title: The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21).
abstract: Heparin-induced thrombocytopenia is a prothrombotic disorder caused by antibodies to platelet factor 4 (PF4)/heparin complexes. The mechanism that incites such prevalent anti-PF4/heparin antibody production in more than 50% of patients exposed to heparin in some clinical settings is poorly understood. To investigate early events associated with antigen exposure, we first examined the interaction of PF4/heparin complexes with cells circulating in whole blood. In healthy donors, PF4/heparin complexes bind preferentially to B cells (>90% of B cells bind to PF4/heparin in vitro) relative to neutrophils, monocytes, or T cells. Binding of PF4 to B cells is heparin dependent, and PF4/heparin complexes are found on circulating B cells from some, but not all, patients receiving heparin. Given the high proportion of B cells that bind PF4/heparin, we investigated complement as a mechanism for noncognate antigen recognition. Complement is activated by PF4/heparin complexes, co-localizes with antigen on B cells from healthy donors, and is present on antigen-positive B cells in patients receiving heparin. Binding of PF4/heparin complexes to B cells is mediated through the interaction between complement and complement receptor 2 (CR2 [CD21]). To the best of our knowledge, these are the first studies to demonstrate complement activation by PF4/heparin complexes, opsonization of PF4/heparin to B cells via CD21, and the presence of complement activation fragments on circulating B cells in some patients receiving heparin. Given the critical contribution of complement to humoral immunity, our observations provide new mechanistic insights into the immunogenicity of PF4/heparin complexes.
authors.affiliation: Division of Hematology, and.
authors.forename: Sanjay
authors.identifier: 0000-0002-5661-3856
authors.initials: S
authors.lastname: Khandelwal
authors.affiliation: Division of Hematology, and.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC.
authors.forename: C Garren
authors.initials: CG
authors.lastname: Hester
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
authors.affiliation: New York Blood Center, New York, NY.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Sachais
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Lubica
authors.initials: L
authors.lastname: Rauova
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC; and.
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC.|Department of Immunology, Duke University Medical Center, Durham, NC; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Frank
authors.affiliation: Division of Hematology, and.
authors.forename: Gowthami M
authors.initials: GM
authors.lastname: Arepally
mesh_terms: D000941:Antigens / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism*; D006493:Heparin / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological; D010978:Platelet Factor 4 / Q000378:metabolism; D011479:Protamines / Q000378:metabolism; D011485:Protein Binding; D017464:Receptors, Complement 3d / Q000378:metabolism*; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000276:immunology*
chemical_list: D000941:Antigens; D011479:Protamines; D017464:Receptors, Complement 3d; D010978:Platelet Factor 4; D006493:Heparin; D003165:Complement System Proteins