A comprehensive guide for the care and use of laboratory animals

Neuroimmunology is one of the fastest-growing fields in the life sciences, and for good reason; it fills the gap between two principal systems of the organism, the nervous system and the immune system Although both systems affect each other through bidirectional interactions, we focus here on one direction - the effects of the nervous system on immunity First, we ask why is it beneficial to allow the nervous system any control over immunity? We evaluate the potential benefits to the immune system that arise by taking advantage of some of the brain's unique features, such as its capacity to integrate and synchronize physiological functions, its predictive capacity and its speed of response Second, we explore how the brain communicates with the peripheral immune system, with a focus on the endocrine, sympathetic, parasympathetic, sensory and meningeal lymphatic systems Finally, we examine where in the brain this immune information is processed and regulated We chart a partial map of brain regions that may be relevant for brain-immune system communication, our goal being to introduce a conceptual framework for formulating new hypotheses to study these interactions

Neuronal regulation of immunity: why, how and where?

Modern societies are experiencing an increasing trend of reduced sleep duration, with nocturnal sleeping time below the recommended ranges for health. Epidemiological and laboratory studies have demonstrated detrimental effects of sleep deprivation on health. Sleep exerts an immune-supportive function, promoting host defense against infection and inflammatory insults. Sleep deprivation has been associated with alterations of innate and adaptive immune parameters, leading to a chronic inflammatory state and an increased risk for infectious/inflammatory pathologies, including cardiometabolic, neoplastic, autoimmune and neurodegenerative diseases. Here, we review recent advancements on the immune responses to sleep deprivation as evidenced by experimental and epidemiological studies, the pathophysiology, and the role for the sleep deprivation-induced immune changes in increasing the risk for chronic diseases. Gaps in knowledge and methodological pitfalls still remain. Further understanding of the causal relationship between sleep deprivation and immune deregulation would help to identify individuals at risk for disease and to prevent adverse health outcomes.

Role of sleep deprivation in immune-related disease risk and outcomes.

Movement, behavioral, and neuropsychiatric disorders in children have been linked to infections and a group of anti-neuronal autoantibodies, implying dopamine receptor-mediated encephalitis within the basal ganglia The purpose of this study was to determine if anti-neuronal biomarkers, when used as a group, confirmed the acute disease in Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) IgG autoantibodies against four neuronal autoantigens (tubulin, lysoganglioside GM1, and dopamine receptors D1 and D2) were detected in SC sera (N=8), sera and/or cerebrospinal fluid (CSF) from two groups of PANDAS cases (N=25 first group and N=35 second group), sera from Tourette's syndrome (N=18), obsessive-compulsive disorder (N=25), attention deficit hyperactivity disorder (N=18), and healthy controls (N=28) by direct enzyme-linked immunosorbent assay (ELISA) IgG specific for neuronal autoantigens was significantly elevated during the acute symptomatic phase, and the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) pathway was significantly elevated in human neuronal cells Five assays confirmed the disease in SC and in two groups of children with PANDAS In 35 acute onset PANDAS patients, 32 sera (914%) were positive for one or more of the anti-neuronal autoantibodies compared with 9 of 28 healthy controls (321%, p<00001) Importantly, CSF of 32 (914%) PANDAS patients had one or more detectable anti-neuronal autoantibody titers and CaMKII activation Among healthy control subjects with elevated serum autoantibody titers for individual antigens, none (0%) were positively associated with elevated positive CaMKII activation, which was a striking contrast to the sera of PANDAS subjects, who had 76-89% positive association with elevated individual autoantibody titers and positive CaMKII activity At 6 months follow-up, symptoms improved for more than 80% of PANDAS subjects, and serum autoantibody titers also significantly decreased Results reported herein and previously published studies in our laboratory suggest the antibody biomarkers may be a useful adjunct to clinical diagnosis of SC, PANDAS, and related disorders and are the first known group of autoantibodies detecting dopamine receptor-mediated encephalitis in children

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Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections.

Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege of the immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences—good and bad—of these epigenetic memories and their implications for human health and disease. A Review on inflammatory memory in non-immune cells of different epithelia and neurons, and the potential mechanisms controlling these epigenetic memories and their implications in human health and disease. 

Inflammatory memory and tissue adaptation in sickness and in health

Insular cortex neurons encode and retrieve specific immune responses

Increasing evidence highlight the involvement of immune cells in brain activity and its dysfunction. The brain's immune compartment is a dynamic ensemble of cells that can fluctuate even in naive animals. However, the dynamics and factors that can affect the composition of immune cells in the naive brain are largely unknown. Here, we examined whether acute sleep deprivation can affect the brain's immune compartment (parenchyma, meninges, and choroid plexus). Using high-dimensional mass cytometry analysis, we broadly characterized the effects of short-term sleep deprivation on the immune composition in the mouse brain. We found that after 6 h of sleep deprivation, there was a significant increase in the abundance of B cells in the brain compartment. This effect can be accounted for, at least in part, by the elevated expression of the migration-related receptor, CXCR5, on B cells and its ligand, cxcl13, in the meninges following sleep deprivation. Thus, our study reveals that short-term sleep deprivation affects the brain's immune compartment, offering a new insight into how sleep disorders can affect brain function and potentially contribute to neurodegeneration and neuroinflammation.

Short-term sleep deprivation in mice induces B cell migration to the brain compartment

Increasing evidence indicates that the brain regulates peripheral immunity. Yet, it remains unclear whether and how the brain represents the state of the immune system. Here, we show that immune-related information is stored in the brain9s insular cortex (InsCtx). Using activity-dependent cell labeling in mice (FosTRAP), we captured neuronal ensembles in the InsCtx that were active under two different inflammatory conditions (DSS-induced colitis and Zymosan-induced peritonitis). Chemogenetic reactivation of these neuronal ensembles was sufficient to broadly retrieve the inflammatory state under which these neurons were captured. Thus, we show that the brain can encode and initiate specific immune responses, extending the classical concept of immunological memory to neuronal representations of immunity.

https://biorxiv.org/content/10.1101/2020.12.03.409813v1.full.pdf

Dorit Farfara

Papers

Insular cortex neurons encode and retrieve specific immune responses

Short-term sleep deprivation in mice induces B cell migration to the brain compartment

Remembering immunity: Neuronal ensembles in the insular cortex encode and retrieve specific immune responses