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.
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Authors | Yongwei Zheng, Alexander W Wang, Mei Yu, Anand Padmanabhan, Benjamin E Tourdot, Debra K Newman, Gilbert C White, Richard H Aster, Renren Wen, Demin Wang |
Journal | Blood
(Blood)
Vol. 123
Issue 6
Pg. 931-4
(Feb 06 2014)
ISSN: 1528-0020 [Electronic] United States |
PMID | 24357731
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Anticoagulants
- Platelet Factor 4
- Heparin
- Protein Kinase C-delta
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Topics |
- 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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