Event From Date: Thursday, 20 June 2019
Event End Date: Thursday, 20 June 2019
Event Title: SCMM organises a seminar by Dr. Sanjay Khandelwal
Event Details:
Special Centre for Molecular Medicine
Jawaharlal Nehru University
Seminar Notice
Title: Mechanism of immune activation against PF4/heparin complexes in heparin induced thrombocytopenia
Speaker
Dr. Sanjay Khandelwal, DVM & PhD
Research Scientist
Division of Hematology, Department of Medicine, Duke Medical Center
Duke University, Durham, NC, USA (an alumni of SLS, JNU)
Abstract: Heparin is a commonly used anticoagulant agent for patients presenting with thrombotic disease. Some patients who receive heparin develop an immune-mediated thrombotic disorder called Heparin Induced Thrombocyopenia (HIT). HIT is caused by antibodies to a multimeric antigenic complex consisting of a positively charged protein, platelet factor 4 (PF4) and heparin, a negatively charged polysaccharide. The mechanism that incites antibody production against PF4/heparin complexes is poorly understood. Since 2013, my studies have focused on understanding the mechanism of immune activation by PF4/heparin complexes, with recent studies showing a major role for complement activation by PF4/heparin complexes (Khandelwal et al., Blood 2016). In these studies, we showed that PF4/heparin complexes robustly activate complement in plasma and whole blood and that complement activation results in uniform antigen deposition on circulating B cells via the complement receptor CD21. In the course of these studies, we developed a novel assay for measuring complement activation (Khandelwal et al., Thromb Haemost 2018) and observed wide, but stable variation, among donor plasmas with respect to complement activation by PF4/heparin complexes with donor responses segregating into a "phenotype" (high, intermediate, or low). Subsequent studies have shown that this phenotype was mediated by polyreactive naturally occurring IgM initiating complement activation through the classical pathway and C1q (Khandelwal et al., Blood 2018). Finally, we showed the clinical relevance of these findings by demonstrating that patients receiving heparin have circulating B cells with PF4/heparin antigen, the complement activation fragment C3 and IgM. Based on these findings, we have developed the following working model for immune activation following heparin exposure: Polyreactive natural IgM 1) binds to circulating PF4/heparin complexes in plasma and 2) activates classical pathway of complement which leads to 3) depositon of complement fragment C3 to PF4/heparin antigenic complexes and 4) promotes binding of these complement coated complexes to B cells via CD21 (Figure 1). As complement activation by natural IgM against particulate antigen and binding of complement coated antigen to CD21 on B cells markedly potentiates its immunogenicity, natural IgM mediated complement activation by PF4/heparin complexes and subsequent binding of these complement coated complexes to B cells may represent early, sensitizing events and antibody generation against PF4/heparin complexes. Our results also suggest that patients who have high IgM might be at higher risk of antibody generation against PF4/heparin complexes. These findings not only provide the mechanism of immune activation in HIT but also provide mechanistic insights into other pathological conditions involving auto or exogenous antigens such as antibody generation in antiphospholipid syndrome and FVIII inhibitor development and opens up future avenues to develop biomarkers and therapeutic interventions in these diseases.
Date: Thursday 20 June, 2019
Time: 11.00 AM
Venue: Seminar Hall, SCMM
All are welcome
