The overall goal of this PPG is to understand how SLAM family (Slamf) members control pathways that regulate the development of systemic lupus erythematosus (SLE). Project 2 will investigate the role of SLAMF2 (CD48) interactions with its binding partner SLAMF4 (CD244,2B4) in controlling immune cell function, establishment and maintenance of tolerance and development of SLE immune cell abnormalities. Based on our published and preliminary data we hypothesize that SLAMF2 and SLAMF4 regulate T cell and APC function, control immune tolerance, and contribute to autoimmunity-related pathology in mice and patients with SLE. Studies in mice and patients with SLE will test this hypothesis by performing complementary and closely interactive experiments.
o Specific Aim #1 : To test the hypothesis that Slamf4 on the surface of mouse APC regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #2 : To test the hypothesis that Slamf2 regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #3 : To test the hypothesis that the SLAMF2 and SLAMF4 receptors function aberrantly in peripheral blood immunocytes isolated from SLE patients.

Public Health Relevance

Our mechanistic studies (genetic manipulation of S1-AI /IF2 and 4 in mice and silencing in human immunocytes), coupled with in vivo and in vitro use of stimulatory and inhibitory Abs, will generate proposals for therapeutic interventions in human SLE and therefore underscore the significance of the proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI065687-07
Application #
8703243
Study Section
Special Emphasis Panel (ZAI1-SV-I (M2))
Project Start
2005-07-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$48,066
Indirect Cost
$15,523
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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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