Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration

Abstract

Lymphotoxin alpha (LTa) plays an important role in lymphoid organ development and cellular cytotoxicity in the immune system. LTa expression is increased in the cerebrospinal fluid of naive and progressive multiple sclerosis (MS) patients and post-mortem meningeal tissue. Here we show that persistently increased levels of LTa in the cerebral meninges can give rise to lymphoid-like structures and underlying MS-like cortical pathology. Stereotaxic injections of recombinant LTa into the rat meninges leads to acute meningeal inflammation and subpial demyelination that resolves after 28 days. Injection of an LTa lentiviral vector induces lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial activation, subpial demyelination and marked neuronal loss occurs in the underlying cortical parenchyma. These results show that chronic LTa overexpression is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration.

Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis

“…Cultured astrocytes and microglia can be induced to synthesise complement components, including C1q, C3, and factor B, when exposed to CSF from lymphotoxin-α treated rats. Lymphotoxinα is elevated in concentration in the MS CSF and when over-expressed in the leptomeninges, recapitulates the pattern of subpial demyelination seen in disease (James Bates et al, 2022). Therefore, complement activation in the connective tissue spaces and parenchyma can stimulate the production of TNFα and other pleiotropic cytokines, which can be directly cytotoxic (and differentially expressed in cases characterised by leptomeningeal inflammation and more extensive cortical demyelination) (Magliozzi et al, 2019b;Picon et al, 2021), whilst cytokine release by activated glia can further drive the transcription of genes encoding early complement proteins.…”

“…The compartmentalised inflammatory response is composed of activated immune cells in the parenchyma, reactive microglia and astroglia, increased numbers of leptomeningeal and connective tissue T and B lymphocytes, long-lived plasma cells, and elevated levels of circulating cytokines in the CSF (Lassmann, 2019). An overtly inflammatory CSF cytokine profile is associated with a more severe MS at presentation and followup, and pathologically, is linked to subpial tissue damage in a gradient-like pattern, which can be replicated in experimental models by the induced expression of inflammatory cytokines in the leptomeninges (Magliozzi et al, 2010(Magliozzi et al, , 2018(Magliozzi et al, , 2020Gardner et al, 2013;James Bates et al, 2022). The levels of complement proteins, including C1q, C2, C4, and C5 in MS CSF and serum are altered in comparison to healthy individuals and between different MS clinical subtypes (Sellebjerg et al, 1998;Jongen et al, 2000;Finehout et al, 2005;Stoop et al, 2008;Ingram et al, 2010;Aeinehband et al, 2015;Magliozzi et al, 2019a;Zelek et al, 2019).…”

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

“…LT-a and LT-b, membrane-bound proteins expressed on activated immune cells, are also critical in generating TLS. LT-a (formerly known as TNF-b) and LT-b are members of the tumor necrosis factor (TNF) family, sharing similar signaling pathways and receptors with other family members (139). LT-a proteins are expressed on activated immune components, while their receptors (e.g., LT-bR) are expressed on stromal or epithelial cells.…”