We will investigate our newly developed inhibitory dual receptor hypothesis regarding the properties of autoantibodies to apoptotic cell membrane (ACM) determinants, which selectively discriminate cells dying from apoptotic death from healthy cells. We have discovered that anti-ACM antibodies form immune complexes with apoptotic cells that trigger anti-inflammatory signal transduction pathways. Therefore, our studies will characterize the mechanistic features by which ACM antibodies are postulated to enhance interactions with dual sets of inhibitory receptor;for early complement factors and for apoptotic cells. In particular, our investigations point to a critical interaction with the TAM family of receptor tyrosine kinases. To understand the greater relevance to pathogenesis, we will also investigate whether and how anti-ACM antibodies block the pro-inflammatory effects of pathogenic IgG autoantibodies to nuclear antigens, postulated to trigger TLR7 and TLR9. We will be characterize and visualize the in vitro inhibitory effects for IgG-nuclear antigen complexes, and we will also study their immune modulatory properties on the in vivo disease activity in murine models of autoimmune glomerulonephritis. Moreover, to investigate the relevance to clinical disease, we will also assess whether there is a correlation between levels in SLE patients of IgM and IgG subclass-specific anti-ACM autoantibodies and with lupus- associated autoantibodies, and with protection from certain features of lupus clinical disease activity. We anticipate that these studies will reveal new insights into immune regulation and autoimmune pathogenesis, and provide the essential bridge from basic studies to the development of a new therapeutic approach to the treatment of SLE.

Public Health Relevance

We will investigate how certain naturally occurring antibodies to dying cells can interact with cell receptors and trigger anti-inflammatory signal transduction pathways. We will also look for such effects in patients with systemic lupus erythematosus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI090118-05
Application #
8473772
Study Section
Special Emphasis Panel (ZRG1-IMM-H (02))
Program Officer
Johnson, David R
Project Start
2010-06-07
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$393,179
Indirect Cost
$160,529
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Grönwall, Caroline; Charles, Edgar D; Dustin, Lynn B et al. (2014) Selection of apoptotic cell specific human antibodies from adult bone marrow. PLoS One 9:e95999
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Gronwall, Caroline; Akhter, Ehtisham; Oh, Cheongeun et al. (2012) IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin Immunol 142:390-8
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Silverman, Gregg J (2010) Regulatory natural autoantibodies to apoptotic cells: Pallbearers and protectors. Arthritis Rheum :