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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-SV-I)
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Beth Israel Deaconess Medical Center
United States
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Kis-Toth, Katalin; Tsokos, George C (2014) Engagement of SLAMF2/CD48 prolongs the time frame of effective T cell activation by supporting mature dendritic cell survival. J Immunol 192:4436-42
Romero, Xavier; Sintes, Jordi; Engel, Pablo (2014) Role of SLAM family receptors and specific adapter SAP in innate-like lymphocytes. Crit Rev Immunol 34:263-99
Sintes, Jordi; Cuenca, Marta; Romero, Xavier et al. (2013) Cutting edge: Ly9 (CD229), a SLAM family receptor, negatively regulates the development of thymic innate memory-like CD8+ T and invariant NKT cells. J Immunol 190:21-6
Keszei, Marton; Detre, Cynthia; Castro, Wilson et al. (2013) Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor. FASEB J 27:3123-31
Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 71:463-8
Chatterjee, Madhumouli; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. J Immunol 188:1206-12
Rivas, Manuel A; Beaudoin, Melissa; Gardet, Agnes et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066-73
Chatterjee, Madhumouli; Kis-Toth, Katalin; Thai, To-Ha et al. (2011) SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells. Autoimmunity 44:211-8
Keszei, Marton; Latchman, Yvette E; Vanguri, Vijay K et al. (2011) Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice. Int Immunol 23:149-58
Brown, Daniel R; Calpe, Silvia; Keszei, Marton et al. (2011) Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity. J Immunol 187:21-5

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