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

Abstract

Lymphotoxin alpha (LT) plays an important role in lymphoid organ development and cellular cytotoxicity in the immune system. LT 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 LT in the cerebral meninges can give rise to lymphoid-like structures and underlying MS-like cortical pathology. Stereotaxic injections of recombinant LT into the rat meninges leads to acute meningeal inflammation and subpial demyelination that resolves after 28 days. Injection of an LT 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 LT overexpression is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration. SummaryIncreased release of lymphotoxin-alpha contributes to the pro-inflammatory milieu of the cerebrospinal fluid of MS patients. A persistent elevated expression of this cytokine in the meninges of rats gives rise to chronic inflammation with lymphoid tissue induction and accompanying neurodegenerative and demyelinating pathology in the underlying brain tissue.