title: The Nlrp3 Inflammasome Does Not Regulate Alloimmunization to Transfused Red Blood Cells in Mice.
abstract: Red blood cell (RBC) transfusions are essential for patients with hematological disorders and bone marrow failure syndromes. Despite ABO matching, RBC transfusions can lead to production of alloantibodies against "minor" blood group antigens. Non-ABO alloimmunization is a leading cause of transfusion-associated mortality in the U.S. Despite its clinical importance, little is known about the immunological factors that promote alloimmunization. Prior studies indicate that inflammatory conditions place patients at higher risk for alloimmunization. Additionally, co-exposure to pro-inflammatory pathogen associated molecular patterns (PAMPs) promotes alloimmunization in animal models, suggesting that RBC alloimmunization depends on innate immune cell activation. However, the specific innate immune stimuli and sensors that induce a T cell-dependent alloantibody response to transfused RBCs have not been identified. The NLRP3 inflammasome senses chemically diverse PAMPs and damage associated molecular patterns (DAMPs), including extracellular ATP and iron-containing heme. We hypothesized that activation of the NLRP3 inflammasome by endogenous DAMPs from RBCs promotes the alloimmune response to a sterile RBC transfusion. Using genetically modified mice lacking either NLRP3 or multiple downstream inflammasome response elements, we ruled out a role for the NLRP3 inflammasome or any Caspase-1 or -11 dependent inflammasome in regulating RBC alloantibody production to a model antigen.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gibb
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Samuele
authors.initials: S
authors.lastname: Calabro
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Tormey
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center-New York Presbyterian Hospital, NY, New York 10032, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Spitalnik
authors.affiliation: Bloodworks NW Research Institute, Seattle, WA 98102, USA; Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98102, USA; Department of Internal Medicine-Division of Hematology, University of Washington School of Medicine, Seattle, WA 98102, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center-New York Presbyterian Hospital, NY, New York 10032, USA. Electronic address: eh2217@cumc.columbia.edu.
authors.forename: Eldad A
authors.initials: EA
authors.lastname: Hod
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: stephanie.eisenbarth@yale.edu.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
mesh_terms: D000818:Animals; D001789:Blood Group Antigens / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D017707:Erythrocyte Transfusion / Q000009:adverse effects; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism*; D056747:Immunomodulation; D016130:Immunophenotyping; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype
chemical_list: D001789:Blood Group Antigens; D016207:Cytokines; D058847:Inflammasomes; D007518:Isoantibodies; D007519:Isoantigens; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
keywords: Alloimmunization; Conventional dendritic cells (cDCs); Inflammasome; NLRP3; Red blood cell (RBC) storage