USP18

The study offers insights into the genetic and epigenetic mechanisms underlying depression through combined mouse and human studies SEOUL, South Korea, Sept. 7, 2023 /PRNewswire/ -- Depression is a common mental health problem that affects people across demographics. Scientists have long known that there may be a genetic component that confers predisposition to depression, but the specific underlying mechanisms have remained elusive. Growing evidence indicates that inflammation and immune-related processes in the brain could play a significant role in depression. A team of researchers including Dr. Se Jin Jeon from Sahmyook University conducted a study to gain deeper insights into these mechanisms. Their study was made available online on 26 June 2023 and was published in October 2023 in Volume 113 of the journal Brain, Behavior, and Immunity. The team employed a mouse model to measure their immobility, a behavior linked to depression, using a forced swim test. Through transcriptional profiling, they found that 141 genes significantly correlated with immobility, with 111 upregulated and 30 downregulated. "We found that these genes were related to the interferon pathway, which is involved in the regulation of inflammation in the body," explains Dr. Jeon enthusiastically. The researchers further validated their findings through real-time PCR, confirming that immune-related genes were expressed at higher levels in mice with higher immobility scores. Additionally, they induced immune responses using an intracerebroventricular injection, which resulted in increased immobility and microglial activation, providing further evidence regarding the link between immune response genes and indicators of depression. Leveraging the findings of murine study, the team aimed to understand the link between DNA methylation, brain structural changes, and depression in humans. For this, 350 patients with major depressive disorder (MDD) and 161 healthy controls were examined. DNA methylation analysis—a technique used to study the epigenetic modifications on DNA—was conducted on the genes USP18 and IFI44, since these were found to be associated with depression-like behavior in mice and were involved in interferon signaling pathways. The researchers found differences in methylation patterns between patients with MDD and controls. In patients with MDD, DNA methylation of a specific region in the USP18 gene correlated with reduced thickness in several brain regions associated with emotions and cognition. Meanwhile, in the control group, DNA methylation of another region in USP18 correlated with increased thickness in brain regions linked to vision and sensory processing. These findings link not only the expression of immune-related genes, but also their epigenetic status and their effect on brain structure, with depression. "In summary, we found elevated expression of inflammation-related genes in patients with depression compared to controls. This can increase inflammatory conditions in the body, including the brain, and ultimately lead to structural abnormalities in brain regions involved in emotional regulation, which may contribute to the development of depression," concludes Dr. Jeon. Thus, with the potential to serve as viable treatment targets, these immune genes offer an alternative approach or supplement to the currently approved pharmacologic treatments. Reference Title of original paper: Correlation between immune-related genes and depression-like features in an animal model and in humans Journal: Brain, Behavior, and Immunity DOI: About the institute Website: ​ View original content to download multimedia: SOURCE Sahmyook University

Individuals with Down syndrome have less-frequent viral infections, but when present, these infections lead to more severe disease. New findings show that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I levels lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack. Individuals with Down syndrome have less-frequent viral infections, but when present, these infections lead to more severe disease. New findings publishing on October 14 in the journal Immunity show that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I levels lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack. "Usually too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections," says senior study author Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai. "What is unusual is that individuals with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts. Here, we discovered how this is possible." Down syndrome is typically caused by triplication of chromosome 21. This syndrome affects multiple organ systems, causing a mixed clinical presentation that includes intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and Alzheimer's disease in older individuals. Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased rates of hospitalization of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infections. While people with Down syndrome show clear signs of immune disturbance, it has yet to be elucidated how a supernumerary chromosome 21 leads to dysregulation of viral defenses. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from individuals with and without Down syndrome, at both the mRNA and protein levels. They focused on the potent antiviral cytokine IFN-I receptor subunits IFNAR1 and IFNAR2, which are located on chromosome 21. The researchers found that increased IFNAR2 expression was sufficient for the hypersensitivity to IFN-I observed in Down syndrome, independent of trisomy 21. But subsequently, the hyper-active IFN-I signaling cascade triggered excessive negative feedback via a protein called USP18, which is a potent IFNAR negative regulator. This process, in turn, suppressed further responses to IFN-I and antiviral responses. Taken together, the findings unveil oscillations of hyper- and hypo-responses to IFN-I in Down syndrome, predisposing to both lower incidence of viral disease and increased infection-related morbidity and mortality. "We have a lot more to do to completely understand the complexities of the immune system in Down syndrome," says first author Louise Malle of the Icahn School of Medicine at Mount Sinai. "We have here, in part, explained the susceptibility to severe viral disease, but this is only the tip of the iceberg."