PIGG defines the Emm blood group system Lane, William J.; Aeschlimann, Judith; Vege, Sunitha ...
Scientific reports,
09/2021, Letnik:
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Journal Article
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Abstract
Emm is a high incidence red cell antigen with eight previously reported Emm− probands. Anti-Emm appears to be naturally occurring yet responsible for a clinically significant acute hemolytic ...transfusion reaction. Previous work suggests that Emm is located on a GPI-anchored protein, but the antigenic epitope and genetic basis have been elusive. We investigated samples from a South Asian Indian family with two Emm− brothers by whole genome sequencing (WGS). Additionally, samples from four unrelated Emm− individuals were investigated for variants in the candidate gene. Filtering for homozygous variants found in the Emm− brothers and by gnomAD frequency of < 0.001 resulted in 1818 variants with one of high impact; a 2-bp deletion causing a frameshift and premature stop codon in
PIGG
NM_001127178.3:c.2624_2625delTA, p.(Leu875*), rs771819481.
PIGG
encodes for a transferase, GPI-ethanolaminephosphate transferase II, which adds ethanolamine phosphate (EtNP) to the second mannose in a GPI-anchor. The four additional unrelated Emm− individuals had various
PIGG
mutations; deletion of Exons 2–3, deletion of Exons 7–9, insertion/deletion (indel) in Exon 3, and new stop codon in Exon 5. The Emm− phenotype is associated with a rare deficiency of
PIGG
, potentially defining a new Emm blood group system composed of EtNP bound to mannose, part of the GPI-anchor. The results are consistent with the known PI-linked association of the Emm antigen, and may explain the production of the antibody in the absence of RBC transfusion. Any association with neurologic phenotypes requires further research.
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine ...carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
The ability to identify the designer of engineered biological sequences-termed genetic engineering attribution (GEA)-would help ensure due credit for biotechnological innovation, while holding ...designers accountable to the communities they affect. Here, we present the results of the first Genetic Engineering Attribution Challenge, a public data-science competition to advance GEA techniques. Top-scoring teams dramatically outperformed previous models at identifying the true lab-of-origin of engineered plasmid sequences, including an increase in top-1 and top-10 accuracy of 10 percentage points. A simple ensemble of prizewinning models further increased performance. New metrics, designed to assess a model's ability to confidently exclude candidate labs, also showed major improvements, especially for the ensemble. Most winning teams adopted CNN-based machine-learning approaches; however, one team achieved very high accuracy with an extremely fast neural-network-free approach. Future work, including future competitions, should further explore a wide diversity of approaches for bringing GEA technology into practical use.
Necroptosis complements apoptosis as a host defense pathway to stop virus infection. Herpes simplex virus shows a propensity to trigger necroptosis of mouse cells and mice even though cell death is ...blocked in human cells through UL39-encoded ICP6. This ribonucleotide reductase large subunit (R1) nucleates RHIM-dependent oligomerization of RIP3 kinase (RIPK3, also known as RIP3) in mouse cells but inhibits activation in cells from the natural human host. By interrogating the comparative behavior of ICP6-deficient viruses in mouse and human cells, here we unveil virus-induced necroptosis mediated by Z-DNA-binding protein 1 (ZBP1, also known as DAI). ZBP1 acts as a pathogen sensor to detect nascent RNA transcripts rather than input viral DNA or viral DNA generated through replication. Consistent with the implicated role of virus-induced necroptosis in restricting infection, viral pathogenesis is restored in Zbp1
, Ripk3
and Mlkl
mice. Thus, in addition to direct activation of RIPK3 via ICP6, HSV1 infection in mice and mouse cells triggers virus-induced necroptosis through ZBP1. Importantly, virus-induced necroptosis is also induced in human HT-29 cells by ICP6 mutant viruses; however, ZBP1 levels must be elevated for this pathway to be active. Thus, our studies reveal a common, species-independent role of this nucleic acid sensor to detect the presence of this virus. HSV1 ICP6 functions as a bona fide RHIM signaling inhibitor to block virus-induced necroptosis in its natural host. Altogether, ZBP1-dependent restriction of herpesvirus infection emerges as a potent antiviral armament of the innate immune system.
The control of bacterial transcription initiation depends on a primary sigma factor for housekeeping functions, as well as alternative sigma factors that control regulons in response to environmental ...stresses. The largest and most diverse subgroup of alternative sigma factors, the group IV extracytoplasmic function sigma factors, directs the transcription of genes that regulate a wide variety of responses, including envelope stress and pathogenesis. We determined the 2.3-A resolution crystal structure of the -35 element recognition domain of a group IV sigma factor, Escherichia coli sigma(E)4, bound to its consensus -35 element, GGAACTT. Despite similar function and secondary structure, the primary and group IV sigma factors recognize their -35 elements using distinct mechanisms. Conserved sequence elements of the sigma(E) -35 element induce a DNA geometry characteristic of AA/TT-tract DNA, including a rigid, straight double-helical axis and a narrow minor groove. For this reason, the highly conserved AA in the middle of the GGAACTT motif is essential for -35 element recognition by sigma(E)4, despite the absence of direct protein-DNA interactions with these DNA bases. These principles of sigma(E)4/-35 element recognition can be applied to a wide range of other group IV sigma factors.
Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non–self-antigens is an unavoidable adverse side effect of transfusion. We ...describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.
•Red blood cell, platelet, and white cell antigens can be typed accurately with a single, unified, DNA-based test.•As this test will be embedded in national genotyping studies, full blood cell typing data will be available for millions of individuals.
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Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients ...still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2.
To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants.
We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades.
Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients.
Summary
Platelet transfusions are a cornerstone of therapy for patients who develop thrombocytopenia while undergoing Hematopoietic Stem Cell Transplantation (HSCT). Many patients who develop ...Platelet Transfusion Refractoriness (PTR) require HLA-matched platelets. Identifying these patients early could lead to better utilization of platelets as well as increased platelet counts. We built a SMART on FHIR visualization tool to aid the oncology, blood bank, and blood donor center teams in identifying these patients by showing trends in thrombocytopenia along with a computer generated calculated Panel Reactive Antibody (cPRA) level. To do this, we required a FHIR interface to our HLA database. We describe our methods and outcome for constructing this FHIR interface, as well as the architecture and data flow of HLA data from its proprietary database to the SMART on FHIR environment and application database along with RESTful cPRA web service calculator. Future work will evaluate the clinical impact of this platelet visualization tool and overall success of our FHIR implementation.
Citation:
Gordon WJ, Baronas J, Lane WJ. A FHIR human leukocyte antigen (HLA) interface for platelet transfusion Support. Appl Clin Inform 2017; 8: 603–611 https://doi.org/10.4338/ACI-2017-01-CR-0010
Technological advances in the field of histocompatibility have allowed us to define anti–human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific ...antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.
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