1.
The synovium in rheumatoid arthritis.
Source
University of Manitoba, Winnipeg, Manitoba, Canada.
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease targeting multiple joints. The synovium is the primary site of the inflammatory process, which if untreated leads to irreversible damage to the adjacent cartilage and bone. It is now well established that autoantibodies that are characteristic of RA, including rheumatoid factor (RF) and anti-citrulluninated protein antibodies (ACPA), are present before clinical disease onset. Studies in both humans and animal models are beginning to provide new insights into how this asymptomatic autoimmunity evolves into an inflammatory process that is localized in the synovium.Once RA synovitis established, a number of amplification mechanisms serve to sustain the process leading to the persistence of the disease. These mechanisms include engagement of the resident mesenchymal cells and the establishment of ectopic lymphoid structures in the synovium, although the relationship between these lymphoid structures and the presence of RA autoantibodies remains unclear.An enhanced understanding of the mechanisms that initiate and sustain RA synovitis offers unprecedented opportunities for therapeutics, and ultimately prevention strategies.
- PMID:
- 22279509
- [PubMed - in process]
Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B.
Source
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida Gainesville, FL, USA.
Abstract
Intramuscular (IM) administration of an adeno-associated viral (AAV) vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency). However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4(+) T cell epitope) caused an induction of regulatory T cells (Treg) with a concomitant apoptosis of antigen-specific effector T cells (Nayak et al., 2009). This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX) in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion). Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1-hF.IX vector resulted in inhibitors of on average 8-10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specificantibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.
- PMID:
- 22279442
- [PubMed - in process]
ANCA-associated Goodpasture's syndrome in a patient with rheumatoid arthritis on penicillamine.
Source
Division of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta - The Medicity, Gurgaon, Haryana, India.
Abstract
Although penicillamine has been used effectively in the management of a variety of diseases, several adverse reactions have been observed with prolonged administration of this agent. We report a case of Goodpasture's syndrome, as a result of induction of anti-myeloperoxidase antineutrophil cytoplasmic antibodies in a 51 year old man who was being treated with this drug for rheumatoid arthritis. This pulmonary-renal syndrome has been described on rare occasions in patients receiving penicillamine. Treatment with steroids and cyclophosphamide resulted in pulmonary and renal functional recovery.
- PMID:
- 22279343
- [PubMed - in process]
Growth and innate immunity are not limited by selection for high egg testosterone content in Japanese quail.
Source
Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic.
Abstract
The effects of maternal androgens on fitness-related traits of offspring are generally assumed to be epigenetic adaptations to the environment that may be encountered by the next generation. Possible constraints of high yolk androgen transfer are still not understood, although a suppressed immune response in offspring is frequently considered. The aim of our study was to examine the innate immune defence in high (HET) and low egg testosterone (LET) lines of Japanese quail, which differ in the hormonal milieu of their eggs, thus providing a good physiological model for the study of androgen-mediated maternal effects. Acute phase response was induced by a lipopolysaccharide injection in 12-day-old quail and plasma corticosterone and the heterophil:lymphocyte ratio were measured at 1 and 3 h post-treatment. Basal levels of non-specific antibodies (IgY) were determined in the circulation. We found that HET quail were heavier than LET quail from the second week of age, indicating enhanced post-hatching growth. At 1 h post-lipopolysaccharide challenge, plasma corticosterone concentrations increased in the HET but not in the LET line. The heterophil:lymphocyte ratio rose in both lines at 3 h post-immune challenge, with a more pronounced response in HET quail. Moreover, HET chicks displayed higher IgY levels than LET chicks, suggesting either enhanced passive immunoprotection or stimulated endogenous antibody production. In conclusion, our data demonstrate that the genetic selection for high egg testosterone content positively influences growth and, simultaneously, does not limit the acute phase response in young quail.
- PMID:
- 22279068
- [PubMed - in process]
Helicobacter pylori Infection Is Associated With an Increased Rate of Diabetes.
Source
Center for Infectious Diseases Epidemiologic Research, Mailman School of Public Health, Columbia University, New York, New York.
Abstract
OBJECTIVEChronic infections could be contributing to the socioeconomic gradient in chronic diseases. Although chronic infections have been associated with increased levels of inflammatory cytokines and cardiovascular disease, there is limited evidence on how infections affect risk of diabetes.RESEARCH DESIGN AND METHODSWe examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998-1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional-hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels.RESULTSIndividuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10-6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection.CONCLUSIONSWe demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.
- PMID:
- 22279028
- [PubMed - as supplied by publisher]
Apparent Involvement of Plasmin in Early-Stage Follicle Rupture During Ovulation in Medaka.
Abstract
Until recently, the role of the proteolytic system involving serine proteases in follicle rupture during ovulation in mammalian species has been a subject of controversy. We undertook the present study to examine whether proteases play a role in follicle rupture using the teleost medaka (Oryzias latipes) model. Various serine protease inhibitors, including a specific plasmin inhibitor, drastically reduced the rate of ovulation, as assessed by an in vitro ovulation assay, which was established for the fish. Biochemical, molecular biological, and immunological analyses demonstrated that plasminogen/plasmin was present in large follicles destined to ovulate. The active protease, plasmin, was detected in follicles approximately 3 to 7 h before the expected time of ovulation. Specific antibodies against the medaka plasmin light-chain suppressed the ovulation rate of the follicles when antibodies were added to the medium during the period in which active plasmin was generated. This finding was an indication that a plasmin-like protease similar if not identical to plasmin plays a role in follicle rupture during ovulation in the medaka. Our data also indicate that this serine protease participates in the rupture for only a few hours prior to the activation of matrix metalloproteinase (Mmp)-mediated hydrolysis at ovulation. Based on our previous and current data, we propose a follicle rupture model involving two different proteolytic enzyme systems, serine protease and Mmp, in medaka ovulation. The current study is the first to provide evidence of the indispensable role of plasmin or a plasmin-like protease in the ovulation of a non-mammalian vertebrate species.
- PMID:
- 22278979
- [PubMed - as supplied by publisher]
Protease activation and the signal transduction pathway regulating motility in sperm from the water strider Aquarius remigis.
Source
Department of Biology, University of California, Riverside.
Abstract
Many motile processes are regulated such that movement occurs only upon activation of a signaling cascade. Sperm from a variety of species are initially quiescent and must be activated prior to beating. The signaling events leading to the activation and regulation of sperm motility are not well characterized. Mature seminal vesicle sperm from the water strider Aquarius remigis are immotile in vitro, but vigorous motility is activated by trypsin. Trypsin-activated motility was blocked by pretreatment of the sperm with BAPTA-AM to chelate intracellular Ca(2+) and was partially rescued by subsequent addition of A23187 and Ca(2+) . Thapsigargin stimulated motility in the absence of trypsin, suggesting that intracellular Ca(2+) stores are available. In addition, motility could be fully activated by the phosphatase inhibitor calyculin A, suggesting that the immotile state is maintained by an endogenous phosphatase and that kinase activity is required for motility. The MEK1/2 inhibitor U0126 significantly reduced trypsin activated motility, and MPM-2, an antibody which recognizes proline-directed phosphorylation by kinases such as MAPK, recognized components of the water strider sperm flagellum. Antibodies specific for the mouse protease activated receptor PAR2 recognized an antigen on the sperm flagellum. These results suggest that trypsin stimulates a Ca(2+) and MAPK mediated signaling pathway and potentially implicate a PAR2-like protein in regulating motility. © 2012 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
- PMID:
- 22278949
- [PubMed - as supplied by publisher]
Development of a human herpesvirus 6 virus species-specific immunoblotting assay.
Source
Department of Pediatrics, Fujita Health University School of Medicine.
Abstract
In order to assess the full spectrum of HHV-6A- and HHV-6B-associated diseases, we sought to develop a HHV-6 virus species-specific serological assay based on immunoblot analysis. The immunodominant proteins encoded by ORF U11, p100 for HHV-6A (strain U1102) and 101K for HHV-6B (strain Z29), were selected to generate virus species-specific antigens. Recombinant p100 and 101K were produced in a prokaryotic expression system. The expression of these proteins was confirmed using anti-His tag and 101K-specific monoclonal antibodies. HHV-6 virus species-specificantibodies were detected by immunoblotting in patient sera. Eighty seven serum samples obtained from various subjects were utilized to determine the reliability of the method for clinical use. Ten of 12 exanthem subitum convalescent sera reacted exclusively with 101K, while none of 12 acute sera reacted with either protein. Two of three sera collected from HHV-6A-infected patients reacted with p100 and 101K. Although all 5 acute and convalescent sera obtained from transplant recipients reacted exclusively with 101K, two of 6 convalescent sera obtained from patients with drug-induced hypersensitivity syndrome reacted with both p100 and 101K. Thirty-one of 38 sera obtained from healthy adults were positive for 101K antibody, while 4 reacted with both proteins. However, PCR analysis of PBMCs and saliva from these subjects did not detect HHV-6A DNA. In conclusion, this novel serological assay based on immunoblot analysis using recombinant HHV-6A p100 and HHV-6B 101K allowed to discriminate between HHV-6A- and HHV-6B-specific antibodies.
- PMID:
- 22278837
- [PubMed - as supplied by publisher]
Menangle virus, a pteropid bat paramyxovirus infectious for pigs and humans, exhibits tropism for secondary lymphoid organs and intestinal epithelium in weaned pigs.
Source
Australian Animal Health Laboratory.
Abstract
This study is the first report of experimental infection and transmission of Menangle virus (MenPV) in pigs. Isolated in 1997 from piglets that were stillborn at a large commercial piggery in New South Wales, Australia, MenPV is a recently identified paramyxovirus of bat origin which causes severe reproductive disease in pigs and an influenza-like illness, with a rash, in humans. Although successfully eradicated from the infected piggery, virus was only isolated from affected foetuses and stillborn piglets during the period of reproductive disease, and thus the mode of transmission between pigs was not established. To investigate the pathogenesis of MenPV, we undertook time-course studies in six-week-old pigs following intranasal administration of a low-passage, non-plaque-purified isolate from the lung of an infected stillborn piglet. Viraemia was of short duration and low titre, as determined by real-time RT-PCR and virus isolation. Following an incubation period of two to three days, virus was shed in nasal and oral secretions, faeces, and urine, typically for less than one week. Cessation of shedding correlated with the development of neutralizing antibodies in sera. Secondary lymphoid organs and intestine were identified, using quantitative real-time RT-PCR, as major sites of viral replication and dissemination, and this was confirmed by positive immunolabelling of viral antigen within various lymphoid tissues and intestinal epithelium. These data provide new insights into the pathogenesis of MenPV in weaned pigs, and will facilitate future control and eradication programs should it ever re-emerge in the pig population.
- PMID:
- 22278823
- [PubMed - as supplied by publisher]
Allergen Arrays for Antibody Screening and Immune Cell Activation Profiling Generated by Parallel Lipid Dip-Pen Nanolithography.
Source
Karlsruher Institut für Technologie (KIT), Institut für Nanotechnologie (INT), Karlsruhe Nano Micro Facility (KNMF), 76021 Karlsruhe Germany. Sylwia.Sekula-Neuner@kit.edu.
Abstract
Multiple-allergen testing for high throughput and high sensitivity requires the development of miniaturized immunoassays that allow for a large test area and require only a small volume of the test analyte, which is often available only in limited amounts. Developing such miniaturized biochips containing arrays of test allergens needs application of a technique able to deposit molecules at high resolution and speed while preserving its functionality. Lipid dip-pen nanolithography (L-DPN) is an ideal technique to create such biologically active surfaces, and it has already been successfully applied for the direct, nanoscale deposition of functional proteins, as well as for the fabrication of biochemical templates for selective adsorption. The work presented here shows the application of L-DPN for the generation of arrays of the ligand 2,4-dinitrophenyl[1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[6-[(2,4-dinitrophenyl)amino]hexanoyl] (DNP)] onto glass surfaces as a model system for detection of allergen-specific Immunoglobin E (IgE) antibodies and for mast cell activation profiling.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- PMID:
- 22278752
- [PubMed - as supplied by publisher]
Differences in cap formation between invasive Entamoeba histolytica and non-invasive Entamoeba dispar.
Source
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, 07360, Mexico, DF, Mexico, bchavez@cinvestav.mx.
Abstract
The rapid redistribution of surface antigen-antibody complexes in trophozoites of the human protozoan parasite Entamoeba histolytica, in a process known as capping, has been considered as a means of the parasite to evade the host immune response. So far, capping has been documented in the invasive E. histolytica, whereas the mobility of surface components in the non-invasive Entamoeba dispar is not known. E. dispar does not induce liver lesions in rodent experimental models, in contrast to the liver abscesses produced by E. histolytica in the same animal model. We have therefore analyzed the mobility of surface receptors to the lectin concanavalin A and of Rab11, a membrane-associated protein, in both species of Entamoebae by confocal fluorescence microscopy and transmission and scanning electron microscopy. The great majority of E. histolytica trophozoites became morphologically polarized through the formation of well-defined caps at the posterior pole of the parasite. Actin colocalized with the lectin caps. Antibodies against the membrane protein Rab 11 also produced capping. In striking contrast, in E. dispar, the mobility of concanavalin A surface receptors was restricted to the formation of irregular surface patches that did no progress to constitute well-defined caps. Also, anti-Rab 11 antibodies did not result in capping in E. dispar. Whether the failure of E. dispar to efficiently mobilize surface molecules in response to lectin or antibodies as shown in the present results is related to its non-invasive character represents an interesting hypothesis requiring further analysis.
- PMID:
- 22278728
- [PubMed - as supplied by publisher]
Biochemical characterization and differential expression of a 16.5kDa tegument- associated antigen from the liver fluke Fasciola hepatica.
Source
Laboratory of Molecular Parasitology and Immunology, Department of Microbiology. University of Puerto Rico, School of Medicine, San Juan, Puerto Rico.
Abstract
A cDNA encoding a 16.5 kDa protein termed FhTP16.5 was identified by immunoscreening of a cDNA library from Fasciola hepatica adult flukes using pooled of sera from rabbits infected with F. hepatica for four weeks. qPCR analysis revealed that FhTP16.5 is not expressed in unembrionated eggs. It is poorly expressed in miracidia and highly expressed in juvenile and adult stages; however, significant differences were found between the expression levels of FhTP16.5 in juveniles versus adult flukes. Recombinant FhTP16.5 was highly expressed in Escherichia coli, purified by affinity chromatography and used to raise anti-FhTP16.5 polyclonal antibodies in rabbits. Immunoblot analysis using the anti-FhTP16.5 IgG antibody identified FhTP16.5 in crude and tegumental extracts and in excretory-secretory products of F. hepatica. The protein was not detected in crude extracts of Schistosoma mansoni or S. japonicum. Antibodies to FhTP16.5 were detected in the sera of rabbits at 3 to 12 weeks of F. hepatica infection as well as in the sera of humans with chronic fascioliasis, which suggest that FhTP16.5 could be a good antigen for serodiagnosis of fascioliasis. Immunohistochemistry demonstrated that FhTP16.5 localizes to the surface of the tegument of various developmental stages and in parenchymal tissues of the adult fluke. Such specific localization makes FhTP16.5 an attractive target for immunoprophylaxis or chemotherapy.
- PMID:
- 22278327
- [PubMed - as supplied by publisher]
Human Papillomavirus antibody reference reagents for post-vaccine surveillance serology.
Source
Centre for Infections, Health Protection Agency, London, UK.
Abstract
Suitably-controlled sero-surveillance surveys are essential for evaluating Human Papillomavirus (HPV) immunization programmes. A panel of plasma samples from 18 year old females was assembled, the majority being from bivalent vaccinees. Antibody specificities were evaluated by three independent laboratories and 3 pools were created that displayed either no antibodies to any HPV type tested, intermediate or high antibody levels to HPV16, HPV18, HPV31 and HPV45. These pools will be useful as control reagents for HPV serology.
- PMID:
- 22278326
- [PubMed - as supplied by publisher]
Protective immunity against tularemia provided by an adenovirus-vectored vaccine expressing Tul4 of Francisella tularensis.
Source
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Abstract
Francisella tularensis, a Category A bioterrorism agent, is a highly infectious organism that is passed on via skin contact and inhalation routes. A live attenuated vaccine strain (LVS) has been developed, but it has not been licensed for public use by the FDA due to safety concerns. Thus, there exists a need for a safer and improved vaccine. In this study, we have constructed a replication incompetent adenovirus, Ad/opt-Tul4, encoding a codon-optimized gene for expression of the membrane protein, Tul4, of F. tularensis LVS. Its ability to protect against lethal challenge and its immunogenicity were evaluated in a murine model. An intramuscular injection of a single dose (1×10(7) PFU) of Ad/opt-Tul4 elicited a robust Tul4-specific antibody response. Assays suggest a Th1-driven response. A single dose elicited 20% protection against challenge with 100×LD50 F. tularensis LVS; two additional booster shots resulted in 60% protection. In comparison, three doses of 5μg recombinant Tul4 protein did not elicit significant protection against challenge. Therefore, the Ad/opt-Tul4 vaccine was more effective than the protein vaccine, and protection was dose-dependent. Compared to LVS, the protection rate is lower, but an adenovirus vectored vaccine may be more attractive due to its enhanced safety profile and mucosal route of delivery. Furthermore, simple genetic modification of the vaccine may potentially produce antibodies protective against a fully virulent strain of F. tularensis. Our data support the development and further research of an adenoviral vectored vaccine against Tul4 of F. tularensis LVS.
- PMID:
- 22278325
- [PubMed - as supplied by publisher]
Evaluation of Coccidioides Antigen Detection in Dogs with Coccidioidomycosis.
Source
MiraVista Diagnostics, Indianapolis, IN.
Abstract
Antigen detection has been reported to be a promising method for rapid diagnosis of coccidioidomycosis in humans. Coccidioides antigen detection has not been previously reported in dogs with coccidioidomycosis, and was evaluated in 60 cases diagnosed based on detection of anti-Coccidioides antibodies at titers of 1:16 or more in serum. Controls included dogs with presumed histoplasmosis or blastomycosis, other fungal infections, non-fungal diseases, and healthy dogs. Urine and serum specimens were tested using an enzyme immunoassay for Coccidioides spp. galactomannan antigen. Antibody testing was performed at commercial veterinary reference laboratories. Antigen was detected in urine or serum of 12 of 60 (20.0%), urine only in two of 57 (3.5%), and serum only in 11 of 58 (19.0%) of dogs with coccidioidomycosis. Antigen was detected in the urine of three of 43 (7.0%) and serum of one of 37 (2.7%) dogs with histoplasmosis or blastomycosis but not in 13 dogs with other fungal infections (serum, 9; urine, 13), 41 dogs with non-fungal diseases (urine, 41; serum, 18), or healthy dogs (serum, 21; urine, 21). Detection of antigen was an insensitive method for diagnosis of coccidioidomycosis in dogs in which the diagnosis was based primarily upon detection of antibodies at titers of 1:16 or higher, and the highest sensitivity was in serum.
- PMID:
- 22278324
- [PubMed - as supplied by publisher]
PAR-1-dependent and PAR-independent pro-inflammatory signalling in human lung fibroblasts exposed to thrombin.
Source
Centre for Respiratory Research, University College London, United Kingdom.
Abstract
Proteinase-activated receptors (PARs) are crucial in orchestrating cellular responses to coagulation proteinases, such as thrombin and FXa. Four PARs have been characterized and have been shown to be differentially expressed in mice and humans and between tissues. We have previously shown that in murine lung fibroblasts, PAR-1 is solely responsible for all cellular responses to thrombin and FXa. In contrast, we report here that in primary human lung fibroblasts, known PARs fail to account for all of the cellular responses to thrombin, in particular in the presence of high, but physiologically achievable concentrations of thrombin. We report that primary human lung fibroblasts secrete CCL2 in a PAR-1-dependent manner at low thrombin concentration (∼ 0.3 nM). At or above 10 nM thrombin, pharmacological antagonism (RWJ-58259) fails to block thrombin-induced CCL2 release; whereas PAR-1 cleavage-blocking monoclonalantibodies (ATAP2 and WEDE15) only partially inhibit thrombin-induced CCL2 secretion. In addition, activation of PAR-3, PAR-4 and transactivation of either PAR-2 or EGFR were ruled out as being responsible for thrombin-mediated CCL2 secretion at high yet standard concentrations of the proteinase. We further provide evidence that PAR-1-dependent and PAR-independent signaling involves the rapid phosphorylation of ERK which in turn is absolutely required for thrombin-induced CCL2 secretion at both low and standard concentration of the proteinase. Our findings suggest the existence of a PAR-independent signaling mechanism in human lung fibroblasts and have important implications for the design of therapeutic strategies aimed at blocking pro-inflammatory signaling responses associated with excessive thrombin generation. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
- PMID:
- 22278285
- [PubMed - as supplied by publisher]
Recombinant dengue type 2 viruses with altered E protein domain III epitopes are efficiently neutralized by human immune sera.
Source
Department of Microbiology and Immunology, and the Southeast Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Research, University of North Carolina School of Medicine, Chapel Hill, NC.
Abstract
Humans develop polyclonal, serotype-specific neutralizing antibody responses after dengue virus (DENV) infection. Many mouse antibodies that neutralize DENV bind to the lateral ridge or A-strand epitopes on domain III of the viral envelope (EDIII) protein. It has been assumed that these epitopes are also the main target of human neutralizingantibodies. Using recombinant dengue serotype 2 viruses with altered EDIII epitopes, we demonstrate that EDIII epitopes are not the main target of human neutralizing antibody.
- PMID:
- 22278250
- [PubMed - as supplied by publisher]
Structural basis for broad detection of genogroup II noroviruses by a monoclonal antibody that binds to a site occluded in the viral particle.
Source
Department of Virology II, National Institute of Infectious Diseases, Tokyo, 208-0011, Japan.
Abstract
Human noroviruses are genetically and antigenically highly divergent. Monoclonal antibodies raised in mice against one kind of norovirus virus-like particle (VLP), however, were found to have broad recognition. In this study, we present the crystal structure of the antigen-binding fragment (Fab) for one of these broadly reactive monoclonal antibodies, 5B18, in complex with the capsid-protruding domain from a genogroup II genotype 10 (GII.10) norovirus at 3.3 Å resolution and also the cryo-electron microscopy structure of the GII.10 VLP at ∼10 Å resolution. The GII.10 VLP structure was more similar in overall architecture to the GV.1 murine norovirus virion than to the prototype GI.1 human norovirus VLP, with the GII.10 protruding domain raised ∼15 Å off the shell domain and rotated ∼40° relative to the GI.1 protruding domain. In the crystal structure, the 5B18 Fab bound to a highly conserved region of the protruding domain. Based on the VLP structure, this region is involved in interactions with other regions of the capsid and is partially buried in the virus particle. Despite the occluded nature of the recognized epitope in the VLP structure, ELISA binding suggested that the 5B18 antibody was able to capture intact VLPs. Together, the results provide evidence that the norovirus particle is capable of conformational flexibility, which may allow for antibody recognition of conserved surfaces that would otherwise be deeply buried on intact norovirus particles.
- PMID:
- 22278249
- [PubMed - as supplied by publisher]
Single-molecule atomic force microscopy on live cells compares aptamer and antibody rupture forces.
Source
Department of Chemistry and Physiology and Functional Genomics, Center for Research at the Bio/Nano interface, Shands Cancer Center, UF Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, FL, 32611-7200, USA.
Abstract
Some researchers have questioned whether synthetic aptamers bind as robustly as natural antibodies. To address this issue, we used single-molecule atomic force microscopy to measure the rupture force between a protein and both its aptamer and its antibody. The rupture force on live cell membranes between the aptamer and protein was 46 ± 26 pN; the force with the antibody was 68 ± 33 pN, we conclude that the binding forces are about equal.
- PMID:
- 22278072
- [PubMed - as supplied by publisher]
Thyroid diseases and female reproduction.
Source
Unit of Reproductive EndocrinologyFirst Department of Obstetrics and Gynecology Medical School Aristotle University of Thessaloniki, Thessaloniki, Greece - dimitrios.goulis@otenet.gr.
Abstract
Thyroid diseases are very common in women of reproductive age. The aim of this study was to review the current evidence on physiology, pathophsiology, diagnosis and management of women with thyroid disorders that are currently seeking fertility, undergoing assisted reproduction technologies (ART) or being pregnant. Normal thyroid function is essential for normal function of the gonadal axis, thus important in maintaining normal reproductive capacity. On the contrary, any type of thyroid dysfunction may reduce the likelihood of pregnancy; the latter can be restored to normal after appropriate treatment. Over eight million children have been born as a result of assisted reproduction techniques (ART) since 1978. As these procedures are becoming more common in clinical practice, the exact impact of thyroid status on reproductive outcomes as well as that of drugs used in ART on thyroid function has to be fully elucidated. Maternal thyroid function is crucial, especially during the first weeks of gestation, for offspring's wellness and brain development. On the other hand, normal physiological mechanisms during gestation can have a major impact on maternal thyroid function. As human chorionic gonadotropin (hCG) has a thyroid stimulating hormone (TSH)-like effect, high hCG concentrations are associated with thyroid stimulation, both functionally (lower serum TSH concentrations) and anatomically (increased thyroid volume). Although the association between maternal hypothyroidism and increased perinatal morbidity has been described for over a century, more recently, even the presence of anti-thyroid antibodieshas been associated with adverse pregnancy outcomes, such as recurrent abortions and placental abruption. This is of major clinical significance, as anti-thyroid antibodies are surprisingly prevalent in pregnancy, especially during the first
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