title: Antigen Density Dictates Immune Responsiveness following Red Blood Cell Transfusion.
abstract: Although RBC transfusion can result in the development of anti-RBC alloantibodies that increase the probability of life-threatening hemolytic transfusion reactions, not all patients generate anti-RBC alloantibodies. However, the factors that regulate immune responsiveness to RBC transfusion remain incompletely understood. One variable that may influence alloantibody formation is RBC alloantigen density. RBC alloantigens exist at different densities on the RBC surface and likewise exhibit distinct propensities to induce RBC alloantibody formation. However, although distinct alloantigens reside on the RBC surface at different levels, most alloantigens also represent completely different structures, making it difficult to separate the potential impact of differences in Ag density from other alloantigen features that may also influence RBC alloimmunization. To address this, we generated RBCs that stably express the same Ag at different levels. Although exposure to RBCs with higher Ag levels induces a robust Ab response, RBCs bearing low Ag levels fail to induce RBC alloantibodies. However, exposure to low Ag-density RBCs is not without consequence, because recipients subsequently develop Ag-specific tolerance. Low Ag-density RBC-induced tolerance protects higher Ag-density RBCs from immune-mediated clearance, is Ag specific, and occurs through the induction of B cell unresponsiveness. These results demonstrate that Ag density can potently impact immune outcomes following RBC transfusion and suggest that RBCs with altered Ag levels may provide a unique tool to induce Ag-specific tolerance.
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Arthur
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Smith
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Ashley
authors.initials: A
authors.lastname: Bennett
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Nourine A
authors.initials: NA
authors.lastname: Kamili
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mener
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerner-Smidt
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Harold C
authors.identifier: 0000-0003-4909-7168
authors.initials: HC
authors.lastname: Sullivan
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.|Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.|Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Andreas
authors.identifier: 0000-0001-9648-7922
authors.initials: A
authors.lastname: Wieland
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.|Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Youngblood
authors.affiliation: Bloodworks Northwest Research Institute, Seattle, WA 98102.|Division of Hematology, Department of Laboratory and Internal Medicine, University of Washington, Seattle, WA 98195; and.
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.affiliation: Department of Laboratory Medicine and Pediatrics, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
authors.affiliation: Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; srstowe@emory.edu.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Stowell
mesh_terms: D000818:Animals; D017707:Erythrocyte Transfusion / Q000009:adverse effects*; D004912:Erythrocytes / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D007518:Isoantibodies / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D008666:Metalloendopeptidases / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D007518:Isoantibodies; D007519:Isoantigens; D008562:Membrane Glycoproteins; C585978:KEL protein, human; D008666:Metalloendopeptidases