Publications by authors named "Ariel M Hay"

7 Publications

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In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

Transfusion 2021 Mar 18;61(3):687-691. Epub 2020 Dec 18.

University of Washington School of Medicine, Seattle, Washington, USA.

Background: Platelet transfusions remain a mainstay of treatment for many patients with thrombocytopenia, but can lead to alloantibodies to Human Leukocyte Antigens (anti-HLA) resulting in inadequate responses to subsequent platelet transfusions (refractoriness), as well as complicate transplantation. Despite substantial decreases in alloimmunization with the implementation of leukoreduction, a significant percentage of patients still become alloimmunized following platelet transfusions. It remains unclear why some patients make anti-HLA antibodies, but others do not make anti-HLA antibodies even with chronic transfusion. Antecedent pregnancy correlates with risk of alloimmunization due to platelet transfusion in humans - however, isolation of pregnancy as a single variable is not possible in human populations.

Study Design And Methods: A tractable murine model of pregnancy and transfusion was engineered by breeding C57BL/6 (H-2 ) dames with BALB/c (H-2 ) sires. After pregnancy, female mice were transfused with leukoreduced platelets from F1 (H-2 ) donors that expressed the same paternal major histocompatibility complex (MHC) H-2 alloantigens as the sires. Control groups allowed isolation of pregnancy or transfusion alone as independent variables. Alloimmunization was determined by testing serum for antibodies to H-2 MHC alloantigens.

Results: No alloantibodies were detected after pregnancy alone, or in response to transfusion of platelets alone; however, significant levels of alloantibodies were detected when pregnancy was followed by transfusion.

Conclusions: These findings isolate antecedent pregnancy as a causal contribution to increased frequencies of alloimmunization by subsequent platelet transfusion in mice and provide a platform for ongoing mechanistic investigation.
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http://dx.doi.org/10.1111/trf.16224DOI Listing
March 2021

IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice.

Front Immunol 2020 16;11:1516. Epub 2020 Jul 16.

Bloodworks Northwest Research Institute, Seattle, WA, United States.

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.
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http://dx.doi.org/10.3389/fimmu.2020.01516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378678PMC
July 2020

Complement activation on endothelium initiates antibody-mediated acute lung injury.

J Clin Invest 2020 11;130(11):5909-5923

Department of Medicine, UCSF, San Francisco, California, USA.

Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.
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http://dx.doi.org/10.1172/JCI138136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598054PMC
November 2020

Impact of taurine on red blood cell metabolism and implications for blood storage.

Transfusion 2020 Jun 27;60(6):1212-1226. Epub 2020 Apr 27.

Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus Denver, Aurora, Colorado, USA.

Background: Taurine is an antioxidant that is abundant in some common energy drinks. Here we hypothesized that the antioxidant activity of taurine in red blood cells (RBCs) could be leveraged to counteract storage-induced oxidant stress.

Study Design And Methods: Metabolomics analyses were performed on plasma and RBCs from healthy volunteers (n = 4) at baseline and after consumption of a whole can of a common, taurine-rich (1000 mg/serving) energy drink. Reductionistic studies were also performed by incubating human RBCs with taurine ex vivo (unlabeled or C N-labeled) at increasing doses (0, 100, 500, and 1000 μmol/L) at 37°C for up to 16 hours, with and without oxidant stress challenge with hydrogen peroxide (0.1% or 0.5%). Finally, we stored human and murine RBCs under blood bank conditions in additives supplemented with 500 μmol/L taurine, before metabolomics and posttransfusion recovery studies.

Results: Consumption of energy drinks increased plasma and RBC levels of taurine, which was paralleled by increases in glycolysis and glutathione (GSH) metabolism in the RBC. These observations were recapitulated ex vivo after incubation with taurine and hydrogen peroxide. Taurine levels in the RBCs from the REDS-III RBC-Omics donor biobank were directly proportional to the total levels of GSH and glutathionylated metabolites and inversely correlated to oxidative hemolysis measurements. Storage of human RBCs in the presence of taurine improved energy and redox markers of storage quality and increased posttransfusion recoveries in FVB mice.

Conclusion: Taurine modulates RBC antioxidant metabolism in vivo and ex vivo, an observation of potential relevance to transfusion medicine.
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http://dx.doi.org/10.1111/trf.15810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995806PMC
June 2020

Passively transferred IgG enhances humoral immunity to a red blood cell alloantigen in mice.

Blood Adv 2020 04;4(7):1526-1537

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.

Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a "dual effect" in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+ T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+ T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.
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http://dx.doi.org/10.1182/bloodadvances.2019001299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160277PMC
April 2020

Differences in Steap3 expression are a mechanism of genetic variation of RBC storage and oxidative damage in mice.

Blood Adv 2019 08;3(15):2272-2285

Bloodworks NW Research Institute, Seattle, WA.

Red blood cells (RBCs) are the most numerous cell type in the body and serve a vital purpose of delivering oxygen to essentially all tissues. In addition to the central role of RBCs in health and disease, RBC storage is a requirement for the >90 million units of RBC transfusions given to millions of recipients each year, worldwide. It is well known that there is genetic donor-to-donor variability in how human RBCs store, rendering blood a nonstandardized therapeutic with a wide range of biological properties from unit to unit, by the time it is transfused. As with humans, genetic variation exists in how murine RBCs, from different strains of mice, store and perform after transfusion. The genetic mechanisms for variation, in humans and mice, both remain obscure. Combining advanced metabolomics, genetics, and molecular and cellular biology approaches, we identify genetic variation in six-transmembrane epithelial antigen of prostate 3 (Steap3) expression as a critical and previously unrecognized mechanism of oxidative damage of RBCs during storage. Increased levels of Steap3 result in degradation of cellular membrane through lipid peroxidation, leading to failure of RBC homeostasis and hemolysis/clearance of RBCs. This article is the first report of a role of Steap3 in mature RBCs; it defines a new mechanism of redox biology in RBCs with a substantial effect upon RBC function and provides a novel mechanistic determinant of genetic variation of RBC storage.
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http://dx.doi.org/10.1182/bloodadvances.2019000605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693009PMC
August 2019

Repeated gestational exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1) modulated effects in maternal and fetal tissues.

Toxicol Sci 2014 Oct 28;141(2):409-22. Epub 2014 Jul 28.

Department of Medicine, Division of Medical Genetics Department of Genome Sciences

Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured enzyme inhibition and fetal-brain gene expression in wild-type (PON1(+/+)), PON1-knockout (PON1(-/-)), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75, or 0.85 mg/kg/d CPO from gestational day (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), red blood cell acylpeptide hydrolase (APH), and plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1(-/-) and tgHuPON1Q192, but not PON1(+/+) or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1(-/-) mice, but not in other genotypes. Weighted gene co-expression network analysis identified five gene modules based on clustering of the correlations among their fetal-brain expression values, allowing for correlation of module membership with the phenotypic data on enzyme inhibition. One module that correlated highly with maternal brain AChE activity had a large representation of homeobox genes. Gene set enrichment analysis revealed multiple gene sets affected by gestational CPO exposure in tgHuPON1Q192 but not tgHuPON1R192 mice, including gene sets involved in protein export, lipid metabolism, and neurotransmission. These data indicate that maternal PON1 status modulates the effects of repeated gestational CPO exposure on fetal-brain gene expression and on inhibition of both maternal and fetal biomarker enzymes.
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http://dx.doi.org/10.1093/toxsci/kfu144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271046PMC
October 2014