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Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4 + T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4 + T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions. Multiple sclerosis (MS) lesions are initiated by the infiltration of T cells to the CNS. Here, Kendirli et al. use a genome-wide CRISPR screen in an MS model to define the molecules that regulate T cell entry to the CNS.

The etiology determines quality and extent of the immune response after udder infection (mastitis). Infections with Gram negative bacteria (e.g. Escherichia coli ) will quickly elicit strong inflammation of the udder, fully activate its immune defence via pathogen receptor driven activation of IκB/NF-κB signaling. This often eradicates the pathogen. In contrast, Gram-positive bacteria (e.g. Staphylococcus aureus ) will slowly elicit a much weaker inflammation and immune response, frequently resulting in chronic infections. However, it was unclear which immune regulatory pathways are specifically triggered by S . aureus causing this partial immune subversion. We therefore compared in first lactating cows the earliest (1–3 h) udder responses against infection with mastitis causing pathogens of either species. Global transcriptome profiling, bioinformatics analysis and experimental validation of key aspects revealed as S . aureus infection specific features the (i) failure to activating IκB/NF-κB signaling; (ii) activation of the wnt/β-catenin cascade resulting in active suppression of NF-κB signaling and (iii) rearrangement of the actin-cytoskeleton through modulating Rho GTPase regulated pathways. This facilitates invasion of pathogens into host cells. Hence, S . aureus mastitis is characterized by eliciting unbalanced immune suppression rather than inflammation and invasion of S . aureus into the epithelial cells of the host causing sustained infection.

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or ‘mixed’ priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell–induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6 + , and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease. Korn and colleagues demonstrate that the site of T cell priming (gut versus skin draining lymph nodes) dictates their effector phenotypes and homing to distal sites of immunopathology.

Whenever we are confronted with action opportunities in everyday life, e.g., when passing an opening, we rely on our ability to precisely estimate our own bodily capabilities in relation to the environmental conditions. So-called affordance judgments can be affected after brain damage. Previous studies with healthy adults showed that such judgments appeared to be trainable within one session. In the current study, we examined whether stroke patients with either right brain damage ( n = 30) or left brain damage ( n = 30) may similarly profit from training in an aperture task. Further, the role of neuropsychological deficits in trainability was investigated. In the administered task, stroke patients decided whether their hand would fit into a presented opening with varying horizontal width (Aperture Task). During one training session, patients were asked to try to fit their hand into the opening and received feedback on their decisions. We analyzed accuracy and the detection theory parameters perceptual sensitivity and judgment tendency. Both patients with right brain damage and patients with left brain damage showed improved performance during training as well as post training. High variability with differential profiles of trainability was revealed in these patients. Patients with impaired performance in a visuo-spatial or motor-cognitive task appeared to profit considerably from the target-driven action phase with feedback, but the performance increase in judgments did not last when the action was withdrawn. Future studies applying lesion analysis with a larger sample may shed further light on the dissociation in the trainability of affordance judgments observed in patients with versus without visuo-spatial or motor-cognitive deficits.

Am I still able to climb the ladder? Aging accompanies changes in physical constitution and a higher risk of injuries. At the same time, the judgment of action opportunities needs to be highly adaptive to the given task setting. We examined older adults’ ( n  = 40) judgment tendencies in four different tasks by use of a detection theory approach. The tasks’ setting differed in their boundaries’ proximity to the actor with either proximal (e.g., judging one’s hand fit into an opening) or distal boundaries (e.g., judging the reachability of a distant object). The older participants showed significantly more liberal judgments in tasks with distal boundaries. Body awareness and alertness were associated with the extent of judgment disparity between setting types. Subsequently, we compared a gender- and education-matched subsample of the group ( n  = 24) to a younger sample ( n  = 24). Older participants’ judgment tendencies were significantly more extreme, with stronger under- or overestimations depending on the type of setting. We discuss potential links between more extreme judgments in older adults and higher reliance on learned patterns. Future research is needed to further unravel these setting-dependent behavioral differences and the factors contributing to more extreme judgment tendencies with growing age.

In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell–mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2°) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood–brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long-lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets.

We present the unique case of a 60-year-old female with neurofibromatosis type 1 (NF1) who underwent laser interstitial thermal therapy (LITT) for metastatic malignant peripheral nerve sheath tumor (MPNST) of the brain. She presented to the emergency room complaining of one week of dysarthria and facial droop. An MRI of the brain demonstrated a homogeneously enhancing left frontal mass; although rare, given her history of pulmonary MPNST, brain invasion was considered likely. No generally accepted guidelines for the treatment of MPNST with cerebral metastases exist; however, LITT was chosen due to tumor morphology and proximity to eloquent brain structures. She did not experience any new or worsening neurological deficits post-operatively. Post-ablation MRI showed white matter edema surrounding the lesion, which is consistent with previously reported cases. This case illustrates the use of LITT for cytoreduction for rare brain metastases located near eloquent brain structures.

Purpose This study aims to conduct a systematic review of the literature comparing pre-operative, intraoperative, and post-operative characteristics between adolescent idiopathic scoliosis (AIS) and young adult idiopathic scoliosis (YAdIS) patients. Methods Following PRISMA guidelines, we conducted a search of the PubMed/Medline, EMBASE, and Cochrane Central databases to identify full-text articles in the English-language literature. Our inclusion criteria were studies that compared preoperative, intraoperative, and postoperative characteristics between AIS and YAdIS patients. We performed a meta-analysis reporting mean difference (MD) for continuous variables and Odds ratios (ORs) to assess differences in postoperative complications. Results Seven studies consisting of 1562 patients were included in the meta-analysis. The AIS group exhibited less intraoperative bleeding and shorter surgical procedures, with a mean difference between groups of 122.3 ml (95% CI 46.2–198.4, p  = 0.002) and 28.7 min (95% CI 6.5–50.8, p  = 0.01), respectively. Although the preoperative Cobb angle did not differ between groups ( p  = 0.65), patients with AIS achieved superior postoperative deformity correction, with a mean difference of 7.3% between groups, MD − 7.3 (95% CI − 9.7, − 4.8, p  < 0.00001), and lower postoperative Cobb angles of the major curve, MD 4.2 (95% CI 3.1, 5.3, p  < 0.00001). YAdIS patients were fused, on average, 0.2 more vertebral levels than AIS patients, MD 0.2 (95% CI 0.01, 0.5, p  = 0.04). AIS patients experienced a significantly shorter length of stay after the surgical procedure, with an MD of 0.8 days (95% CI 0.1, 1.6, p  = 0.02). No significant difference was found between groups in terms of complications ( p  = 0.19). Conclusions YAdIS should be regarded as a distinct surgical entity, characterized by increased bleeding, longer surgical duration, greater deformity correction challenges, and the need for fusion of additional vertebral levels compared to AIS. Surgeons should be mindful of these differences and discuss them with patients and their families, especially in cases where the correction of the AIS deformity is delayed and there is a high risk of progression after skeletal maturity. Further research is needed to explore alternative surgical techniques and enhance outcomes for YAdIS patients.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.

Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.