10. In contrast, PBMC from only one patient with other chronic disorders and one healthy control secreted type 2 cytokines in response to peak E. The observed heightened type 2 reactivity towards the more immunogenic contaminant 1,1′-ethylidenebis[l-tryptophan] in FSS patients may therefore be taken as an additional argument for our concept that EMS may have developed as a kind of drug-induced allergic disease.
Autoantibodies from patients with coeliac disease recognize distinct functional domains of the autoantigen tissue transglutaminase
Authors: Seissler J , Wohlrab U , Wuensche C , Scherbaum W A , Boehm B O 
Published: March 2003

SummaryThe enzyme tissue transglutaminase (tTG) has been recently identified to represent a highly sensitive and specific target of autoantibodies in coeliac disease. To characterize autoantigenic epitopes, we generated novel tTG deletion mutants by polymerase chain reaction, produced radiolabelled fragments by in vitro transcription/translation, immunoprecipitated the mutants using sera from patients with coeliac disease, and related the binding data with putative structural and functional domains of human tTG. We show that tTG antibody positive sera display a heterogeneous autoantibody response covering distinct regions of the molecule. The N-terminal and C-terminal third of tTG, comprising amino acid (aa) 1–281 and aa 473–687, harbour the dominant epitopes (67·4% and 69·4% positive), whereas the catalytic region is of minor antigenicity (22·5% positive). Autoantibodies directed to one, two and three domains were observed in 36·7%, 28·6% and 22·4% of patients, respectively. Comparative analysis revealed the presence of strictly conformational epitopes which were dependent on the N-terminus (aa 1–12) or the intact β-barrel domains in the C-terminus (aa 473–497, aa 649–687). In conclusion, we here demonstrate for the first time that the humoral autoimmunity is directed against distinct functional tTG domains. The spectrum of autoantibodies indicates that the native folded protein may be the target of autoantibodies.
Endothelial tissue factor stimulation by proteinase 3 and elastase
Authors: Haubitz M , Gerlach M , Kruse H J , Brunkhorst R 
Published: March 2003

Summary
In ANCA-associated vasculitis the activation of primed leucocytes by autoantibodies with subsequent release of proteases such as myeloperoxidase (MPO), proteinase 3 (PR3) and elastase is thought to play an important pathogenetic role. Whether these proteases contribute to the vascular lesions by stimulating the procoagulant activity of these cells is unknown. Tissue factor (TF) expression and activity were investigated in human umbilical vein endothelial cells after stimulation with MPO, PR3 and elastase. TF activity was measured using a one-stage clotting assay. Polyclonal antibodies to TF were used to prove specificity. TF mRNA was detected by reverse transcriptase-polymerase chain reaction. PR3 and elastase led to a significant increase in TF mRNA expression and increased activity. The stimulation was not mediated by IL-1. The stimulatory effect of PR3 did not depend on its proteolytic activity (no inhibition by α-1-antitrypsin), whereas the effect of elastase was blocked by α-1-antitrypsin. MPO had no effect on TF activity. These results show that PR3 and elastase stimulate TF expression in human endothelial cells. In ANCA-associated vasculitis the increased release of proteases may contribute to the development of microthrombi and consecutive necrosis.
X-Linked lymphoproliferative disease: three atypical cases
Authors: Nistala K , Gilmour K C , Cranston T , Davies E G , Goldblatt D , Gaspar H B , Jones A M 
Published: March 2003

SummaryCommon variable immunodeficiency (CVID) is the most frequently occurring primary immunodeficiency in both children and adults. The molecular basis of CVID has not been defined, and diagnosis involves exclusion of other molecularly defined disorders. X-linked lymphoproliferative disease (XLP) is a rare disorder in which severe immunodysregulatory phenomena typically follow Epstein–Barr virus (EBV) infection. Boys who survive initial EBV infection have a high incidence of severe complications, including progressive immunodeficiency, aplastic anaemia, lymphoproliferative disease and lymphoma. Survival beyond the second decade is unusual, although bone marrow transplantation can be curative. Until recently reliable diagnostic testing for XLP has not been available, but the identification of the XLP gene, known as SH2D1A, and coding for a protein known as SAP, means that molecular diagnosis is now possible, both by protein expression assays, and mutation detection, although the mutation detection rate in several series is only 55–60%. We describe three male patients initially diagnosed as affected by CVID, one of whom developed fatal complications suggestive of XLP, and all of whom lack expression of SAP. Two out of three have disease-causing mutations in the SAP gene, consistent with published data for XLP. These findings raise the possibility that a subgroup of patients with CVID may be phenotypic variants of XLP. Further studies are necessary to investigate this possibility, and also to clarify the prognostic significance of SAP abnormalities in such patients in the absence of typical features of XLP.
Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-γ, IL-4, IL-10 and IL-13) in patients with allergic asthma
Authors: Wong C K , Ho C Y , Ko F W S , Chan C H S , Ho A S S , Hui D S C , Lam C W K 
Published: March 2003

SummaryAllergen-reactive T helper type-2 (Th2) cells and proinflammatory cytokines have been suggested to play an important role in the induction and maintenance of the inflammatory cascade in allergic asthma. We compared the plasma concentrations of novel proinflammatory cytokines IL-17 and IL-18, other proinflammatory cytokines IL-6 and IL-12, Th2 cytokines IL-10 and IL-13, and intracellular interferon-γ (IFN-γ) and IL-4 in Th cells of 41 allergic asthmatics and 30 sex- and age-matched health control subjects. Plasma cytokines were measured by enzyme-linked immunosorbent assay. Intracellular cytokines were quantified by flow cytometry. Plasma IL-18, IL-12, IL-10, IL-13 concentrations were significantly higher in allergic asthmatic patients than normal control subjects (IL-18: median 228·35 versus 138·72 pg/ml, P &lt; 0·001; IL-12: 0·00 versus 0·00 pg/ml, P = 0·001; IL-10: 2·51 versus 0·05 pg/ml, P &lt; 0·034; IL-13: 119·38 versus 17·89 pg/ml, P &lt; 0·001). Allergic asthmatic patients showed higher plasma IL-17 and IL-6 concentrations than normal controls (22·40 versus 11·86 pg/ml and 3·42 versus 0·61 pg/ml, respectively), although the differences were not statistically significant (P = 0·077 and 0·053, respectively). The percentage of IFN-γ-producing Th cells was significantly higher in normal control subjects than asthmatic patients (23·46 versus 5·72%, P &lt; 0·001) but the percentage of IL-4 producing Th cells did not differ (0·72 versus 0·79%, P &gt; 0·05). Consequently, the Th1/Th2 cell ratio was significantly higher in normal subjects than asthmatic patients (29·6 versus 8·38%, P &lt; 0·001). We propose that allergic asthma is characterized by an elevation of both proinflammatory and Th2 cytokines. The significantly lower ratio of Th1/Th2 cells confirms a predominance of Th2 cells response in allergic asthma.
Diagnostic features of pemphigus vulgaris in patients with pemphigus foliaceus: detection of both autoantibodies, long-term follow-up and treatment responses
Authors: Sami N , Bhol K C , Ahmed A R 
Published: March 2003

Summary
There are several studies that describe the simultaneous presence and conversion of pemphigus foliaceus into pemphigus vulgaris and vice versa. We describe eight patients with clinical, histological and immunopathological features of pemphigus foliaceus, at the time of the initial diagnosis. After a mean period of 2·5 years, additional serological features of pemphigus vulgaris were observed. During a long-term follow-up, systemic therapies, their durations and treatment outcomes were recorded. These patients did not respond to conventional systemic therapy and developed multiple side-effects from these drugs. Hence, they were treated with intravenous immunoglobulin therapy (IVIg). Prior to the initiation of IVIg therapy, different assays were performed to detect the presence of autoantibodies, including indirect immunofluorescence (IIF), immunoblot assay using bovine gingival lysate, and ELISA. Twenty-five healthy normal individuals, 12 patients with pemphigus vulgaris, and eight patients with pemphigus foliaceus served as controls for comparison of serological studies. At the time of initial diagnosis, the sera of all eight study patients also demonstrated binding on an immunoblot assay to a 160-kDa protein (desmoglein 1) only. This is typically observed in pemphigus foliaceus. Prior to staring IVIg therapy, binding was observed to both the 160 kDa and 130 kDa (desmoglein 3) proteins on an immunoblot assay which was characteristic of pemphigus vulgaris. The antidesmogleins, 1 and 3 autoantibodies, were predominantly of the IgG4 subclass in all eight patients studied. IVIg therapy induced remission in four patients and control in four of the eight patients. The total follow-up period ranged from 2·6 to 9·5 years (mean 5·3 years). It is difficult to determine the exact time at which these patients with pemphigus foliaceus developed pemphigus vulgaris. It is possible that the disease was nonresponsive to conventional immunosuppressive therapy owing to the simultaneous presence of two autoantibodies.
Clonal evolution of CD8+ T-cell expansions in HIV-infected patients on long-term HAART
Authors: King D J S , Larsson-Sciard E -L 
Published: March 2003

SummaryHIV-1 continually replicates in spite of long-term highly active anti-retroviral therapy (HAART) and therefore, it is conceivable that the low level, persistent viral activity could continue to stimulate the hosts immune system despite remaining below the detection limit of the current assays. In this study, we performed a longitudinal analysis of the CD8+ T-cell receptor Vβ repertoire in HAART-treated and untreated HIV patients. HAART-mediated control of viremia, for up to 18 months, did not prevent similar perturbations within the CD8+ Vβ repertoire in both study groups as defined by CDR3 spectratyping. Oligoclonal Vβ expansions, with new dominant CDR3 lengths, were observed throughout the study period. Our findings are compatible with antigen-driven CD8+ immune responses to bursts of replication from a continuously changing viral reservoir, regardless of HAART-mediated suppression of HIV-1 viremia.