Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation

Abstract

People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.

Maternal exposure to polystyrene nanoplastics impacts developmental milestones and brain structure in mouse offspring

“…Images were acquired on a 7 Tesla 306 mm horizontal bore magnet (BioSpec 70/30 USR, Bruker, Ettlingen, Germany) with a ParaVision 6.0.1 console. 20,21 Using a custom-built 8coil solenoid array, 8 brain samples were imaged in parallel using the following scan parameters: T2-weighted 3D fast spin-echo sequence using a cylindrical k-space acquisition with TR = 350 ms, TE = 12 ms, TE eff = 30 ms, echo train length = 6, four effective averages, eld-of-view = 20.2 mm × 20.2 mm × 25.2 mm, matrix size = 504 × 504 × 630. Total imaging time was 13.2 hours with resulting anatomical images of 40 mm voxel isotropic resolution.…”

B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans

“…To test the impact of anti-CD20–mediated B cell depletion in a setting where gray matter injury is provoked by adoptive transfer of T H 17 cells ( 13 , 15 ), we first confirmed the efficacy of anti-CD20 B cell depletion in secondary lymphoid tissues in SJL/J mice by testing different anti-CD20 monoclonal antibody (18B12) isotypes (IgG2a, IgG2c, and glycoengineered IgG2a and IgG2c) (fig. S1A).…”

“…2C), with the signal intensity being most prominent in areas that were relatively poor in B220 + B cells. Reanalyzing single-cell RNA sequencing of leptomeningeal immune cells assessed at the peak of adoptive transfer SJL/J EAE ( 15 ), we found that the majority of Tnfsf13b mRNA was expressed by myeloid cells (fig. S3, A to C).…”

“…The most widely used MS animal model, myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55 )–induced experimental autoimmune encephalomyelitis (EAE), does not replicate cortical gray matter pathology but rather manifests as a spinal-cord dominant disease. We have previously described an EAE model in Swiss Jim Lambert (SJL)/J mice that recapitulates not only gray matter cortical pathology but also the presence of tertiary lymphoid tissues (TLTs) in the brain leptomeninges, which is associated with subpial gray matter cortical injury ( 13 – 15 ). This model is driven by adoptive transfer of encephalitogenic T helper 17 (T H 17) cells that enter the spinal cord to initiate paralysis and the brain leptomeninges to induce TLT formation.…”

Biological aging in multiple sclerosis

“…Studies have explored the effects of aging on CNS autoimmune disease by inducing experimental autoimmune encephalomyelitis (EAE), the most popular preclinical rodent model of MS. 10 In two recent studies, middle-aged EAE mice (aged 40-44 weeks) exhibited an exacerbated, protracted disease course with chronic disability, whereas younger adults (aged 8-12 weeks) experienced milder disease and frequent clinical remission. 11,12 Using reciprocal bone marrow chimeras, wherein bone marrow cells from young adult or middle-aged EAE donors were transferred into lethally irradiated healthy young or middle-aged hosts, it was demonstrated that the exacerbated, chronic course of EAE is dependent on the presence of aged non-hematopoietic, radio-resistant cells, including glia. 11 Reminiscent of progressive MS, middle-aged mice with EAE had widespread microglial activation.…”