Prior immunization against an intracellular antigen enhances subsequent red blood cell alloimmunization in mice

Ryan Jajosky, Seema R. Patel, Shang Chuen Wu, Kashyap Patel, Mischa Covington, Mary Vallecillo-Zúniga, Diyoly Ayona, Ashley Bennett, C. John Luckey, Krystalyn E. Hudson, Jeanne E. Hendrickson, Stephanie C. Eisenbarth, Cassandra D. Josephson, Patricia E. Zerra, Sean R. Stowell*, Connie M. Arthur*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Antibodies against red blood cell (RBC) alloantigens can increase morbidity and mortality among transfusion recipients. However, alloimmunization rates can vary dramatically, as some patients never generate alloantibodies after transfusion, whereas others not only become alloimmunized but may also be prone to generating additional alloantibodies after subsequent transfusion. Previous studies suggested that CD4 T–cell responses that drive alloantibody formation recognize the same alloantigen engaged by B cells. However, because RBCs express numerous antigens, both internally and externally, it is possible that CD4 T–cell responses directed against intracellular antigens may facilitate subsequent alloimmunization against a surface RBC antigen. Here, we show that B cells can acquire intracellular antigens from RBCs. Using a mouse model of donor RBCs expressing 2 distinct alloantigens, we demonstrate that immune priming to an intracellular antigen, which would not be detected by any currently used RBC compatibility assays, can directly influence alloantibody formation after exposure to a subsequent distinct surface RBC alloantigen. These findings suggest a previously underappreciated mechanism whereby transfusion recipient responders may exhibit an increased rate of alloimmunization because of prior immune priming toward intracellular antigens.

Original languageEnglish (US)
Pages (from-to)2642-2653
Number of pages12
Issue number21
StatePublished - May 25 2023

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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