Role of PROTEIN S and TYRO3 receptor tyrosine kinase in the pathogenesis of Multiple Sclerosis and the type-2 protective environment

ORTIZ WILCZYÑSKI JUAN M; OLEXEN CINTHIA M; ERRASTI ANDREA E; SCHATTNER MIRTA; ROTHLIN CARLA V; CORREALE JORGE; CARRERA SILVA EUGENIO A

Mar del Plata

Congreso; Reunión Conjunta de Sociedades Científicas SAIC-­‐SAI-­‐SAFE; 2016

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disorder causing centralnervous system demyelination and axonal injury by infiltration of autoreactive Th1/Th17cells. The inflammatory environment is the main driver of damage and loss of neurologicfunction. Interestingly, helminth-infected MS patients showed lower number of relapses,lesion activity and minimal changes in disability scores compared with uninfected individualswith MS. Parasite-driven protection was associated with a reduction of pro-inflammatorycytokines via SOCS3, induction of Tregs and IL-10. TYRO3, AXL and MERTK (TAM)tyrosine kinase receptors and its ligand Protein S (PROS1) are critical regulators of theimmune response and we have recently demonstrated that Th2 environment enhancesPROS1 and TYRO3 expression. We hypothesize that the engagement of PROS1-TYRO3axis will be enhanced during helminth infection negatively regulating an associatedinflammatory response Th1/Th17. We evaluated TAM receptors and PROS1 expression inperipheral blood monocytes, dendritic and T cells compartment of patients with diagnosedMS (N=18), helminth-infected patients (HP, N=8) and healthy controls (HC, N=13-20). Wefound a significant increased level of PROS1 and MERTK in blood CD4 T cells of MSpatients compared to HC. However, after in-vitro TCR activation, CD4 T cells from MSinduced lower levels of PROS1 (100.3 ± 5.6) vs HC (120.7± 2.6) or HP (137.8 ± 6.0)measured as mean fluorescence intensity. Furthermore, PROS1 levels in CD4+/IFNg+ andCD4+/IL13+ was higher in HP > HC > MS. Interesting, CD1c dendritic cells showed higherTYRO3 expression in HP (10.4 ± 0.9) vs HC (6.5 ± 0.3) and MS (4.9 ± 0.3) measured as foldincrease referred to isotype. Our results suggest that the enhanced PROS1/TYRO3 axis inHP could be favoring a more efficient engagement of this anti-inflammatory pathway andcould contribute to explain the parasite-driven protection observed in helminth-infected MS.