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At least 19 recordsLinked to original sources
PubMed2017

Novel Influences of IL-10 on CNS Inflammation Revealed by Integrated Analyses of Cytokine Networks and Microglial Morphology.

Coordinated interactions between cytokine signaling and morphological dynamics of microglial cells regulate neuroinflammation in CNS injury and disease. We found that pro-inflammatory cytokine gene expression in vivo showed a pronounced recovery following systemic LPS. We performed a novel multivariate analysis of microglial morphology and identified changes in specific morphological properties of microglia that matched the expression dynamics of pro-inflammatory cytokine TNFα. The adaptive recovery kinetics of TNFα expression and microglial soma size showed comparable profiles and dependence on anti-inflammatory cytokine IL-10 expression. The recovery of cytokine variations and microglial morphology responses to inflammation were negatively regulated by IL-10. Our novel morphological analysis of microglia is able to detect subtle changes and can be used widely. We implemented in silico simulations of cytokine network dynamics which showed-counter-intuitively, but in line with our experimental observations-that negative feedback from IL-10 was sufficient to impede the adaptive recovery of TNFα-mediated inflammation. Our integrative approach is a powerful tool to study changes in specific components of microglial morphology for insights into their functional states, in relation to cytokine network dynamics, during CNS injury and disease.

CNS inflammation↗
PubMed2026

Ruxolitinib Penetrates Blood Brain Barrier and Reduces the Cytokine Storm in Patients With Haemophagocytic Lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis (HLH), complicated by the involvement of the central nervous system (CNS), contributes to high morbidity and mortality with rapid development and violent cytokine storms in the CNS. Consequently, intrathecal dexamethasone and methotrexate must be administered in a timely manner to treat CNS inflammation. No effective pharmacotherapy targeting cytokine pathways is available to suppress cytokine storms that occur in the CNS. Ruxolitinib, a JAK1/2 inhibitor, has been recommended for the treatment of HLH by multiple guidelines. Conventional studies have reported that ruxolitinib cannot penetrate the blood brain barrier (BBB), thereby impeding the implementation of numerous therapies. Our team previously identified the efficacy of ruxolitinib in patients with CNS-HLH. Ten patients with secondary HLH (two with CNS involvement and eight without) received ruxolitinib, and BBB permeability was evaluated. Ruxolitinib exhibited BBB penetrability, ranging from 5.31% to 18.08%, suggesting its promising potential in CNS therapy.

Humans↗
PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Animals↗
PubMed1978

Determination of k/l immunoglobulin light chain ratios in CSF from patients with multiple sclerosis and other neurological diseases.

Using antisera against Bence-Jones protein, the concentration of light chains type k and l can be determined in CSF. The calculation of the ratio of type k to type I light chains in CSF represents a sensitive measure for the evaluation of immunological processes involving the CNS. Our results demonstrate that an increase k/l ratio is encountered in 48% of CSF specimen from multiple sclerosis (MS) patients, but also in 50% from patients with other inflammatory diseases involving the CNS, in contrast to only 18% from other neurological diseases. In none of the MS or inflammatory cases is the altered k/l ratio the only indicator of a CNS inflammation, most commonly it is accompanied by an overproportional CSF-IgG elevation (increased QG ratio), an increased cell count or both. For these reasons determination of CSF k/l ratios is helpful in the differentiation of MS and other neurological diseases, but not for the differentiation of other inflammatory CNS diseases from MS.

Central Nervous System Diseases↗
PubMed1977

Studies on the encephalitogenic effects of purified preparations of human and bovine oligodendrocytes.

Bulk-isolated human and bovine oligodendroglia, practically free from myelin, have been used in attempts to elicit an autoimmune response which has been compared with acute experimental allergic encephalomyelitis (EAE). For these experiments, a total of 20 Hartley guinea pigs, 33 Lewis rats and 16 rabbits have been studied. Animals were inoculated with a range of doses of purified preparations of both human and bovine oligodendroglial cells in complete Freund's adjuvant (CFA) and compared with others challenged with whole white matter in CFA. The latter animals all developed clinical and histological signs of experimental allergic encephalomyelitis (EAE) 2-3 weeks post-inoculation. In general, oligodendroglial cells were encephalitogenically less potent than white matter. Guinea pigs were the most susceptible to inoculations of oligodendroglia. In several given human oligodendroglia 14 days earlier, a paraparesis indistinguishable from conventional EAE was seen. Animals receiving bovine cells showed no clinical signs. Histologically, the CNS of afflicted guinea pigs displayed severe inflammation but, in contrast to conventional EAE in the same species, demyelination was rare in the small group of animals tested. After sensitization with oligodendroglia, rats displayed no clinical disease. Histologically, some given human cells had positive evidence of disease while bovine cells in others gave a mild response. Rabbits showed no clinical and very little histological disease. Although more extensive studies are needed to confirm the findings, from the animals studied it appears that (1) variation in response to inocula containing oligodendroglia exists among the species tested, (2) that human oligodendroglia are more potent immunologically than bovine cells, (3) that CNS lesions produced by these cells in guinea pigs, lack a strong demyelinative component and (4) a specific antigen might exist in oligodendrocytes which is distinct from myelin basic protein. The possible reasons underlying our findings are discussed.

Animals↗
PubMed1979

Early events in canine distemper demyelinating encephalomyelitis.

The early neuropathological development of demyelinating Canine Distemper Encephalomyelitis (CDE) was studied in SPF dogs. Neural tissues were examined up to 30 days post infection (PI). Three phases of activity were observed. The primary event (first observed 8 days PI) was a nonsuppurative encephalomyelitis associated with the initiation of central nervous system (CNS) infection by virus-laden lymphocytes. At 24 days PI noninflammatory demyelination occurred in well defined, subependymal foci. Cell fusion and syncytia formation accompanied this early demyelination. The third phase, found at day 30 PI in one dog showing signs of recovery, was a second wave of nonsuppurative inflammation. The initial encephalomyelitis was widely disseminated throughout the CNS but subsequent demyelination appeared to be initiated from within the ventricular system. Myelin was phagocytosed by endogeneous CNS macrophages often infected with Canine Distemper Virus (CDV). The possible importance of viral induced cell fusion as well as immune factors in the mechanism of demyelination are discussed.

Animals↗
PubMed2025

Exploring proteomic immunoprofiles: common neurological and immunological pathways in multiple sclerosis and type 1 diabetes mellitus.

BACKGROUND: Interest in the study of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) has increased because of their significant negative impact on the patient quality of life and the profound implications for the health care system. Although the clinical symptoms of T1DM differ from those of MS, such as pancreatic β-cell failure in T1DM and demyelination in the central nervous system (CNS) in MS, both pathologies are considered as autoimmune-related diseases with shared pathogenic pathways, which include autophagy, inflammation and degeneration, among others. Considering the challenges in obtaining pancreatic β-cells and CNS tissue from patients with T1DM and MS, respectively, it is fundamental to explore alternative methods for evaluating disease status. Proteomic analysis of peripheral blood mononuclear cells (PBMCs) is an ideal approach for identifying novel and potential biomarkers for both autoimmune diseases. METHODS: We conducted a proteomic analysis of PBMCs from patients with T1DM and relapsing remitting Multiple Sclerosis (herein forth MS) patients (n = 9 per condition), using a label-free quantitative proteomics approach. The patients were diagnosed following the American Diabetes Association (ADA) criteria for T1DM and McDonald criteria for MS respectively, and were aged over 18 years and more than 2 years from the onset respectively. RESULTS: A total of 2476 proteins were differentially expressed in PBMCs from patients with T1DM and MS patients compared with those form healthy controls (H). Predictive analysis highlighted 15 common proteins, up- or downregulated in PBMCs from patients with T1DM and MS patients vs. healthy controls, involved in the immune system activity (BTF3, TTR, CD59, CSTB), diseases of the neuronal system (TTR), signal transduction (STMN1, LAMTOR5), metabolism of nucleotides (RPS21), proteins (TTR, ENAM, CD59, RPS21, SRP9) and RNA (SRSF10, RPS21). In addition, this study revealed both shared and distinct molecular patterns between the two conditions. CONCLUSIONS: Compared with H, patients with T1DM and MS presented a specific expression pattern of common proteins has been identified. This pattern underscores the shared mechanisms involved in their immune responses and neurological complications, alongside dysregulation of the autophagy pathway. Notably, CSTB has emerged as a differential biomarker, distinguishing between these two autoimmune diseases.

Humans↗
PubMed1975

Inhibition of release of prostaglandins as an explanation of some of the actions of anti-inflammatory corticosteroids.

Corticosteroids as well as non-steroid anti-inflammatory drugs inhibit the prostaglandin-mediated vasodilatation accompanying lipolysis in subcutaneous fat. Whereas the non-steroids produce their effect by inhibition of prostaglandin synthesis, however, corticosteroids inhibit their release. This mechanism may be the basis of some actions of corticosteroids in inflammation, in the gastric mucosa and in the CNS.

Adipose Tissue↗
PubMed2025

Spatiotemporal profile of an optimal host response to virus infection in the primate central nervous system.

Viral infections of the central nervous system (CNS) are a major cause of morbidity largely due to lack of prevention and inadequate treatments. While mortality from viral CNS infections is significant, nearly two thirds of the patients survive. Thus, it is important to understand how the human CNS can successfully control virus infection and recover. Since it is not possible to study the human CNS throughout the course of viral infection at the cellular level, here we analyzed a non-lethal viral infection in the CNS of nonhuman primates (NHPs). We inoculated NHPs intracerebrally with a high dose of La Crosse virus (LACV), a bunyavirus that can infect neurons and cause encephalitis primarily in children, but with a very low (≤ 1%) mortality rate. To profile the CNS response to LACV infection, we used an integrative approach that was based on comprehensive analyses of (i) spatiotemporal dynamics of virus replication, (ii) identification of types of infected neurons, (iii) spatiotemporal transcriptomics, and (iv) morphological and functional changes in CNS intrinsic and extrinsic cells. We identified the location, timing, and functional repertoire of optimal transcriptional and translational regulation of the primate CNS in response to virus infection of neurons. These CNS responses involved a well-coordinated spatiotemporal interplay between astrocytes, lymphocytes, microglia, and CNS-border macrophages. Our findings suggest a multifaceted program governing an optimal CNS response to virus infection with specific events coordinated in space and time. This allowed the CNS to successfully control the infection by rapidly clearing the virus from infected neurons, mitigate damage to neurophysiology, activate and terminate immune responses in a timely manner, resolve inflammation, restore homeostasis, and initiate tissue repair. An increased understanding of these processes may provide new therapeutic opportunities to improve outcomes of viral CNS diseases in humans.

Animals↗
PubMed1977

Infection of the central nervous system produced by mixtures of defective-interfering particles and wild-type vesicular stomatitis virus in mice.

In contrast to wild-type vesicular stomatitis virus (VSV), which produces a fulminant illness with death in two to three days, mixtures of homologous defective autointerfering (DI) particles and wild-type VSV (DI-wild-type VSV) injected intracerebrally into mice resulted in a slowly progressive disease of the central nervous system (CNS). In fact, mice inoculated with DI-wild-type VSV survived up to nine days after infection and displayed striking paralysis of the hind limbs. The slowly progressive CNS disease accompanying infection with DI-wild-type VSV was characterized by production of only 1% of the amount of VSV recovered when wild-type VSV was injected alone. Morphologically, mice infected with DI-wild-type VSV displayed a spectrum of pathologic changes not encountered with disease due to wild-type VSV alone. These changes included the presence of parenchymal necrosis in the spinal cord, changes in and secondary demyelination of the white matter, striking leptomeningeal inflammation, and spongiform changes in the gray matter of the neuropil. Since these pathological features are not found when CNS disease results from either wild-type VSV or temperature-sensitive (ts) mutants of VSV, it is suggested that CNS infection with ts VSV is not mediated principally by production of DI particles. Furthermore, in vivo CNS infection with DI-wild-type VSV did not appear to be mediated by production of ts VSV mutants.

Animals↗
PubMed1975

An immunopathologic component in experimental togavirus encephalitis.

The effects of immune manipulation upon survival and histopathology in two experimental group B togavirus encephalitides were studied in inbred mice. The median survival time 8 days after intracerebral injection of Langat virus increased to 10 days with an immunosuppressive course of cyclophosphamide, with concomitant reduction in the inflammatory response. Adoptive immunization with immune lymphoid cells or serum also tended to prolong Langat virus survival while increasing inflammation. Survival following intracerebral West Nile virus (7 days) was unaffected by immunosuppression or adoptive transfer, although suppression was associated with less severe CNS lesions, and immune serum with less necrosis. These findings indicate that the immune response may be both protective and pathology-inducing in some togarvirus encephalitides. The differences in host response to these two related agents suggest caution in generalizing about the role of the immune response in viral infections.

Animals↗
PubMed2026

Mutational signatures in blood-brain barrier: mechanisms, computational insights, and clinical applications in precision oncology.

The blood - brain barrier (BBB) plays a central role in maintaining central nervous system (CNS) homeostasis, and its disruption is a defining feature of malignant brain tumors such as glioblastoma. Emerging evidence indicates that BBB dysfunction not only alters the tumor microenvironment but also shapes the mutational processes that drive genomic instability in CNS malignancies. This review synthesizes current understanding of the biological mechanisms linking BBB breakdown with distinct mutational signatures, including those arising from oxidative stress, hypoxia-induced replication stress, lipid peroxidation, inflammation, and metabolic reprogramming. Advances in next-generation sequencing, coupled with computational tools such as non-negative matrix factorization, Bayesian modeling, and deep learning, have enabled precise extraction of these signatures and their integration with multi-omics data. Clinically, BBB-associated mutational signatures offer significant promise for therapeutic stratification, prediction of treatment response, and noninvasive monitoring through cerebrospinal fluid - derived circulating tumor DNA. Despite these advances, challenges persist due to limited tissue accessibility, low-yield CSF samples, incomplete mechanistic models, and the lack of CNS-specific analytical frameworks. A deeper understanding of BBB-driven mutational processes, supported by improved computational approaches and integrative datasets, holds potential to advance precision oncology in neuro-oncology.

Humans↗
PubMed2025

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

Journal Article↗
PubMed2025

The RORγt ligand-binding domain controls the pathogenicity of IL-17A+ T cells differently in autoimmune diseases of the skin and CNS.

The transcription factor RORγt orchestrates Th17 lineage differentiation, thymic T cell development, and the pathogenesis of several autoimmune disorders. Lipid ligands are required for appropriate regulation of RORγt activity, but it is unclear to what extent lipid recognition controls RORγt function in vivo. Here, we show that the mutation of RORγt alanine-304 in the ligand-binding domain (LBD) to isoleucine (A304I) abrogates lipid-dependent Th17 differentiation and selectively ameliorates γδT17 cell-mediated psoriatic skin inflammation. In contrast, there is no improvement in experimental autoimmune encephalomyelitis in RORγtA304I mice. Consistent with this, the expression of genes characteristic of Th17 cells decreases in RORγtA304I mice, along with a compensatory increase of genes characteristic of Th1-like Th17 cells with pathogenic signatures. Thus, RORγt alanine-304 in the LBD is indispensable for generating γδT17 and conventional Th17 cells and for the suppression of the Th1-like Th17 pathogenic population, which decouples the pathogenicity of skin and CNS autoimmune diseases.

Animals↗
PubMed1977

The ultrastructure of early visna lesions.

The ultrastructure of visna, a slowly progressive menigo-encephalomyelitis of sheep, was studied in animals sacrificed one month after intracerebral inoculation of visna virus. The major pathological changes, representative of those seen during the first year after infection, consist of inflammation and minor focal destructive lesions of grey and white matter. The inflammatory infiltrates, both subependymal and perivascular as well as of the choroid plexus, were composed mainly of lymphocytes and macrophages with varying numbers of plasma cells. The demyelination seen was of the secondary or Wallerian type. There was no evidence of primary demyelination. Visna virions were not seen in any of the CNS material studied. The ultrastructural findings are compatible with the view that lesions in visna may be induced by a cell-mediated immune response. However, changes characteristic of an autoimmune reaction to myelin antigens were not observed.

Animals↗
PubMed1976

Immuneglobulin investigations in inflammatory diseases.

1. The agar electrophoresis of the cerebrospinal fluid and the quantitative immune globulin determination contribute essentially to an assessment of the immunity state in inflammatory diseases of the CNS. 2. It is necessary to distinguish protein augmentation due to brain-barrier disturbances (accompanying proteinosis of the cerebrospinal fluid), which we find in metabolic and traumatic diseases, from a genuine increase in cerebrospinal fluid protein. 3. Autochthonous formation of cerebrospinal fluid protein can be demonstrated by means of quantitative IgG, IgA and gamma3-globulin determination.

Blood-Brain Barrier↗