To investigate the therapeutic implications of the current paradigm that autoimmune disease can result from defects in the clearance of dying/apoptotic cells, we have conducted preliminary studies that have shown that infusions of a natural antibody derived from innate-like B cells can greatly improve the survival of lupus- prone mice. We believe that these findings reflect the properties of a larger class of natural antibodies with common immunobiologic properties that derive from their self-reactive specificities, and by affecting other facets of the innate and adaptive immune system these antibodies can ameliorate or prevent autoimmune pathogenesis. To advance these studies, we will further characterize the properties of these antibodies, and investigate their roles in immunoregulation. We will assess whether the protective properties of specific natural antibodies are linked to binding specificities for neo-determinants on oxidized phospholipids that enable the recognition of apoptosis-associated epitopes, and whether such antibody autospecificities convey enhanced phagocytosis of dying cells. Non-autoimmune and well-defined lupus models will also be used to elucidate the molecular and cellular mechanisms by which such antibody treatments protect from the initiation and/or progression of autoimmune pathogenesis, which includes lupus nephritis and autoimmune cytopenias. These studies will dissect the effects of such antibody treatments on the co-stimulatory properties of mononuclear cells, with a special interest in determining whether treatments can recruit immunomodulatory dendritic cells. Based on interim findings, we will directly test mechanistic hypotheses using engineered antibody variants predicted to have enhanced protective properties and assay their in vivo activities. To determine the clinical relevance of these findings, we will evaluate the profile of natural and pathologic autoantibody responses in clinical populations, including close siblings and sets of monozygotic and dizygotic twins with lupus and other autoimmune diseases. These studies will test the hypothesis that clinical disease in individuals with inherited genetic susceptibility to autoimmune disease (in)directly correlates with levels of natural antibodies of autospecificities, which are postulated to provide protective properties. Together, these important investigations will test paradigm-shifting hypotheses regarding the functional roles of the products of innate-like B cells and their contributions to homeostatic pathways that protect the host. These studies are relevant to the mission of the agency as the results should lead to the development of new therapeutic approaches that provide benefits to many individuals with diverse types of chronic inflammatory, degenerative and autoimmune diseases, which affect their blood cells, kidneys, blood vessels, joints or other major organs. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068063-02
Application #
7256983
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
2006-07-15
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$356,990
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
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
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
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:
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
Grönwall, Caroline; Silverman, Gregg J (2014) Natural IgM: beneficial autoantibodies for the control of inflammatory and autoimmune disease. J Clin Immunol 34 Suppl 1:S12-21
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

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