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 #
5R01AI090118-03
Application #
8082626
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
2011-06-01
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$418,275
Indirect Cost
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
Pelzek, Adam J; Grönwall, Caroline; Rosenthal, Pamela et al. (2017) Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-Expressing Memory B Cells in Rheumatoid Arthritis in Clinical Remission. Arthritis Rheumatol 69:1176-1186
Grönwall, Caroline; Clancy, Robert M; Getu, Lelise et al. (2016) Modulation of natural IgM autoantibodies to oxidative stress-related neo-epitopes on apoptotic cells in newborns of mothers with anti-Ro autoimmunity. J Autoimmun 73:30-41
Huck, Daniel M; Okello, Emmy; Mirembe, Grace et al. (2016) Role of Natural Autoantibodies in Ugandans With Rheumatic Heart Disease and HIV. EBioMedicine 5:161-6
Strazza, Marianne; Azoulay-Alfaguter, Inbar; Silverman, Gregg J et al. (2015) T cell chemokine receptor patterns as pathogenic signatures in autoimmunity. Discov Med 19:117-25
Silverman, Gregg J (2015) Protective natural autoantibodies to apoptotic cells: evidence of convergent selection of recurrent innate-like clones. Ann N Y Acad Sci 1362:164-75
Frost, Simon D W; Murrell, Ben; Hossain, A S Md Mukarram et al. (2015) Assigning and visualizing germline genes in antibody repertoires. Philos Trans R Soc Lond B Biol Sci 370:
Pedoeem, Ariel; Azoulay-Alfaguter, Inbar; Strazza, Marianne et al. (2014) Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol 153:145-52
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
Silverman, Gregg J; Pelzek, Adam (2014) Rheumatoid arthritis clinical benefits from abatacept, cytokine blockers, and rituximab are all linked to modulation of memory B cell responses. J Rheumatol 41:825-8
Grönwall, Caroline; Reynolds, Harmony; Kim, June K et al. (2014) Relation of carotid plaque with natural IgM antibodies in patients with systemic lupus erythematosus. Clin Immunol 153:1-7

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