Contributions
Abstract: P965
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Immunology
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system mediated by local inflammatory T cells. Disease onset is often preceded by a clinically isolated syndrome (CIS), the earliest clinical presentation of MS. However, only half of the patients with an initial attack meet the standard MRI criteria at baseline or do not develop clinically definite MS at all. Hence, in-depth analyses of pro-inflammatory CD4+ T helper (Th) cells in early MS could lead to a better understanding and more accurate prediction of disease development. We performed a CIS prediction (n=30) and case-control (treatment-naive RRMS; n=40) study to explore differentiation and activation of blood Th cell subsets with distinct pro-inflammatory cytokine profiles using 12-colour flow cytometry. In fast CIS converters (developed clinically definite MS within 1 year), CXCR3+CCR6- ("Th1") and CXCR3+CCR6+ ("Th1/17"), but not CXCR3-CCR6+ ("Th17") cells showed lower frequencies and reduced proportions of effector memory cells compared to slow CIS converters (remained CIS for more than 5 years; p< 0.01). These reductions correlated with fatigue scores (r=0.56, p=0.002), which are predictive for CIS conversion (Runia et al., J Neurol Neurosurg Psychiatry 2015), and were also found in RRMS versus control blood (p< 0.01). In RRMS, Th1/17 cells were highly activated (HLA-DR+CD38+; p< 0.001), while this was the case for Th17 cells in CIS. After sorting and in vitro activation, Th1/17 cells prominently expressed IFN-γ (33%) and GM-CSF (36%), which was much stronger than in Th1 (15% and 12%) and Th17 (3% and 16%) cells. Finally, the downregulation of CXCR3 on in vitro-activated Th cells, as well as the predominance of Th1 and Th1/17 memory cells within the total CD4+ T cell population in MS brain tissue (n=16) are possible explanations for the reduced Th1 and Th1/17 cell frequencies in early MS blood. These data indicate that conversion of activated Th17 into Th1/17 cells and their preferential migration with Th1 cells into the brain are key mechanisms underlying early MS development.
Disclosure: van Langelaar: nothing to disclose
van der Vuurst de Vries: nothing to disclose
Janssen: nothing to disclose
Wierenga-Wolf: nothing to disclose
Spilt: nothing to disclose
van Nierop: nothing to disclose
Mescheriakova: nothing to disclose
Runia: nothing to disclose
van Luijn: nothing to disclose
Hintzen: nothing to disclose
Funding
Dutch MS Research Foundation, Stichting Zabawas
Abstract: P965
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Immunology
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system mediated by local inflammatory T cells. Disease onset is often preceded by a clinically isolated syndrome (CIS), the earliest clinical presentation of MS. However, only half of the patients with an initial attack meet the standard MRI criteria at baseline or do not develop clinically definite MS at all. Hence, in-depth analyses of pro-inflammatory CD4+ T helper (Th) cells in early MS could lead to a better understanding and more accurate prediction of disease development. We performed a CIS prediction (n=30) and case-control (treatment-naive RRMS; n=40) study to explore differentiation and activation of blood Th cell subsets with distinct pro-inflammatory cytokine profiles using 12-colour flow cytometry. In fast CIS converters (developed clinically definite MS within 1 year), CXCR3+CCR6- ("Th1") and CXCR3+CCR6+ ("Th1/17"), but not CXCR3-CCR6+ ("Th17") cells showed lower frequencies and reduced proportions of effector memory cells compared to slow CIS converters (remained CIS for more than 5 years; p< 0.01). These reductions correlated with fatigue scores (r=0.56, p=0.002), which are predictive for CIS conversion (Runia et al., J Neurol Neurosurg Psychiatry 2015), and were also found in RRMS versus control blood (p< 0.01). In RRMS, Th1/17 cells were highly activated (HLA-DR+CD38+; p< 0.001), while this was the case for Th17 cells in CIS. After sorting and in vitro activation, Th1/17 cells prominently expressed IFN-γ (33%) and GM-CSF (36%), which was much stronger than in Th1 (15% and 12%) and Th17 (3% and 16%) cells. Finally, the downregulation of CXCR3 on in vitro-activated Th cells, as well as the predominance of Th1 and Th1/17 memory cells within the total CD4+ T cell population in MS brain tissue (n=16) are possible explanations for the reduced Th1 and Th1/17 cell frequencies in early MS blood. These data indicate that conversion of activated Th17 into Th1/17 cells and their preferential migration with Th1 cells into the brain are key mechanisms underlying early MS development.
Disclosure: van Langelaar: nothing to disclose
van der Vuurst de Vries: nothing to disclose
Janssen: nothing to disclose
Wierenga-Wolf: nothing to disclose
Spilt: nothing to disclose
van Nierop: nothing to disclose
Mescheriakova: nothing to disclose
Runia: nothing to disclose
van Luijn: nothing to disclose
Hintzen: nothing to disclose
Funding
Dutch MS Research Foundation, Stichting Zabawas