Author Of 2 Presentations
LB1270 - DICAM : A new cell adhesion molecule involved in myeloid cells infiltration in Multiple Sclerosis (ID 2168)
Abstract
Background
Disruption of the blood-brain barrier (BBB) and migration of leukocytes from the periphery to the central nervous system (CNS) are early events in lesion formation during multiple sclerosis (MS). Among CNS-infiltrated leukocytes, macrophages and dendritic cells are important contributors to inflammation and tissue damage. They readily cross the BBB to infiltrate the CNS and express pro-inflammatory cytokines. Using proteomic and RNA sequencing techniques, we have identified Dual Ig domain containing Cell Adhesion Molecule (DICAM) as a new adhesion molecule expressed by human TH17 lymphocytes and BBB endothelial cells (ECs). The expression and function of DICAM in MS pathogenesis remain unexplored.
Objectives
The current study aims to evaluate DICAM’s role in monocytes/macrophages and dendritic cells migration to the central nervous system.
Methods
To explore the DICAM expression profile, we performed flow cytometry and qPCR on human BBB-ECs and immune cells subsets isolated from healthy control peripheral blood. Confocal microscopy, flow cytometry and qPCR have been performed to explore DICAM expression in MS lesions and on peripheral immune cells in situ and ex vivo. To further investigate the expression of DICAM by myeloid cells in patients with MS, we performed flow cytometry analysis of peripheral blood mononuclear cells from males and females patients with relapsing remitting MS (n= 19), secondary progressive MS (n= 19) and primary progressive MS (n= 21) aged and sex-matched with controls individuals (n= 39) samples. The role of DICAM in monocytes adhesion to the BBB-ECs was assessed in vitro by blocking DICAM in a flow adhesion assay on a monolayer of human BBB-ECs. Different animal models of MS (EAE) were also used to explore DICAM function in vivo.
Results
We first demonstrated that DICAM and its ligand αvβ3 are upregulated on the BBB within inflammatory lesions in the brains of MS patients. In peripheral blood preliminary results indicates that DICAM expression by myeloid DCs and classical monocytes is associated with RRMS and SPMS forms of the disease. Moreover, blockade of DICAM restricts the adhesion of monocytes on human BBB-ECs and decreases disease severity in several EAE models.
Conclusions
This study aims to characterize the interaction mediated by DICAM between infiltrating leukocytes and the BBB. This adhesion molecule might be involved in MS pathogenesis and therefore, could become a new therapeutic target for MS treatment.
P1142 - “The contribution of sex hormones to disease incidence and phenotype in the spontaneous TCR1640 mouse model.” (ID 1487)
Abstract
Background
TCR1640 transgenic mice, a model of spontaneous experimental autoimmune encephalomyelitis (EAE), are a powerful tool to study the sexual dimorphism seen in MS patients. Being at higher risk of developing EAE, TCR1640 females develop a relapsing-remitting (RR) disease course while male TCR1640 develop mostly a primary progressive (PP) form. Clinical observations in MS patients and other EAE models suggest a potentially protective role of sex hormones but their contribution to disease development remains to be elucidated.
Objectives
We aim to characterize the role of sex hormones, in both sexes, on multiple aspects of the MS course including disease incidence, phenotype and severity in a unique and relevant mouse model.
Methods
Gonadectomies have been performed on TCR1640 mice between 21-28 days postnatal, before onset of puberty (n= 22 males, n= 25 females). These mice, as well as sham control mice (n= 17 males, n= 21 females), were scored daily for signs of paralysis and ataxia and were followed up for >150 days.
Results
For both male and female TCR1640 mice, gonadectomy seems to affect disease incidence. Absence of sex hormones in males display a major protective role on the disease 75 days after surgery whereas the protective effect of female sex hormones becomes apparent ~90 days after surgery. Not only there are fewer male and females sham mice that do fall ill in theses period, but mice that do fall ill do so with delayed onset compared to their gonadectomized littermates. Preliminary results show that gonadectomy does not seem to affect disease phenotype for either sex. More advanced bioinformatical analysis will now be used to define different phenotype clusters based on EAE score evolution, allowing us to zoom in on the potential influence of sex hormones on each of these different phenotypes.
Conclusions
We have demonstrated that both male and female sex hormones have a potential protective role in the TCR1640 model, appearing to decrease disease incidence as well as delaying disease onset. Sex hormones however do not seem to control disease phenotype, strongly suggesting that the sexual dichotomy seen in clinical disease course is dictated by sex chromosomes rather than sex hormones.