Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer half-life, which are completely or partly due to FcγR-mediated functions of the molecules. ...Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse FcγRs is available. The orthologous mouse and human FcγRs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse and human IgG subclasses to mouse FcγR. Human IgGs bound to mouse FcγR with remarkably similar binding strengths as we know from binding to human ortholog receptors, with relative affinities IgG3>IgG1>IgG4>IgG2 and FcγRI>>FcγRIV>FcγRIII>FcγRIIb. This suggests human IgG subclasses to have similar relative FcγR-mediated biological activities in mice.
Summary
To guide anti‐D prophylaxis, Dutch D‐ pregnant women are offered a quantitative fetal‐RHD‐genotyping assay to determine the RHD status of their fetus. This allowed us to determine the ...frequency of different maternal RHD variants in 37 782 serologically D‐ pregnant women. A variant allele is present in at least 0·96% of Dutch D‐ pregnant women The D‐ serology could be confirmed after further serological testing in only 54% of these women, which emphasizes the potential relevance of genotyping of blood donors. 43 different RHD variant alleles were detected, including 15 novel alleles (11 null‐, 2 partial D‐ and 2 DEL‐alleles). Of those novel null alleles, one allele contained a single missense mutation (RHD*443C>G) and one allele had a single amino acid deletion (RHD*424_426del). The D‐ phenotype was confirmed by transduction of human D‐ erythroblasts, consolidating that, for the first time, a single amino acid change or deletion causes the D‐ phenotype. Transduction also confirmed the phenotypes for the two new variant DEL‐alleles (RHD*721A>C and RHD*884T>C) and the novel partial RHD*492C>A allele. Notably, in three additional cases the DEL phenotype was observed but sequencing of the coding sequence, flanking introns and promoter region revealed an apparently wild‐type RHD allele without mutations.
It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived ...anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.
Aims. We performed a spatially resolved spectral X-ray study of the pulsar wind nebula (PWN) in the supernova remnant G0.9+0.1. Furthermore, we modeled its nonthermal emission in the X-ray and very ...high-energy (VHE, E > 100 GeV) γ-ray regime. Methods. Using Chandra ACIS-S3 data, we investigated the east-west dependence of the spectral properties of G0.9+0.1 by calculating hardness ratios. We analyzed the EPIC-MOS and EPIC-pn data of two on-axis observations of the XMM-Newton telescope and extracted spectra of four annulus-shaped regions, centered on the region of brightest emission of the source. A radially symmetric leptonic model was applied in order to reproduce the observed X-ray emission of the inner part of the PWN. Using the optimized model parameter values obtained from the X-ray analysis, we then compared the modeled inverse Compton (IC) radiation with the published H.E.S.S. γ-ray data. Results. The spectral index within the four annuli increases with growing distance to the pulsar, whereas the surface brightness drops. With the adopted model we are able to reproduce the characteristics of the X-ray spectra. The model results for the VHE γ radiation, however, strongly deviate from the H.E.S.S. data.
Aims. To explore the nature of the unidentified very-high-energy (VHE, E > 100 GeV) gamma-ray source HESS J1626−490, we investigated the region in X-ray, sub-millimeter, and infrared energy bands. ...Methods. So far only detected with the HESS array of imaging atmospheric Cherenkov telescopes, HESS J1626−490 could not be unambiguously identified with any source seen at lower energies. Therefore, we analyzed data from an archival XMM-Newton observation, pointed towards HESS J1626−490, to classify detected X-ray point sources according to their spectral properties and their near-infrared counterparts from the 2MASS catalog. Furthermore, we characterized in detail the diffuse X-ray emission from a region compatible with the extended VHE signal. To characterize the interstellar medium surrounding HESS J1626−490 we analyzed 12CO(J = 1−0) molecular line data from the Nanten Galactic plane survey, H i data from the Southern Galactic Plane Survey (SGPS) and Spitzer data from the GLIMPSE and MIPSGAL surveys. Results. None of the detected X-ray point sources fulfills the energy requirements to be considered as the synchrotron radiation counterpart to the VHE source assuming an inverse-Compton (IC) emission scenario. We did not detect any diffuse X-ray excess emission originating in the region around HESS J1626−490 above the Galactic background and the derived upper limit for the total X-ray flux disfavors a purely leptonic emission scenario for HESS J1626−490. We found a good morphological match between molecular and atomic gas in the −27 km s-1 to −18 km s-1 line-of-sight velocity range and HESS J1626−490. The cloud has a mass of 1.8 × 104 M⊙ and is located at a mean kinematic distance of d = 1.8 kpc. Furthermore, we found a density depression in the H i gas at a similar distance, which is spatially consistent with the SNR G335.2+00.1. We discuss various scenarios for the VHE emission, including the CO molecular cloud being a passive target for cosmic ray protons accelerated by the nearby SNR G335.2+00.1.
The High Energy Stereoscopic System (H.E.S.S.) is a system of Imaging Atmospheric Cherenkov Telescopes (IACTs) located in the Khomas Highland in Namibia. It measures cosmic gamma rays of very high ...energies (VHE; >100GeV) using the Earth’s atmosphere as a calorimeter. The H.E.S.S. Array entered Phase II in September 2012 with the inauguration of a fifth telescope that is larger and more complex than the other four. This paper will give an overview of the current H.E.S.S. central data acquisition (DAQ) system with particular emphasis on the upgrades made to integrate the fifth telescope into the array. At first, the various requirements for the central DAQ are discussed then the general design principles employed to fulfil these requirements are described. Finally, the performance, stability and reliability of the H.E.S.S. central DAQ are presented. One of the major accomplishments is that less than 0.8% of observation time has been lost due to central DAQ problems since 2009.
Aims. H.E.S.S. observes an increasing number of large extended sources. A new technique based on the structure of the sky map is developed to account for these additional structures by comparing them ...with the common point source analysis. Methods. Minkowski functionals are powerful measures from integral geometry. They can be used to quantify the structure of the counts map, which is then compared with the expected structure of a pure Poisson background. Gamma-ray sources lead to significant deviations from the expected background structure. The standard likelihood ratio method is exclusively based on the number of excess counts and discards all further structure information of large extended sources. The morphometric data analysis incorporates this additional geometric information in an unbiased analysis, i.e., without the need of any prior knowledge about the source. Results. We have successfully applied our method to data of the H.E.S.S. experiment. The morphometric analysis presented here is dedicated to detecting faint extended sources.
► The Richardson–Lucy-Algorithm was applied to very high-energy gamma-ray images. ► Systematic studies of the RLA with respect to source characteristics were performed. ► Deconvolution allows to ...study structural details below instrumental angular resolution. ► Deconvolution is applicable on 2 of the known 5 VHE shell-type SNRs.
The Richardson–Lucy deconvolution algorithm was applied to astronomical images in the very high-energy regime with photon energies above 100GeV. Through a systematic study with respect to source significance, background level and source morphology we were able to derive optimal deconvolution parameters. The results presented show that deconvolution makes it possible to study structural details well below the angular resolution of the very high-energy γ-ray experiment.
BACKGROUND
Human immunoglobulin G (IgG) includes four different subtypes (IgG1, IgG2, IgG3, and IgG4), and it is also now appreciated that there are genetic variations within IgG subtypes (called ...isoallotypes). Twenty‐nine different isoallotypes have been described, with 7, 4, 15, and 3 isoallotypes described for IgG1, IgG2, IgG3, and IgG4, respectively. The reactivity of anti‐IgG with different isoallotypes has not been characterized.
STUDY DESIGN AND METHODS
A novel monoclonal anti‐K antibody (PugetSound Monoclonal Antibody 1 PUMA1) was isolated and sequenced, and a panel of PUMA1 variants was expressed, consisting of the 29 known IgG isoallotypes. The resulting panel of antibodies was preincubated with K‐positive red blood cells (RBCs) and then subjected to testing with currently approved anti‐IgG by flow cytometry, solid phase systems, gel cards, and tube testing.
RESULTS
A US Food and Drug Administration (FDA)‐approved monoclonal anti‐IgG (gamma‐clone) failed to recognize 2 of 15 IgG3 isoallotypes (IgG3‐03 and IgG3‐13) and 3 of 3 IgG4 isoallotypes (IgG4‐01, IgG4‐02, and IgG4‐03). In contrast, an FDA‐approved rabbit polyclonal anti‐IgG recognized each of the known human IgG isoallotypes.
CONCLUSION
These findings demonstrate “blind spots” in isoalloantibody detection by a monoclonal anti‐IgG. If a patient has anti‐RBC antibodies predominantly of an IgG3 subtype (the IgG3‐03 and/or IgG3‐13 variety), then it is possible that a clinically significant alloantibody would be missed. IgG‐03 and IgG‐13 have an estimated frequency of 1% to 3% in Caucasian populations and 20% to 30% in certain African populations. Nonreactivity with IgG4 is a known characteristic of this monoclonal anti‐IgG, but IgG4 isoallotypes have not been previously reported.
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