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SCMM organises a seminar by Dr. Sanjay Khandelwal

SCMM organises a seminar by Dr. Sanjay Khandelwal

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SCMM organises a seminar by Dr. Sanjay Khandelwal
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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

A warm welcome to the modified and updated website of the Centre for East Asian Studies. The East Asian region has been at the forefront of several path-breaking changes since 1970s beginning with the redefining the development architecture with its State-led development model besides emerging as a major region in the global politics and a key hub of the sophisticated technologies. The Centre is one of the thirteen Centres of the School of International Studies, Jawaharlal Nehru University, New Delhi that provides a holistic understanding of the region.

Initially, established as a Centre for Chinese and Japanese Studies, it subsequently grew to include Korean Studies as well. At present there are eight faculty members in the Centre. Several distinguished faculty who have now retired include the late Prof. Gargi Dutt, Prof. P.A.N. Murthy, Prof. G.P. Deshpande, Dr. Nranarayan Das, Prof. R.R. Krishnan and Prof. K.V. Kesavan. Besides, Dr. Madhu Bhalla served at the Centre in Chinese Studies Programme during 1994-2006. In addition, Ms. Kamlesh Jain and Dr. M. M. Kunju served the Centre as the Documentation Officers in Chinese and Japanese Studies respectively.

The academic curriculum covers both modern and contemporary facets of East Asia as each scholar specializes in an area of his/her interest in the region. The integrated course involves two semesters of classes at the M. Phil programme and a dissertation for the M. Phil and a thesis for Ph. D programme respectively. The central objective is to impart an interdisciplinary knowledge and understanding of history, foreign policy, government and politics, society and culture and political economy of the respective areas. Students can explore new and emerging themes such as East Asian regionalism, the evolving East Asian Community, the rise of China, resurgence of Japan and the prospects for reunification of the Korean peninsula. Additionally, the Centre lays great emphasis on the building of language skills. The background of scholars includes mostly from the social science disciplines; History, Political Science, Economics, Sociology, International Relations and language.

Several students of the centre have been recipients of prestigious research fellowships awarded by Japan Foundation, Mombusho (Ministry of Education, Government of Japan), Saburo Okita Memorial Fellowship, Nippon Foundation, Korea Foundation, Nehru Memorial Fellowship, and Fellowship from the Chinese and Taiwanese Governments. Besides, students from Japan receive fellowship from the Indian Council of Cultural Relations.