Specific Meningeal Layers Involved in CNS Autoimmune Responses
Post by Elisa Guma
The takeaway
The meningeal layers of the central nervous system play distinct roles in acute and chronic CNS autoimmunity. The outermost dural layer seems to be largely unaffected by inflammation, while the internal leptomeningeal layers are heavily involved in the inflammatory response.
What's the science?
The central nervous system is surrounded and protected by a three-layered membrane called the meninges, which include the leptomeninges (including the pia layer, closest to the brain, followed by the arachnoid layer), and pachymeninx (also known as the dura mater). In addition to their physically protective role, the meningeal layers are densely populated by immune cells and are involved in the autoimmune response of the CNS, both in acute and chronic conditions (such as autoimmune diseases like multiple sclerosis). However, the distinct role of the three meningeal layers in CNS autoimmunity has yet to be fully understood. This week in Nature Neuroscience, Merlini and colleagues investigate the differential role of the meningeal layers in modulating autoimmune inflammation in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and human MS patients.
How did they do it?
The authors studied the meninges (pachymeninx or dura mater vs. the leptomeninges) in both rat and mouse models of autoimmune encephalomyelitis (EAE), which exhibits signs of autoimmune inflammation, similar to those seen in human patients with multiple sclerosis. To induce meningeal inflammation, the authors gave healthy rodents T cells that specifically activate in the presence of certain proteins that exist in the brain (myelin basic protein or beta synuclein). Four to five days following exposure, rodents exhibit clinical symptoms.
To characterize the immune response of the meninges, the authors tracked the migration of fluorescently labeled immune cells using two-photon laser scanning microscopy in the EAE model. Next, to assess the properties of the meningeal vasculature they injected rats with fluorescent tracers that rapidly leak out of vessels and measured accumulation in the perivascular space, which would indicate regions where the vasculature is leaky.
Next, the authors investigated the stimulatory capacity of T cells present in the dural layer and the leptomeningeal compartment. They also measured the motility of T cells and if they made contact with antigen-presenting cells, a group of cells that mediate the immune response by processing and presenting antigens for recognition to certain T cells, to determine whether differences in immune response across the layers were due to reduced opportunity for inflammation. They also investigated the role of lymphatic drainage in modulating the immune response. Finally, to confirm the observations they made in the rodent autoimmune models, they studied the immune profile of post-mortem samples of the meninges of patients with chronic MS.
What did they find?
In the rodent EAE models, the authors found evidence of massive inflammation of the leptomeninges and parenchyma but hardly any inflammation in the dura. These results were replicated in meningeal samples from human patients with chronic multiple sclerosis.
To better understand these results, the authors studied the meningeal vasculature: they found that the dura had high vessel permeability (based on leakage of a fluorescent tracer), which indicated that a lack of permeability is not preventing the dura from accumulating inflammatory cells. Transcriptional analysis of the dural and leptomeningeal vessels identified distinct gene expression profiles, whereby genes encoding blood-brain barrier components, and molecules relevant for effector T cell adhesion to the vessels, were expressed at significantly lower levels in the dura, which may limit the ability of the T cells to adhere to the dural vessels. In inflammatory conditions, however, the dural endothelia enabled T cell adhesion. Therefore, other mechanisms should be accounting for the reduced involvement of the dura in the CNS autoimmune process.
The authors investigated if the reduced levels of inflammation within the dura could be due to 1) T cell anergy (a state in which cells fail to produce a response), 2) to an immune suppressive environment in the dura, or 3) to the inability of the locally resident phagocytes to present antigen. However, they found that the dural T cells had the same intrinsic stimulatory capacity as the T cells in the leptomeninges and that dural antigen-presenting cells were also fully competent. What they did find was that the substrate for successful autoreactive T cell activation, namely CNS autoantigens, did not reach the dura in sufficient quantities to activate the T cells.
Finally, the authors investigated the role of lymphatic vessels in the inflammatory response. They found that although antigens could be transported from the CNS to the dura and the deep cervical lymph nodes, there was higher uptake in the leptomeningeal cells than in the dura or deep cervical lymph nodes.
What's the impact?
This study highlights the differential role of the meningeal layers in both acute and chronic autoimmune disease, with the dura playing a passive role relative to the leptomeninges. The findings presented here are surprising since the dura would be expected to play a more active role in these inflammatory processes, given its location, vascularity, and dense population of immune cells. Future research is needed to investigate potential immunomodulatory therapies specifically targeted at the leptomeninges.
