SLAMF receptors and their adapters SAP and EAT-2 play a major role in human and mouse innate and adaptive immune response. Investigators in this Program Project have discovered that in mice several of these receptors either positively or negatively regulate the development of autoimmunity, including lupus related pathology. Excitingly, preliminary studies have revealed deviations in signaling pathways initiated by several SLAMF receptors in immunocytes isolated from patients with systemic lupus erythematosus (SLE). The overall hypothesis of Project #1 is that the mouse receptors Slamf3, 5, and 6 and their isoforms govern immune responses involved in the pathogenesis of murine lupus. The experiments that are designed to test this hypothesis are grouped as follows:
Specific Aim#1 : Testing the hypothesis that the three Slamf6 receptor isoforms initiate distinct positive and negative regulatory pathways to lupus.
Specific Aim #2 : Testing the hypothesis that the Slamf5 receptor governs signaling in T and B cells and DC during the pathogenesis of mouse lupus.
Specific Aim #3 : Testing the hypothesis that Slamf3 receptor initiated signaling controls autoantibody production.

Public Health Relevance

Results of these studies should lead to 1) better diagnostic tools to complement currently used indexes, 2) reliable and specific biomarkers to monitor and hopefully predict disease actlvitiy and 3) novel treatment protocols for SLE patients to replace or add to immunosuppressive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI065687-08
Application #
8707310
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, Ninghai; Keszei, Marton; Halibozek, Peter et al. (2016) Slamf6 negatively regulates autoimmunity. Clin Immunol 173:19-26
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6
McArdel, Shannon L; Terhorst, Cox; Sharpe, Arlene H (2016) Roles of CD48 in regulating immunity and tolerance. Clin Immunol 164:10-20
Chaudhary, Anu; Leite, Mara; Kulasekara, Bridget R et al. (2016) Human Diversity in a Cell Surface Receptor that Inhibits Autophagy. Curr Biol 26:1791-801
Kis-Toth, Katalin; Comte, Denis; Karampetsou, Maria P et al. (2016) Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4-Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus. Arthritis Rheumatol 68:164-73
Cuenca, Marta; Romero, Xavier; Sintes, Jordi et al. (2016) Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses. J Immunol 196:726-37
Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih et al. (2016) A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells. Oncotarget 7:26346-60
Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin et al. (2016) Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. J Immunol 196:4915-24
Wang, Guoxing; van Driel, Boaz J; Liao, Gongxian et al. (2015) Migration of myeloid cells during inflammation is differentially regulated by the cell surface receptors Slamf1 and Slamf8. PLoS One 10:e0121968
O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4

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