Pathogenic utoantibodies often return following treatment in systemic lupus erythematosus (SLE), suggesting that long-lived plasma cells (PC) are not sensitive to such interventions. Therefore, their elimination is a key therapeutic goal in treatment. The goal of these studies is to validate P-selection glycoprotein ligand-1 (PSGL-1) as a novel marker for plasma cells in lupus, and as a therapeutic target in SLE. This work is based upon the observation that a subset of B cells differentiating into antibody secreting cells in germinal centers, the site of B cell memory and PC formation, express PSGL-1, with its expression highly upregulated on PC. The hypothesis to be tested is that PSGL-1 expression on antibody-secreting cells plays an important role in their trafficking to the bone marrow and splenic red pulp, niches for their survival. To address this hypothesis, three specific aims are planned. First, PSGL-1 expression and function on PC in normal mice following immunization will be assessed. Next, similar studies will be carried in lupus-prone mice, followed by blockade of PSGL1 interactions with its ligands, asking if PC trafficking to survival niches is altered, leading to diminished survival. Finally, PSGL- 1+CD38hi PC will be characterized in the peripheral blood of lupus patients, correlating their numbers with disease activity in an effort to support the idea that PSGL-1 on PC is an appropriate therapeutic target in SLE.

Public Health Relevance

B cells that produce antibodies in the spleen and other lymphoid organs are critical for normal and autoimmune responses. Much remains to be learned about the biology of these cells in autoimmunity, including the requirements for their maturation and function, and how to block the latter as a potential therapy for autoimmune diseases. The results of the proposed studies should help address these issues, and advance knowledge of how autoimmune responses develop in humans and how they can be abrogated therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR062842-01
Application #
8285600
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$223,931
Indirect Cost
$88,931
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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