B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia

• Published in: Blood 2014-02, Vol.123 (6), p.931-934
• Main Authors: Zheng, Yongwei, Wang, Alexander W., Yu, Mei, Padmanabhan, Anand, Tourdot, Benjamin E., Newman, Debra K., White, Gilbert C., Aster, Richard H., Wen, Renren, Wang, Demin
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibody Formation - immunology; Anticoagulants - adverse effects; Anticoagulants - metabolism; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Brief Report; Cells, Cultured; Heparin - adverse effects; Heparin - metabolism; Humans; Immune Tolerance; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Factor 4 - immunology; Platelet Factor 4 - metabolism; Prognosis; Protein Kinase C-delta - physiology; Thrombocytopenia - chemically induced; Thrombocytopenia - immunology; Thrombocytopenia - metabolism; Transfusion Medicine
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-11-540781

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. •B-cell tolerance plays a critical role in controlling production of PF4/heparin-specific antibodies.