Electronic Poster | Session 1

067 – Cell adhesion molecule DICAM: a new player in Multiple Sclerosis pathogenesis

Camille Grasmuck (1) – Soufiane Ghannam (1) – Marc Charabati (1) – Evelyn Peelen (1) – Lyne Bourbonnière (1) – Sandra Larouche (1) – Olivier Fortin (1) – Jorge Ivan Alvarez (2) – Hania Kebir (1) – Alexandre Prat (1)
CRCHUM, Department of Neurosciences, Faculty of Medicine, Université de Montreal, Montréal, Canada (1) – Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States (2)

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, TH17 lymphocytes 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. The current study aims to evaluate DICAM’s role in encephalitogenic TH17 lymphocytes’ migration to the CNS. 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. The role of DICAM in human TH17 lymphocytes in transmigration was assessed in vitro by blocking DICAM in a migration assay across a monolayer of human BBB-ECs. Its role in adhesion was explored in vitro by a flow adhesion assay of mouse TH17 lymphocytes on brain ECs in presence of DICAM blocking antibody or isotype control. Different animal models of MS (EAE) were also used to explore DICAM function in vivo.
We showed that DICAM expression is strongly associated with expression of ROR-gamma, IL-17 and IFN-gamma. These data demonstrate that DICAM is expressed on the surface of potentially encephalitogenic TH17 lymphocytes and that expression of DICAM is regulated by IL-23, IL-1b and IL-6, cytokines which are involved in CNS autoimmune diseases. The proportion of DICAM+ CD4+ lymphocytes is significantly increased in the blood and CNS of MS patients compared with healthy controls. Furthermore, DICAM expression is upregulated on the BBB within inflammatory lesions in the brains of MS patients. Moreover, blockade of DICAM restricts the adhesion and the migration of TH17 lymphocytes across BBB-ECs and decreases EAE severity. This study aims to characterize the interaction mediated by DICAM between TH17 lymphocytes and the BBB. This adhesion molecule might be involved in MS pathogenesis and therefore, could become a new therapeutic target for MS treatment.