Lack of junctional adhesion molecule (JAM)-B ameliorates experimental autoimmune encephalomyelitis.

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) autoaggressive CD4+ T cells cross the blood-brain barrier (BBB) and cause neuroinflammation. Therapeutic targeting of CD4+ T-cell trafficking into the CNS by blocking α4-integrins has proven beneficial for the treatment of MS but comes with associated risks, probably due to blocking CD8+ T cell mediated CNS immune surveillance. Our recent observations show that CD8+ T cells also rely on α4ß1-integrins to cross the BBB. Besides vascular cell adhesion molecule-1 (VCAM-1), we identified junctional adhesion molecule-B (JAM-B) as a novel vascular α4ß1-integrin ligand involved in CD8+ T-cell migration across the BBB. This prompted us to investigate, if JAM-B also mediates CD4+ T-cell migration across the BBB. We first ensured that encephalitogenic T cells can bind to JAM-B in vitro and next compared EAE pathogenesis in JAM-B-/- C57BL/6J mice and their wild-type littermates. Following immunization with MOGaa35-55 peptide, JAM-B-/- mice developed ameliorated EAE compared to their wild-type littermates. At the same time, we isolated higher numbers of CD45+ infiltrating immune cells from the CNS of JAM-B-/- C57BL/6J mice suffering from EAE. Immunofluorescence staining revealed that the majority of CD45+ inflammatory cells accumulated in the leptomeningeal and perivascular spaces of the CNS behind the BBB but do not gain access to the CNS parenchyma. Trapping of CNS inflammatory cells was not due to increased inflammatory cell proliferation. Neither a loss of BBB integrity or BBB polarity potentially affecting local chemokine gradients nor a lack of focal gelatinase activation required for CNS parenchymal immune cell entry across the glia limitans could be detected in JAM-B-/- mice. Lack of a role for JAM-B in the effector phase of EAE was supported by the observation that we did not detect any role for JAM-B in EAE pathogenesis, when EAE was elicited by in vitro activated MOG aa35-55-specific CD4+ effector T cells. On the other hand, we also failed to demonstrate any role of JAM-B in in vivo priming, proliferation or polarization of MOGaa35-55-specific CD4+ T cells in peripheral immune organs. Finally, our study excludes expression of and thus a role for JAM-B on peripheral and CNS infiltrating myeloid cells. Taken together, although endothelial JAM-B is not required for immune cell trafficking across the BBB in EAE, in its absence accumulation of inflammatory cells mainly in CNS leptomeningeal spaces leads to amelioration of EAE.

Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination.

Myelination occurs selectively around neuronal axons to increase the efficiency and velocity of action potentials. While oligodendrocytes are capable of myelinating permissive structures in the absence of molecular cues, structurally permissive neuronal somata and dendrites remain unmyelinated. Utilizing a purified spinal cord neuron-oligodendrocyte myelinating co-culture system, we demonstrate that disruption of dynamic neuron-oligodendrocyte signaling by chemical cross-linking results in aberrant myelination of the somatodendritic compartment of neurons. We hypothesize that an inhibitory somatodendritic cue is necessary to prevent non-axonal myelination. Using next-generation sequencing and candidate profiling, we identify neuronal junction adhesion molecule 2 (JAM2) as an inhibitory myelin-guidance molecule. Taken together, our results demonstrate that the somatodendritic compartment directly inhibits myelination and suggest a model in which broadly indiscriminate myelination is tailored by inhibitory signaling to meet local myelination requirements.