Meningeal lymphoid structures are activated under acute and chronic spinal cord pathologies.

Merav Cohen,Michal Schwartz,Julia Ruckh,Baoguo Li,Ravid Shechter,Ido Amit,Amir Giladi,Aleksandra Deczkowska,Boaz Mohar,Rachel G Lichtenstein,Mor Zada,Catarina Raposo

doi:10.26508/lsa.202000907

Merav Cohen, Michal Schwartz + Show 10 more

Open Access

https://doi.org/10.26508/lsa.202000907

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Abstract

Tertiary lymphoid structures (TLS) are organized aggregates of B and T cells formed ectopically during different stages of life in response to inflammation, infection, or cancer. Here, we describe formation of structures reminiscent of TLS in the spinal cord meninges under several central nervous system (CNS) pathologies. After acute spinal cord injury, B and T lymphocytes locally aggregate within the meninges to form TLS-like structures, and continue to accumulate during the late phase of the response to the injury, with a negative impact on subsequent pathological conditions, such as experimental autoimmune encephalomyelitis. Using a chronic model of spinal cord pathology, the mSOD1 mouse model of amyotrophic lateral sclerosis, we further showed by single-cell RNA-sequencing that a meningeal lymphocyte niche forms, with a unique organization and activation state, including accumulation of pre-B cells in the spinal cord meninges. Such a response was not found in the CNS-draining cervical lymph nodes. The present findings suggest that a special immune response develops in the meninges during various neurological pathologies in the CNS, a possible reflection of its immune privileged nature.

Highlights

Following any deviation from homeostasis in the central nervous system (CNS), the immune response is activated to facilitate repair and to resolve the detrimental parenchymal inflammation
By using the mSOD1 mouse model of chronic spinal cord degeneration, often used as a model of amyotrophic lateral sclerosis (ALS), we found that lymphocytes isolated from spine meninges, but not from draining cervical lymph nodes (cLNs), showed dynamic changes in lymphocyte activation, and in B-cell differentiation, along disease progression
We found that SCI induced the accumulation of CD45+ cells in general, and of B and T cells, mainly of the CD4+ subset, in a spatially restricted manner; the increase in lymphocyte numbers was observed in meningeal tissues that were isolated from areas in close proximity to the lesion site, and not from distal regions (Fig 1G)

Summary

Introduction

Following any deviation from homeostasis in the central nervous system (CNS), the immune response is activated to facilitate repair and to resolve the detrimental parenchymal inflammation. Recent studies in the field of CNS lymphatic drainage revealed that in homeostasis, a lymphatic vasculature is present in the dural sinuses of the brain meninges (Weller et al, 2009; Aspelund et al, 2015; Louveau et al, 2015), in addition to the perivascular pathways that drain interstitial fluid from the brain parenchyma, and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes (cLNs) (Carare et al, 2014; Lochhead et al, 2015) These observations, together with our findings that entry of immuno-regulatory cells to sites of injured CNS parenchyma is orchestrated through the brain’s border, the choroid plexus (CP) epithelium (Kunis et al, 2013; Shechter et al, 2013; Raposo et al, 2014), suggest that the meningeal lymphatic niche might become activated and participate in the immunological network triggered by CNS injury. Within the CNS, their formation in the form of B-cell aggregates that execute a GC response was mainly identified in brain meninges under inflammatory diseases of the brain, such as multiple sclerosis, and its mouse model, experimental autoimmune encephalomyelitis (EAE) (Columba-Cabezas et al, 2006; Howell et al, 2011; Peters et al, 2011; Kuerten et al, 2012; Pikor et al, 2015; Lehmann-Horn et al, 2016; Bevan et al, 2018; Magliozzi et al, 2019)

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