Alcohol induces concentration-dependent transcriptomic changes in oligodendrocytes.

Oligodendrocytes are a key cell type within the central nervous system (CNS) that generate the myelin sheath covering axons, enabling fast propagation of neuronal signals. Alcohol consumption is known to affect oligodendrocytes and white matter in the CNS. However, most studies have focused on fetal alcohol spectrum disorder and severe alcohol use disorder. Additionally, the impact of alcohol dosage on oligodendrocytes has not been previously investigated. In this study, we evaluated transcriptomic changes in C57BL6/J cultured mature oligodendrocytes following exposure to moderate and high concentrations of alcohol. We found that high concentrations of alcohol elicited gene expression changes across a wide range of biological pathways, including myelination, protein translation, integrin signaling, cell cycle regulation, and inflammation. Further, our results demonstrate that transcriptomic changes are indeed dependent on alcohol concentration, with moderate and high concentrations of alcohol provoking distinct gene expression profiles. In conclusion, our study demonstrates that alcohol-induced transcriptomic changes in oligodendrocytes are concentration-dependent and may have critical downstream impacts on myelin production. Targeting alcohol-induced changes in cell cycle regulation, integrin signaling, inflammation, or protein translation regulation may uncover mechanisms for modulating myelin production or inhibition. Furthermore, gaining a deeper understanding of alcohol's effects on oligodendrocyte demyelination and remyelination could help uncover therapeutic pathways that can be utilized independent of alcohol to aid in remyelinating drug design.

Longitudinal COVID-19 immune trajectories in patients with neurological autoimmunity on anti-CD20 therapy.

BACKGROUND AND OBJECTIVES: During the COVID-19 pandemic, B cell depleting therapies pose a clinical concern for patients with neuroimmune conditions, as patients may not mount a sufficient immune response to SARS-CoV-2 infection and vaccinations. Studies to-date have reported conflicting results on the degree of antibody production post-SARS-CoV-2 infection and vaccinations in B cell depleted patients, focusing primarily on short-term immune profiling. Our objective was to follow longitudinal immune responses in COVID-19 B cell depleted patients with neuroimmune disorders post-COVID-19 and SARS-CoV-2-vaccination. METHODS: CD20 B cell depleted autoimmune patients and age/sex-matched controls positive for SARS-CoV-2 were recruited at Dell Medical School, UT Austin between 2020 and 2021, followed prospectively for 12 months and evaluated at multiple time points for spike S1 receptor binding domain (RBD) antibody titers, B and T cell composition, and frequency of T cells specific for SARS-CoV-2 antigens. RESULTS: Immune responses post-SARS-CoV-2 infection and vaccination were evaluated in a cohort of COVID-19 B cell depleted neuroimmune patients (n = 5), COVID-19 non-B cell depleted autoimmune patients (n = 15), COVID-19 immunocompetent patients (n = 117), and healthy controls (n = 6) for a total of 259 samples in 137 participants. 4/5 B cell-depleted patients developed detectable anti-spike RBD antibodies, which were boosted by vaccination in 2 patients. While spike RBD antibodies were associated with presence of CD20+ B cells, very few B cells were required. In contrast, patients whose B cell compartment primarily consisted of CD19+CD20- Bcells during acute COVID-19 disease or vaccination did not seroconvert. Interestingly, circulating Bcells in B cell depleted patients were significantly CD38high with co-expression of CD24 and CD27, indicating that B cell depletion may impact B cell activation patterns. Additionally, all B cell depleted patients mounted a sustained T cell response to SARS-CoV-2 antigens, regardless of seroconversion. Specifically, all patients developed naïve, central memory, effector memory, and effector memory RA+ T cells, suggesting intact T cell memory conversion in B cell depleted patients compared to controls. DISCUSSION: We present the longest COVID-19 immune profiling analysis to date in B cell depleted patients, demonstrating that both humoral and cellular immune responses can be generated and sustained up to 12 months post SARS-CoV-2 infection and vaccination. Notably, failure to establish humoral immunity did not result in severe disease. We also highlight specific T and B cell signatures that could be used as clinical biomarkers to advise patients on timing of SARS-CoV-2 vaccinations.

Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: To determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD. METHODS: We combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro. RESULTS: Multiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01). CONCLUSIONS: The composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.