SLAMF molecules are involved in the expression and regulation of multiple aspects ofthe innate and adaptive immune response. Work in mice carried out under the auspices of this Program have revealed important roles in the expression of autoimmunity, and more importantly, lupus-related pathology. Interestingly, disputed SLAMF-llnked single nucleotide polymorphism (SNP) associations have been reported in patients with systemic lupus erythematosus (SLE) while the expression of SLAMF isoforms and their modulatory role on immune cell function has not been studied systematically. We hypothesize that the expression of isoforms of SLAMF is aberrant in Immune cells in SLE patients and that their homotypic engagement leads to aberrant immune cell function including cytokine and autoantibodyproduction. To test this hypothesis we propose experiments grouped in four Specific Alms.
The significance of the proposed work is that it points out to the need to consider blockade of the homotypic SLAMF Interaction to suppress autoimmunity. This project borrows concepts from Projects 1 and 2 and provides direct feedback for murine preclinical studies.
|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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