RESUMO
Modifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation, but it is unclear if the signatures from blood translate to the target tissue of interest-the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNA methylation from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936. Using these matched samples, we found that correlations between blood and brain DNA methylation scores for smoking, high-density lipoprotein cholesterol, alcohol and body mass index were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (r = 0.5, n = 14, P = 0.07) and smoking behaviour (r = 0.56, n = 9, P = 0.12). This was also the brain region which exhibited the largest correlations for DNA methylation at site cg05575921 - the single strongest correlate of smoking in blood-in relation to blood (r = 0.61, n = 14, P = 0.02) and smoking behaviour (r = -0.65, n = 9, P = 0.06). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggest that lifestyle-related DNA methylation is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available our results must be considered as preliminary and should therefore be used as a basis for further investigation.
RESUMO
Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.