Montini, Federico

Gut wall physiology in multiple sclerosis (MS) and autoimmune neurologic diseases remains underexplored. This review examines gut wall dysfunctions’ contribution to MS and autoimmune neurological disorder pathogenesis and progression. We discuss 3 inter‐related aspects of gut physiology: intestinal barrier, enteric nervous system (ENS), and mucosal immunity. We highlight the ENS as a putative target of immune injury in selected antibody‐mediated and T cell‐associated neurologic diseases. Finally, we propose a unifying framework in which the gut functions as a site of immune priming and target of autoimmune injury, bridging microbiome‐driven mechanisms in MS with ENS‐directed autoimmunity across neurologic diseases. ANN NEUROL 2026

Abstract The discovery of pathogenic neuroglial surface-directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognized, diseases. Annual descriptions of novel CNS-targeting antibodies create a continuous stream of new conditions in which to evaluate distinct phenotypes, specific tumour associations and immunotherapy responses. Alongside this clinical growth, increasing basic knowledge has highlighted origins and mechanisms underlying disease causation, most comprehensively interrogated in the well-established autoantibody-mediated conditions of autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The corresponding most common ‘big six’ autoantigens are LGI1, the N-methyl-D-aspartate (NMDA) receptor, CASPR2, IgLON5, in forms of AE, AQP4 and MOG. Each of these autoantigens associates with a homogenous set of basic clinical features, across age, sex, tumour associations and ethnicities, coupled with partly distinctive profiles of triggers and predispositions, paradigms of immune tolerance escape in the periphery, how cells and autoantibodies gain access to the CNS, and discrete mechanisms by which the CNS autoantibodies induce neuroglial dysfunction. These observations lead us to reconstruct a proposed chronological series of events as the ‘cascade to pathogenicity’, which together culminate in a rare CNS disease. By extension, we hypothesize elucidating the underlying biology of each condition will present differing precision medicine approaches to optimize patient care. Despite distinctions, there are also clinical and biological overlaps between these diseases, collectively creating opportunities to compare and contrast their individual features. Here, in each condition, we review current knowledge regarding the similarities and differences between the triggering events, underlying immunological processes and pathogenic mechanisms of autoantibodies. In some instances, we identify scientific clues that drive hypothetical pathways of pathogenesis and, for others, highlight striking observations that aim to generate hypothesis-driven next steps. Our aim is to construct a model across the major autoantibody-mediated CNS diseases to highlight distinct components of cascades to pathogenicity, which may offer targeted therapeutic approaches to improve patient outcomes, and identify key areas and questions for future research.