Genetics

This post covers Absinta and colleagues' 2021 Nature study, which used the paramagnetic rim MRI biomarker to direct single-nucleus RNA sequencing of 66,432 nuclei from the edge of chronic active MS lesions. It follows the imaging-informed sampling design, the two inflamed microglial subclusters and the inflamed astrocyte phenotype defined by transcriptional programme rather than lineage, the NicheNet ligand-target modelling that identifies T cells and plasma cells as the upstream regulators, the complement expression pattern linking microglia to astrocytes in both directions, and three separate genetic and pharmacological tests of C1q: complement risk variants genotyped against rim lesion burden in 1,272 patients, a microglia-specific C1q conditional knockout in mice, and antibody blockade, closing on the trial power analysis and the authors' own limitations.