title: B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia.
abstract: Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to the pathogenesis of heparin-induced thrombocytopenia (HIT). It is as yet unclear what triggers the initial induction of pathogenic antibodies. We identified B cells in peripheral blood of healthy adults that produce PF4/heparin-specific antibodies following in vitro stimulation with proinflammatory molecules containing deoxycytosine-deoxyguanosine (CpG). Similarly, B cells from unmanipulated wild-type mice produced PF4/heparin-specific antibodies following in vitro or in vivo CpG stimulation. Thus, both healthy humans and mice possess preexisting inactive/tolerant PF4/heparin-specific B cells. The findings suggest that breakdown of tolerance leads to PF4/heparin-specific B-cell activation and antibody production in patients developing HIT. Consistent with this concept, mice lacking protein kinase Cδ (PKCδ) that are prone to breakdown of B-cell tolerance produced anti-PF4/heparin antibodies spontaneously. Therefore, breakdown of tolerance can lead to PF4/heparin-specific antibody production, and B-cell tolerance may play an important role in HIT pathogenesis.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Zheng
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wang
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Anand
authors.initials: A
authors.lastname: Padmanabhan
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Tourdot
authors.forename: Debra K
authors.initials: DK
authors.lastname: Newman
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: White
authors.forename: Richard H
authors.initials: RH
authors.lastname: Aster
authors.forename: Renren
authors.initials: R
authors.lastname: Wen
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D000925:Anticoagulants / Q000009:adverse effects* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006493:Heparin / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism*; D011379:Prognosis; D051745:Protein Kinase C-delta / Q000502:physiology*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D010978:Platelet Factor 4; D006493:Heparin; D051745:Protein Kinase C-delta