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

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.
AuthorsYongwei Zheng, Alexander W Wang, Mei Yu, Anand Padmanabhan, Benjamin E Tourdot, Debra K Newman, Gilbert C White, Richard H Aster, Renren Wen, Demin Wang
JournalBlood (Blood) Vol. 123 Issue 6 Pg. 931-4 (Feb 6 2014) ISSN: 1528-0020 [Electronic] United States
PMID24357731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anticoagulants
  • Platelet Factor 4
  • Heparin
  • Protein Kinase C-delta
  • Adult
  • Animals
  • Antibody Formation (immunology)
  • Anticoagulants (adverse effects, metabolism)
  • B-Lymphocytes (immunology, metabolism, pathology)
  • Cells, Cultured
  • Heparin (adverse effects, metabolism)
  • Humans
  • Immune Tolerance
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Factor 4 (immunology, metabolism)
  • Prognosis
  • Protein Kinase C-delta (physiology)
  • Thrombocytopenia (chemically induced, immunology, metabolism)

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