Buitrago-Pocasangre, N. | bioRxiv Science

bioRxiv2025

Inflamed Microglia like Macrophages in the Central Nervous System of Prodromal Parkinson's Disease

We hypothesized that prodromal Parkinsons Disease (PD), characterized by REM Sleep Behavior Disorder and hyposmia, is an inflammatory disorder initiated in the gut that evolves into a neurodegenerative process manifest as classical PD. To test this hypothesis, we performed single-cell RNAseq analysis of cerebrospinal fluid (CSF) and blood from 118 individuals, comparing healthy subjects with prodromal PD and manifest PD to patients with the central nervous system (CNS) autoimmune disease, multiple sclerosis (MS). Surprisingly, we identified increased numbers of immune cells in the CSF of patients with prodromal PD. Single-cell RNA sequencing revealed increases in CSF-specific microglia-like macrophages with enhanced JAK-STAT and TNF signaling signatures in prodromal PD. CSF macrophages exhibited similar transcriptional profiles to dural macrophages and gut muscularis macrophages from -synuclein-expressing PD model mice. Finally, shared memory T cell clones were found in humans between gut and CSF T cells. These findings uncover a myeloid-mediated TNF inflammatory process in the CNS of patients with prodromal PD, with an immunological linkage between the gut and the CNS.

immunology↗

bioRxiv2024

Systematic Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven "in vivo perturbation" modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency post-B cell depletion. This was accompanied by increases in TNF messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNF treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4+ T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

immunology↗