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B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood 2014 Feb 06;123(6):931-4

Date

12/21/2013

Pubmed ID

24357731

Pubmed Central ID

PMC3916881

DOI

10.1182/blood-2013-11-540781

Scopus ID

2-s2.0-84897574667   18 Citations

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.

Author List

Zheng Y, Wang AW, Yu M, Padmanabhan A, Tourdot BE, Newman DK, White GC, Aster RH, Wen R, Wang D

Authors

Richard H. Aster MD Professor in the Medicine department at Medical College of Wisconsin
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Renren Wen PhD Associate Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Gilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Animals
Antibody Formation
Anticoagulants
B-Lymphocytes
Cells, Cultured
Heparin
Humans
Immune Tolerance
Mice
Mice, Inbred C57BL
Mice, Knockout
Platelet Factor 4
Prognosis
Protein Kinase C-delta
Thrombocytopenia
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5