bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double blind, placebo-controlled, crossover therapy study with natural human IL-2 (nhuIL-2) in combination with regular intravenous gammaglobulin (IVIG) infusions in 10 patients with common variable immunodeficiency (CVID)
Authors: RUMP J A , JAHREIS A , SCHLESIER M , STECHER S , PETER H H 
Published: August 2010

SUMMARY
Ten CVID patients with defective IL-2 synthesis in vitro were treated with nhuIL-2 in a placebo-controlled, double blind, crossover therapy study during a period of 12 months. No severe side-effects of nhuIL-2 were recorded. Marginal serum nhuIL-2 levels were measurable in individual patients only during the therapy phase. Serum levels of soluble IL-2 receptors were unaffected by the therapy. nhuIL-2 and placebo groups did not differ significantly with respect to requirement of IVIG substitutions which were performed whenever serum IgG levels dropped below 5 g/l: a total of 53 IVIG infusions (corresponding to 17.6 g IgG/month per patient) was necessary during the placebo phase, and 48 infusions (16-4 g IgG/month per patient) during the nhuIL-2 treatment phase. Thus, nhuIL-2 therapy was ineffective in improving spontaneous IgG synthesis in vivo. Nevertheless, the group of patients receiving nhuIL-2 during the first 6 months of the study exhibited a significant reduction of severe infections (n= 25) during the following 6 months of placebo treatment (n = 7) (P&lt; 0–045). The infection score dropped in this group from 181 to 23 (P &lt; 0015). Patients of the second group receiving first placebo and then nhuIL-2 did not experience a significant difference in number and score of infectious episodes: 25 infections were recorded during the first 6 months and 24 during the following 6 months. We suppose that nhuIL-2 therapy of CVID patients reduces susceptibility to severe infections, possibly via the induction of a specific antibody response, which is effective at the earliest 6 months after initiating nhuIL-2 therapy.
Isotypic analysis of maternally transmitted Plasmodium falciparum-specific antibodies in Cameroon, and relationship with risk of P. falciparum infection
Authors: DELORON P , DUBOIS B , LE HESRAN J Y , RICHE D , FIEVET N , CORNET M , RINGWALD P , COT M 
Published: August 2010

SUMMARY
In malaria-endemic areas, infants are relatively protected against malaria infection. Such protection is though to be related principally to the transplacental transfer of maternal antibodies. We measured total and Plasmodium falciparum-specific IgG (including subclasses), IgM, and IgE antibodies in 154 paired maternal-cord serum samples from an area of meso- to hyperendemic malaria in South Cameroon. Among peripheral mother blood samples, total IgG and IgM were detected in all samples, IgE in all but two. Plasmodium falciparum-specific IgG were detected in all serum samples, IgM and IgE in &lt; 75% of samples. The prevalence rates of anti-P. falciparum IgG subclasses varied from 75% to 97%. With the exception of P. falciparum-sptcifxc IgG, all antibody class and subclass levels were lower in cord blood than in peripheral mother blood. Plasmodium falciparum-spccific IgGl and IgG3 isotypes were transferred to the offspring more often and more efficiently than IgG2 and IgG4. The detection of total and P. falciparum-specific IgM and IgE in some cord serum samples demonstrated that fetuses can mount humoral response against malaria parasites. We also determined whether transplacentally acquired antibodies protect against malaria infection by relating the antibody levels at birth to the risk of acquiring P. falciparum infection during the first 6 months of life. Among various classes and subclasses of P. falciparum-spccific antibodies, only IgG2 were related to a decrease in the risk of acquiring a P. falciparum peripheral blood infection from birth to 6 months of age.
Specificities of anti-neutrophil autoantibodies in patients with rheumatoid arthritis (RA)
Authors: BRIMNES J , HALBERG P , JACOBSEN S , WIIK A , HEEGAARD N H H 
Published: August 2010

SUMMARYThe objective of this study was to characterize antigens recognized by neutrophil-specific autoantibodies from patients with RA. Sera from 62 RA patients were screened by indirect immunofluorescence (IIF). Positive sera were further tested by ELISAs for antibodies against various granule proteins and by immunoblotting of electrophoretically separated cell, granule or nuclear extracts. Forty-two sera (68%) reacted with ethanol-fixed neutrophils. In the ELISAs 32% of the 28 medium to strongly IIF-positive sera were negative, while 43% were weakly positive for more than one antigen. Immunoblots of whole neutrophils showed IgG reactions at 25–35 kD, in the 55-kD region, at 80 kD, and at 110kD. Most sera reacted with more than one band. Except for the 55-kD antigen, none of the antigens appeared in lymphocytes. The most notable reactivity in subcellular fractions was with lactoferrin and with bands of 25–35 kD from nuclei. In conclusion, anti-neutrophil autoantibodies from RA patients recognize different antigens in the cytoplasm and in the nucleus. Lactoferrin is one of the common antigens recognized, but also unknown nuclear antigens of 25–35 kD mol. wt are involved.
Alteration of DNA methylation levels in MRL lupus mice
Authors: MIZUGAKI M , YAMAGUCHI T , ISHIWATA S , SHINDO H , HISHINUMA T , NOZAKI S , NOSE M 
Published: August 2010

SUMMARYRecent reports suggest that DNA methylation is involved in the cause of autoimmune disease. We investigated the alteration of DNA methylation levels in lupus strains of mice, MRL/lpr as a model, which develop an age-dependent lymphadenopathy and autoimmune disease. DNA methylation levels of thymus and axillary lymph nodes in 20-week-old MRL/lpr mice, which are in an autoimmune disease state, were lower than those of 4-week-old MRL/lpr mice with no symptoms as yet. No significant changes were observed in MRL/4- strain mice, which seemed normal at least 20 weeks, while DNA methylation levels in the spleen of both strains of mice increased significantly from the age of 4 to 20 weeks. However, no significant changes of DNA methylation levels in peripheral blood were observed with ageing in MRL strains. Moreover, we clarified that administration of 5-azacytidine had a strong effect on longer survival of MRL/lpr mice and reduced DNA methylation levels in the axillary lymph nodes and spleen. The possible relevance of DNA methylation levels to the progression of autoimmune disease is discussed.
Studies of epitope restriction on myeloperoxidase (MPO), an important antigen in systemic vasculitis
Authors: SHORT A K , LOCKWOOD C M 
Published: August 2010

SUMMARYAnti-neutrophil cytoplasmic antibodies are important components of the inflammatory response in patients with systemic vasculitis. Their role in the pathogenesis of these conditions remains incompletely defined. Several antigens have been identified, and MPO is one of the most important. To gain more understanding of the immune mechanisms involved, we were keen to see if the antibody response to MPO was restricted, or whether there was a general loss of tolerance to the whole surface of the molecule. To study the epitopes we employed both ELISA and biosensor technology, and were able to demonstrate restriction both in the number and localization of the epitopes being recognized.
Antigen-presenting properties of gingival fibroblasts in chronic adult periodontitis
Authors: WASSENAAR A , SNIJDERS A , ABRAHAM-INPIJN L , KAPSENBERG M L , KIEVITS F 
Published: August 2010

SUMMARYChronic periodontitis is characterized by dense infiltrations of T lymphocytes in the connective tissue, which consists mainly of gingival fibroblasts. It is becoming increasingly clear that T lymphocytes and gingival fibroblasts are capable of influencing each other. For example, the T cell cytokine interferon-gamma (IFN-γ) is able to induce MHC class II molecules on the surface of several cell types, including gingival fibroblasts. Histological sections of chronically inflamed gingival tissue showed a great number of CD4+ and CD8+ T cells that produced IFN-γ, and in addition showed abundant expression of MHC class II molecules on gingival fibroblasts. Therefore, we investigated whether these gingival fibroblasts acquire the capacity to carry out MHC class II-restricted functions such as antigen presentation to local T cells. In this study, we show that IFN-γ-treated gingival fibroblasts were able to function as antigen-presenting cells (APC) for superantigen-mediated T cell proliferation. However, these fibroblasts failed to present whole-cell antigens of periodontitis-associated bacteria. Moreover, gingival fibroblasts inhibited the presentation of the whole-cell antigens of these bacteria by professional APC. This inhibition could be overcome by the addition of IL-2. These results suggest that gingival fibroblasts play an important role in the local specific immune response in chronic inflammatory periodontal lesions by regulating the response of infiltrating T cells.
Anti-heat shock protein (hsp)72 antibodies are present in patients with Graves' disease (GD) and in smoking control subjects
Authors: PRUMMEL M F , VAN PAREREN Y , BARKER O , WIERSINGA W M 
Published: August 2010

SUMMARY
Hsp72 is expressed in thyroidal tissue and on retroocular fibroblasts from patients with GD. In this study we investigated whether GD patients have hsp72 antibodies, and if they correlate with disease characteristics. Because smoking is associated with GD and might up-regulate hsp72 expression, we also studied the effect of smoking on hsp antibody levels. Hsp72 IgG antibodies were determined by dot-blotting, using recombinant human stress-inducible hsp72. Dot-blot densities were measured using a videoimaging system in 38 healthy controls, 45 patients with GD, including 34 with varying degrees of ophthalmopathy, and in 13 GD patients before and after treatment of thyrotoxicosis with methimazole. Hsp72 antibodies were detectable more frequently in GD patients (26/45, 58%), than in controls (12/38, 32% P&lt;0·02). GD patients had higher antibody levels than controls; mean ± s.e.m. optical densities: 26·8 ± 2·6 versus 18·8 ± 2·4 (P = 0·018). Levels did not correlate with any parameter of disease severity or activity. Hsp72 antibody levels did not change upon reaching euthiyroidism. In controls, but not in patients, hsp72 antibodies could be detected more frequently in smokers (6/10, 60%) versus non-smokers (6/28, 21%; P = 0·024). Patients with GD have higher hsp72 IgG antibody levels than controls, without correlation with any disease characteristic. Among healthy controls, smoking is associated with elevated hsp72 antibodies. This suggests that these antibodies might be a marker for autoimmune susceptibility.
Quantification of Bax/Bcl-2 ratios in peripheral blood lymphocytes, monocytes and granulocytes and their relation to susceptibility to anti-Fas (anti-CD95)-induced apoptosis
Authors: VAN DER VLIET H J J , WEVER P C , VAN DIEPEN F N J , YONG S-L , TEN BERGE I J M 
Published: August 2010

SUMMARYNeutrophils have the shortest half-life among circulating leucocytes and rapidly undergo apoptosis in vitro. The homologous Bcl-2 and Bax proteins have opposing effects, with Bcl-2 extending cellular survival and Bax promoting cell death following an apoptotic stimulus. We determined Bcl-2 to Bax expression ratios in peripheral blood lymphocytes, monocytes and granulocytes and related them to the susceptibility of these cells to anti-Fas (anti-CD95)-induced apoptosis. Here, we show that Bax/Bcl-2 ratios are high in granulocytes and relatively low in monocytes and lymphocytes. Furthermore, we show a relation between this ratio in the different leucocyte subsets and their susceptibility to anti-Fas-induced apoptosis, with granulocytes showing the highest susceptibility, followed by monocytes and lymphocytes. It is concluded that the balance between Bcl-2 and Bax forms an apoptotic rheostat, which seems to determine sensitivity to apoptosis.
Translational Mini-Review Series on Toll-like Receptors:&#x2028;Networks regulated by Toll-like receptors mediate innate and adaptive immunity
Authors: Parker L C , Prince L R , Sabroe I 
Published: August 2010

SummaryThe Toll-like receptor (TLR) family provide key components of mammalian immunity and are part of the earliest surveillance mechanisms responding to infection. Their activation triggers the innate immune response, and is crucial to the successful induction of Th1/Th2-phenotyped adaptive immunity. Innate immunity was long considered to be non-specific and somewhat simple compared to adaptive immunity, mediated via the engulfment and lysis of microbial pathogens by phagocytic cells such as macrophages and neutrophils, and involving no complex protein–protein interactions. The emergence of the TLR field has contributed to a revision of our understanding, and innate immunity is now viewed as a highly complex process, in line with adaptive immunity. This review will give a brief overview of our current knowledge of TLR biology, and will focus on TLRs as key components in complex networks that activate, integrate and select the appropriate innate and adaptive immune responses in the face of immunological danger.
Translational Mini-Review Series on Type 1 Diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes
Authors: Di Lorenzo T P , Peakman M , Roep B O 
Published: August 2010

SummaryT cell epitopes represent the molecular code words through which the adaptive immune system communicates. In the context of a T cell-mediated autoimmune disease such as type 1 diabetes, CD4 and CD8 T cell recognition of islet autoantigenic epitopes is a key step in the autoimmune cascade. Epitope recognition takes place during the generation of tolerance, during its loss as the disease process is initiated, and during epitope spreading as islet cell damage is perpetuated. Epitope recognition is also a potentially critical element in therapeutic interventions such as antigen-specific immunotherapy. T cell epitope discovery, therefore, is an important component of type 1 diabetes research, in both human and murine models. With this in mind, in this review we present a comprehensive guide to epitopes that have been identified as T cell targets in autoimmune diabetes. Targets of both CD4 and CD8 T cells are listed for human type 1 diabetes, for humanized [human leucocyte antigen (HLA)-transgenic] mouse models, and for the major spontaneous disease model, the non-obese diabetic (NOD) mouse. Importantly, for each epitope we provide an analysis of the relative stringency with which it has been identified, including whether recognition is spontaneous or induced and whether there is evidence that the epitope is generated from the native protein by natural antigen processing. This analysis provides an important resource for investigating diabetes pathogenesis, for developing antigen-specific therapies, and for developing strategies for T cell monitoring during disease development and therapeutic intervention.
Agonistic antibodies to Fas induce a breach in the endothelial lining of the liver and a breakdown in B cell tolerance
Authors: Newkirk M M , Nowak U , Skamene E , Iera D , Desbarats J 
Published: August 2010

SummaryLiver disease can be associated with a breakdown in self-tolerance and the production of autoantibodies such as rheumatoid factors (RF), which bind to IgG. Here we investigated whether primary, non-infectious liver damage was sufficient to induce autoantibody production. We established a model of targeted liver damage induced by weekly sublethal injections of pro-apoptotic anti-Fas (CD95) antibodies. Liver damage, monitored by measurements of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was minimal 1 week after anti-Fas injection. However, the sublethal Fas stimulation was sufficient to trigger significant haemorrhage in the liver, as assessed by Evans Blue dye leakage into the organ 5 h after anti-Fas antibody injection. We observed an induction of RF in response to the weekly injections of sublethal anti-Fas antibodies but not of isotype control antibodies, indicating a breakdown of self-tolerance induced by Fas engagement. RF induction was unlikely to be due to direct activation of B cells, as splenocytes stimulated with anti-Fas antibodies in vitro did not produce RF. These studies show that sublethal damage to the liver by Fas engagement leads to liver haemorrhage and is sufficient to trigger the breakdown of self-tolerance.
Production of interleukin (IL)-5 and IL-10 accompanies T helper cell type 1 (Th1) cytokine responses to a major thyroid self-antigen, thyroglobulin, in health and autoimmune thyroid disease
Authors: Nielsen C H , Hegedüs L , Rieneck K , Moeller A C , Leslie R G Q , Bendtzen K 
Published: August 2010

SummaryTumour necrosis factor (TNF)-α and interferon (IFN)-γ exert detrimental effects in organ-specific autoimmune disease, while both destructive and protective roles have been demonstrated for interleukin (IL)-10, IL-4 and IL-5. We examined the production of these cytokines by peripheral blood mononuclear cells (PBMC) from patients with Hashimoto's thyroiditis (HT), Graves' disease (GD) and healthy controls, upon exposure to a thyroid self-antigen, human thyroglobulin (Tg), in the presence of autologous serum. Initially, TNF-α and IL-2 were produced in all three groups, accompanied by IL-10. Release of IFN-γ, IL-4 and, notably, IL-5 ensued. Both patient groups exhibited increased TNF-α, IL-2, IFN-γ and IL-10 responses, and PBMC from HT patients secreted lower amounts of IL-5 than male, but not female, controls. Enhanced TNF-α production by HT cells also occurred in the presence of pooled normal sera, indicating a dependency on intrinsic cellular factors. Conversely, higher production of TNF-α and IL-5 occurred in the presence of autologous sera than in the presence of pooled normal sera in both patient groups, indicating a dependency on serum constituents. Complement appeared to promote the production of IL-2 and particularly IL-5, the levels of which were reduced by neutralization of complement by heat- or zymosan treatment. The production of IFN-γ and IL-2 of the three groups together correlated directly with the serum anti-Tg activity. Moreover, TNF-α, IFN-γ, IL-5 and IL-10 responses were markedly inhibited by partial denaturation of Tg by boiling. We hypothesize that autoantibodies and complement may promote mixed Th1/Th2 cell cytokine responses by enhancing the uptake of autoantigens by antigen-presenting cells.
Mycobacterium bovisbacillus Calmette–Guérin (BCG) induces human CC- and CXC-chemokinesin vitroandin vivo
Authors: Luo Y , Chen X , O'Donnell M A 
Published: August 2010

SummaryBoth CC- and CXC-chemokines are known to be potent leucocyte activators and chemoattractants and play important roles in inflammatory responses. However, chemokine response to bacillus Calmette–Guérin (BCG) infection remains incompletely defined. In this study, we investigated human CC- [macrophage-derived chemokine (MDC), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α and eosinophil chemoattractant activity (eotaxin)] and CXC-interferon-inducible protein (IP)-10 chemokine production in response to BCG stimulation. BCG efficiently induced all chemokines tested in the urine of four bladder cancer patients undergoing intravesical BCG immunotherapy. The peak urinary chemokine responses occurred generally between the fourth and sixth weekly treatment, except eotaxin, which was less predictable. To evaluate the effect of BCG on induction of chemokines in vitro, urothelial cell lines and peripheral blood mononuclear cells (PBMCs) were used. Although BCG induced no or marginal chemokines from urothelial SV-HUC-1, RT4 and T24 cells, BCG-derived cytokines [interleukin (IL)-1β, interferon (IFN)-γ and tumour necrosis factor (TNF)-α] induced all chemokines tested except eotaxin from these cell lines. BCG also efficiently induced all chemokines tested except eotaxin from PBMCs of both BCG-naive and BCG-vaccinated subjects. MCP-1 and MIP-1α emerged at 4–5 h post-BCG exposure (early chemokines); IP-10 elevated at day 1 and peaked at day 2 (intermediate chemokine); and MDC elevated at day 1 and peaked at day 7 (late chemokine). This kinetic pattern was paralleled with that of BCG-induced cytokines [early: TNF-α; intermediate: IL-6 and IL-10; and late: IFN-γ and granulocyte–macrophage colony-stimulating factor (GM-CSF)]. Taken together, these results indicate that BCG directly or indirectly induces human CC- and CXC-chemokine production, which may represent one of the mechanisms by which BCG exerts its anti-tumour activity.
The European internet-based patient and research database for primary immunodeficiencies: results 2004–06
Authors:   ESID Registry Working Party, Eades-Perner A-M , Gathmann B , Knerr V , Guzman D , Veit D , Kindle G , Grimbacher B 
Published: August 2010

Summary
Because primary immunodeficiencies (PID) are rare diseases, transnational studies are essential to maximize the scientific outcome and lead to improved diagnosis and therapy. Immunologists in Europe have united to determine the prevalence of PID in Europe and to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID as well as to improve the awareness of PID in Europe. In order to achieve this aim we have developed an internet-based database for clinical and research data on patients with PID. This database forms the platform for studies of demographics, the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. The database is completely secure, while providing access to researchers via a standard browser using password and encrypted log-in sessions and conforms to all European and national ethics and data protection guidelines. So far 2386 patients have been documented by 35 documenting centres in 20 countries. Common variable immunodeficiency (CVID) is the most common entity, accounting for almost 30% of all entries. First statistical analyses on the quality of life of patients show the advantages of immunoglobulin replacement therapy, at the same time revealing a mean diagnostic delay of over 4 years. First studies on specific questions on selected PID are now under way. The platform of this database can be used for any type of medical condition.
Innate-immunity cytokines induced by very small size proteoliposomes, a Neisseria-derived immunological adjuvant
Authors: Venier C , Guthmann M D , Fernández L E , Fainboim L 
Published: August 2010

SummaryNeisserial outer membrane proteins have been combined with monosialoganglioside GM3 to form very small size proteoliposomes (VSSP), a nanoparticulated formulation used as a cancer vaccine for the treatment of cancer patients with GM3-positive tumours. VSSP were shown to elicit anti-GM3 and anti-tumour immune responses. VSSP have also been shown to be an efficient adjuvant for tumour-cell and peptide-antigen vaccines in mice. In vitro studies showed that VSSP promote maturation of both murine and human dendritic cells, suggesting that VSSP could be used as efficient adjuvants. In order to study further the capacity of VSSP to elicit innate immune responses, human peripheral blood mononuclear cells and monocytes derived thereof were assessed for in vitro secretion of interleukin (IL)-10, IL-6, IL-12 and interferon (IFN)-γ. VSSP most prominently induced the secretion of IL-6. IL-10 was secreted at a lower level. IL-12 p40 (but no p70) was also detected. IFN-γ response was observed in 56% of the tested samples. Cytokine secretion was not related to lipopolysaccharide (LPS) content and involved Toll-like receptor 2 (TLR2)-mediated signal transduction. VSSP also induced DC maturation and a cytokine secretion pattern (high IL-6/low IL-10) which differs from that induced by LPS. The observed proinflammatory cytokine secretion pattern and the capacity of VSSP to drive DC maturation are examined in the light of the properties of other bacterial derivatives currently being user for immunotherapy purposes. Our results suggest that VSSP could be tested in clinical settings where T helper 1-type immune responses would be beneficial.