Biology subjects

Lassmann, H.

Publications and source records attributed to Lassmann, H..

4 recordsLinked to original sources

bioRxiv2026

Age-related loss of brain demyelinating and remyelinating potential is overcome by microglia renewal

Multiple sclerosis (MS) is an immune-mediated demyelinating disease, with progressive neurodegeneration that is refractory to current therapies. Here, we identify microglia aging as a major factor responsible for age-related loss of beneficial demyelinating and remyelinating brain functions. Brain transcriptomics and in situ spatial gene transcription analysis revealed significant oligodendrocyte loss in both young and aged mice during cuprizone-induced experimental demyelination, but impaired microglial activation in aged mice. Age-related defects in microglial activation were associated with reduced clearance of dead myelin and accumulation of lipid droplets, and impaired remyelination, implying exhaustion of microglial function in the aged mouse brain. Transcriptomic analysis of human brain samples from MS donors with matched disease course and severity and with chronic active and inactive lesions, validated that microglial activation is strongly reduced with increasing age. To investigate microglial responses after repeated demyelinating insults and their direct impact on myelin integrity, we established an experimental model of repeated demyelinating episodes in young and aged mice to recapitulate MS features. Notably, aged mice developed a progressive neuroinflammatory response following sequential demyelinating episodes, in contrast to the alternating cycles of demyelination and remyelination reminiscent of relapsing-remitting MS that were observed in young mice. Microglia depletion and repopulation using a CSF1R antagonist recovered demyelination-remyelination capacity in aged mice. The results indicate that microglia aging is a major determinant in the pathogenesis of progressive MS, and that microglia replacement represents a promising therapeutic approach.

immunology↗

bioRxiv2025

Myelin antigen-specific effector CD8+ T cells induce chronic CNS autoimmunity in a CD4+ T cell-dependent manner.

Both CD4+ and CD8+ T cells play critical roles in the immunopathogenesis of multiple sclerosis (MS). 1C6 T cell receptor transgenic (TcR-Tg) mice on the nonobese diabetic (NOD) background have a MOG[35-55]-specific, MHC class II-restricted, TcR that selects for both CD4+ and CD8+ T cells. Adoptive transfer of 1C6 CD4+ T helper 17 (Th17) cells can induce experimental autoimmune encephalomyelitis (EAE) with a progressive disease course. In the current study, we assessed the function and pathogenicity of 1C6 CD8+ T cells. We found that they proliferated and produced inflammatory cytokines in response to MOG[35-55] peptide under both T cytotoxic 1 (Tc1) and Tc17 differentiation conditions, albeit with reduced expansion relative to their Th1 or Th17 counterparts. Both 1C6 Tc1 and Tc17 cells were able to induce EAE upon adoptive transfer to NOD.Scid mice. Intriguingly, we noted in vivo expansion of CD4+ T cells in the spleen and CNS of NOD.Scid recipients as well as in lymphocyte-sufficient animals, despite 1C6 Tc cells being purified on CD8 expression prior to transfer. Furthermore, 1C6 Tc17 cells expressed ThPOK, a master differentiation factor for CD4+ T cells. Finally, anti-CD4+ T cell blockade abrogated CD8+ T cell infiltration of the CNS and disease induction in Tc17 recipient mice. Our data provide insight into the interplay of CD4+ and CD8+ T cells in CNS autoimmunity.

immunology↗

bioRxiv2021

The role of complex IV activity in the axonal response of mitochondria to demyelination in experimental disease models of multiple sclerosis

Axon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS and experimental disease models is most frequently detected in acutely demyelinating regions. Furthermore, acute axonal injury consistently correlates with the extent of inflammatory demyelination. Following lysolecithin-induced demyelination, we recently reported a compensatory response in neurons, where mitochondria move from the cell body to the acutely demyelinated axon and increase the mitochondrial content. We termed this energetics phenomenon, that is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (COX) of axons and related these to axonal injury in nine different experimental disease models. We consistently found ARMD in all experimental disease models. However, the increase in mitochondrial content within demyelinated axons was not always accompanied by a proportionate increase in COX activity, particularly in experimental autoimmune encephalomyelitis (EAE). Axonal COX activity inversely correlated with the extent of axonal injury in experimental disease models. Our findings indicate that ARMD is a consistent and prominent finding and emphasises the need to preserve axonal mitochondrial COX activity in inflammatory demyelination, paving the way for the development of novel neuroprotective therapies.

neuroscience↗

bioRxiv2019

Male sex exacerbates the plasticity and pathogenicity of Th17 cells in a chronic model of CNS autoimmunity.

Sex differences in the incidence and severity of multiple sclerosis (MS) have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive and debilitating disease remain poorly defined. Using an T cell adoptive transfer model of chronic EAE, we find that male Th17 cells induced disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produced the heterodox cytokine IFN{gamma}, a hallmark of pathogenic Th17 responses. Intriguingly, sex chromosomal complement, and not hormones, were responsible for the increased pathogenicity of male Th17 cells and an X-linked immune regulator, Jarid1c, was downregulated in both pathogenic male Th17 and CD4+ T cells from men with MS. Together, our data indicate that male sex critical regulates Th17 cell plasticity and pathogenicity via sex chromosomal complement.

immunology↗