Reyes-Sepulveda, C. J. | Search bioRxiv

bioRxiv2026

Genetic background shapes SEZ6L2 autoimmunity and reveals coordinated immune responses linked to neurological dysfunction

SEZ6L2 autoantibodies have been identified in patients with subacute cerebellar ataxia, but the underlying immune mechanisms and pathogenic pathways remain poorly understood. We previously established a C57BL/6 mouse model of SEZ6L2 autoimmunity that recapitulates key features of the disease. Here, we evaluated whether genetic background influences the magnitude and organization of SEZ6L2-directed immune responses. Pilot screening of autoimmune-prone strains identified SJL mice as exhibiting accelerated and enhanced antibody responses following SEZ6L2 immunization. In a large-cohort study, SEZ6L2-immunized SJL mice developed robust and sustained antibody responses, along with antigen-specific CD4 and CD8 T-cell activation. Expanded immune profiling revealed increased CNS infiltration of multiple lymphocyte populations, including CD4 T cells, CD8 T cells, B cells, and dendritic cells, as well as the presence of SEZ6L2-specific B cells within the brain. In addition, SJL mice exhibited strain-specific immunodominant T-cell epitopes distinct from those observed in C57BL/6 mice. Functionally, SEZ6L2-immunized SJL mice developed motor deficits consistent with cerebellar dysfunction. Integration of behavioral outcomes demonstrated a consistent overall impairment, and multivariate analysis revealed that coordinated humoral and cellular immune responses were associated with behavioral deficits. Together, these findings demonstrate that SEZ6L2-directed immune responses produce coordinated adaptive immune activation linked to neurological dysfunction and establish the SJL strain as an enhanced model for studying SEZ6L2 autoimmunity. This model also provides a platform for investigating disease mechanisms and therapeutic strategies.

immunology↗

bioRxiv2025

Sez6L2 autoimmunity induces cerebellar ataxia in mice

Sez6L2 autoantibodies have been reported in patients with subacute cerebellar ataxia, presenting with gait disturbances, frequent falls, slurred speech, and repetitive eye movements. These case studies suggest that autoimmunity against Sez6L2 causes cerebellar damage leading to ataxia. Sez6L2 is a transmembrane protein expressed by most neurons, with the highest levels in the cerebellum. We tested whether immunizing C57BL/6 mice against Sez6L2 could produce an autoimmune response resulting in ataxia symptoms and immune attack on the brain/cerebellum. We found that immunized mice generated significant levels of anti-Sez6L2 antibodies, with IgGs present in the cerebellar parenchyma. Additionally, Sez6L2-immunized mice developed a significant population of Sez6L2-specific T cells targeting two immunodominant epitopes and showed increased CD4+ T cell infiltration into the brain. These mice exhibited mild mobility impairments in open field, wire grid walk, and pole test assays. Our results indicate that an autoimmune response to Sez6L2 in mice can lead to mobility impairments and pathology consistent with human cerebellar ataxia associated with Sez6L2 autoantibodies. This new mouse model should be useful for mechanistic studies on this poorly understood autoimmune disease and for pre-clinical testing of therapeutic strategies targeting the immune system in patients with Sez6L2 antibodies.

neuroscience↗