Bertrand, N. | bioRxiv Science

bioRxiv2026

Immunoglobulins are rapidly internalized by neurons after CNS injury and cleared through lysosomal degradation

Spinal cord injury (SCI) causes hemorrhage and blood-spinal cord barrier disruption, allowing blood-derived molecules to infiltrate the parenchyma. While immunoglobulins (Ig) are abundant plasma proteins, their distribution and cellular targets within the injured spinal cord remain poorly defined. Here, we show that circulating non-autoimmune immunoglobulins rapidly infiltrate the spinal cord after injury in mice and disseminate beyond the lesion core. IgG, IgM, and IgA accumulate within the parenchyma early post-injury, with IgG displaying the widest spatial distribution, reaching distant spinal segments within hours. Neurons are the predominant cell type internalizing immunoglobulins in the gray matter, whereas astrocytes exhibit moderate uptake in white matter. Intra-cisterna magna administration of fluorescent serum-derived IgG reveals that neurons and astrocytes internalize IgG under physiological conditions, independently of Fc receptor engagement. Although the neonatal Fc receptor (FcRn) has minimal impact on CNS IgG recycling, its genetic deletion significantly improves locomotor recovery after SCI. Both in vitro and in vivo, neurons clear IgG through lysosomal degradation. Following SCI, inhibition of lysosomal proteases with the clinically approved drug E64d increases CNS IgG retention without compromising locomotor recovery. These findings establish neurons as key targets of circulating immunoglobulins after CNS injury and reveal IgG uptake and clearance pathways that may be leveraged to improve therapeutic performance of monoclonal antibody treatments.

neuroscience↗

bioRxiv2019

MOG-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.

immunology↗