EXPLORING THE MOLECULAR CIRCUITS AT BRAIN BORDERS PARTICULARLY THE ROLE OF B-CELL RICH LYMPHOID STRUCTURES IN THE MENINGES IN DRIVING GRAY MATTER INJURY IN MULTIPLE SCLEROSIS

Abstract

In Multiple Sclerosis, long-term disability and neurodegeneration depends on injury of gray matter, which is one of the central determinants. Even though historically treated as a white matter disorder, Multiple Sclerosis is currently considered to have an early cortical demyelination, synaptic changes, and neuronal degeneration that have a strong impact on the disease progression, especially during its progressive phases. The meninges appear to be dynamic immune niches in which inflammation can become compartmentalized and structured into B-cell rich tertiary lymphoid structures. These systems maintain persistent immune responses in the form of chemokines like CXCL13 and CCL19/CCL21 and survival factors like BAFF and APRIL thereby maintaining the B-cell persistence, plasma cell maturation, and intrathecal antibody generation. Diffused Soluble inflammatory mediators of tertiary lymphoid structures such as cytokines, antibodies and complement components cause neuronal degeneration, microglial and astrocytic activation, oxidative damage, and synaptic dysfunction. Coalescing neuropathology, cerebral fluid biomarker and advanced imaging, and animal model findings associate the tertiary lymphoid structures of the meninges with subpial cortical demyelination and rapid progression. Although B-cell therapeutic approaches and associated pathway therapies are promising, more mechanistic research and valid in vivo biomarkers are needed to establish approaches that are effective in preventing or restricting cortical neurodegeneration.