Biology subjects

Hammond, J. W.

Publications and source records attributed to Hammond, J. W..

4 recordsLinked to original sources

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↗

bioRxiv2020

The Sez6 family inhibits complement at the level of the C3 convertase.

The Sez6 family consists of Sez6, Sez6L, and Sez6L2. Its members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. They are also linked to various neurological and psychiatric disorders. All Sez6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation. We show that all Sez6 family members inhibit C3 deposition by the classical and alterative pathways with varying degrees of efficacy. For the classical pathway, Sez6 is a strong inhibitor, Sez6L2 is a moderate inhibitor, and Sez6L is a weak inhibitor. Using Sez6L2 as the representative family member, we show that it specifically deactivates C3 convertases by accelerating the decay or dissociation of the C3 convertase components. Sez6L2 also deactivates C3 convertases of the alternative pathway by serving as a cofactor for Factor I to facilitate the cleavage of C3b. However, Sez6L2 has no cofactor activity toward C4b. In summary, the Sez6 family are novel complement regulators that inhibit C3 convertases.

neuroscience↗

bioRxiv2019

Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein levels were elevated in EAE mice. Genetic loss of C1qa provided a small degree of protection from EAE-induced decreases in synaptic density. However, C1qa knockout EAE mice had similar levels of microglial activation and identical clinical scores as WT EAE mice. C3 knockout mice were largely protected from EAE-induced synapse loss and microglial activation, results that correlated with a reduction in the EAE clinical score. Thus, pathologic expression and activation of the early complement pathway drives a portion of the synapse elimination observed in the EAE grey matter.

neuroscience↗