Regulatory T cells (Treg cells) maintain peripheral immune tolerance but display considerable plasticity in peripheral tissues. The molecular mechanisms governing their function and plasticity, particularly under inflammatory conditions, remain poorly defined. Here, we identify the NF-κB-associated transcriptional cofactor IκBζ as a critical regulator of Treg cell plasticity and function. Enforced expression of IκBζ in Treg cells triggered the excessive expansion of functionally impaired Treg cells, resulting in lymphadenopathy, splenomegaly, and systemic type 2 inflammation, most prominently in the lung. Mechanistically, IκBζ modified BATF expression and function, thereby driving the cell-intrinsic production of Th2-associated cytokines by Treg cells. Conversely, Treg-specific deletion of IκBζ constrained IL-33-mediated expansion of tissue Treg cells and surprisingly attenuated type 2 inflammation. Thus, IκBζ functions as a molecular switch that reprograms regulatory T cells into Th2-like Treg cells, thereby perturbing peripheral immune tolerance.

Neurosyphilis is a severe disease which can manifest with various clinical signs. The diagnosis can be challenging. Patients with positive syphilis serology and neurological or psychiatric symptoms should undergo cerebrospinal fluid (CSF) examination. The definite diagnosis is based on CSF findings, including evidence of inflammation, intrathecal production of treponemal antibodies (plus reactive non-treponema specific tests in the CSF). However, these criteria are not always fulfilled and a diagnosis of probable neurosyphilis may be established using less stringent diagnostic criteria. Treatment with intravenous penicillin or ceftriaxone is recommended for neurosyphilis. Here, a short version of the recommendations of the German guidelines on neurosyphilis that were published in 2026 is presented.

When immune cells interact, they frequently exchange membrane-bound antigens. Our evolving understanding of these processes challenges the cellular specificity of lineage markers and therapeutic monoclonal antibodies. By using mouse and human B-T cell co-cultures, we report that CD19, an assumingly exclusive B cell marker, is transferred via trogocytosis when B cells activate T cells. In a B cell-driven model of experimental autoimmune encephalomyelitis, CD19+ T cells expand and show enhanced features of activation, differentiation, and encephalitogenic potential ex vivo. Additionally, co-transfer of CD19 and functional IgM from B cells results in the gain of B cell function by T cells. In patients with chronic central nervous system (CNS) demyelination, CD19+ T cells display a pro-inflammatory phenotype and are concomitantly depleted by inebilizumab, an approved anti-CD19 antibody, which raises important considerations for the therapeutic use of monoclonal antibodies overall. Finally, we report that myeloid cells acquire CD19 and functional IgM after phagocytosis of apoptotic B cells and thereby gain functional B cell properties. These findings highlight the commonness of membrane and antigen-transfer between cells, resulting in transmission of cellular function.

BACKGROUND:The greatest impact on the burden of CNS infections resulted from preventive measures, mainly vaccination programs, that have decreased the incidence of many CNS infections significantly. Here, we highlight the main cornerstones of vaccination programs on bacterial and viral CNS infections and point at future chances of upcoming vaccines. MAIN BODY:Vaccination programs have significantly decreased the number of cases due to Haemophilus influenzae type B and Neisseria meningitidis. For pneumococcal meningitis, new vaccines that prevent neuroinvasive serotypes have the potential to decrease numbers in the future. Whereas a vaccine is available for tick-borne encephalitis, prevention of neuroborreliosis is limited to contact precautions. However, vaccination rates against tick-borne encephalitis remain too low in many countries. Another neurotropic virus that can be prevented effectively by vaccination is varicella zoster virus (VZV). Interestingly, vaccination against VZV also seems to reduce the risk of dementia as recently shown. While vaccination is important in general, patients with immunosuppression benefit most from vaccinations. Finally, recent measles outbreaks impressively underline the efficacy of vaccination programs and demonstrate what can happens if vaccination rates decrease. CONCLUSION:Vaccination programs have shown to be effective in reducing the burden of CNS infections. As vaccination rates are generally still too low and as new vaccines are coming up, it is obvious that the potential of vaccines to prevent CNS infections is not maxed out yet.

Pro-inflammatory T-helper 17 (Th17) cells are of vital importance in human autoimmune diseases such as multiple sclerosis (MS). Due to differentiation and functional plasticity, Th17 cells are able to produce a variety of pro-inflammatory cytokines such as interleukin (IL)-17A, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), and modulation of Th17 cell activities represents a desirable tool for disease-modifying treatment. Here, we aimed to understand the role of the surface molecule CD5 and its intracellular interaction partner casein kinase 2 (CK2) in human Th17 effector function as well as their role in multiple sclerosis. We performed targeted single-cell RNA sequencing from CSF obtained from people with multiple sclerosis and non-inflammatory neurological diseases, and high-sensitivity proteomic analysis of serum and CSF from 114 people with multiple sclerosis by using a proximity extension assay (PEA) together with functional investigations on CD4+ memory T cells differentiated into a Th17-polarized phenotype. Blockade of CD5 reduced the production of IL-17A, IFN-γ and GM-CSF by Th17-polarized cells without affecting proliferation. In comparison, blockade of its intracellular interaction partner CK2 exerted partly similar effects with a decrease in IL-17A and GM-CSF production but also impaired T cell proliferation. Both blocking agents resulted in a decreased phosphorylation of the downstream signalling molecule STAT3. The CD5 targeting treatment was able to abolish cytotoxic effects caused by Th17-polarized cells. Importantly, transcriptomic and proteomic analysis showed that CD5 expression correlates with an inflammatory immune profile in multiple sclerosis in serum as well as CSF. Our study highlights the importance of the CD5-CK2-STAT3 signalling axis for inflammatory responses of human Th17-polarized cells. Since in humans CD5 expression correlates with inflammation and cellular injury, targeting the CD5 signalling pathway provides future therapeutic opportunities for-among other diseases-multiple sclerosis.

ABSTRACT:The lysine acetyltransferase (KAT) activity of EP300 lysine acetyltransferase (p300)/CREB-binding protein (CREBBP) has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as histone H3 lysine 27 acetylation (H3K27ac), a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated transcription factors (TFs)/coregulators (inferred from chromatin pulldown proteomics, acetyl proteomics, and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP, and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at interferon regulatory factor (IRF) motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation, and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro, and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.

IntroductionIn pneumococcal meningitis, a massive inflammatory reaction is triggered by the host immune system, leading to neurological damage. However, the mechanisms underlying the initiation and regulation of this response, particularly by resident cells, remain incompletely understood. Despite their strategic localization at the host-pathogen interface, the role of meningeal fibroblasts in pneumococcal meningitis remains poorly defined. This study therefore aimed to investigate their contribution to the immune response against Streptococcus pneumoniae.MethodsPrimary meningeal fibroblasts were exposed to Streptococcus pneumoniae, and their cytokine responses were quantified in monoculture and in co-culture with macrophages using both direct contact and indirect systems.ResultsMeningeal fibroblasts responded to pneumococcal challenge by producing a selective set of cytokines. This activation occurred independently of Toll-like receptor signaling. In co-culture, macrophages markedly enhanced fibroblast-derived cytokine production (including IL-6, IL-8, and CCL2) in both direct and indirect systems, indicating a robust amplification of the immune response. Mechanically, this effect was driven by macrophage-derived IL-1β, which we identified as the key factor of meningeal fibroblast activation.DiscussionThese findings establish an IL-1β-driven macrophage-fibroblast axis as a key driver of inflammatory amplification in pneumococcal central nervous system infection and suggest a tractable target for therapeutic intervention.

Natural killer and CD8+ T cells are critical in the elimination of blood-borne viruses such as cytomegalovirus (CMV); however, the role of B cells in this process is less clear. Here, using a murine CMV (MCMV) infection model, we demonstrated that B-cell-deficient mice mounted a weaker primary virus-specific CD8+ T-cell response than their wild-type counterparts did, which was associated with increased viral transcription. Notably, we found that the contribution of B cells to the CD8+ T-cell-mediated antiviral response was not associated with their ability to generate antibodies but with their ability to sustain Langerin+ type 1 conventional dendritic cells (cDC1s), a dendritic cell (DC) subset known for being involved in viral and bacterial clearance in the marginal zone of the spleen. Furthermore, we found that the presence of Langerin+ cDC1s is dependent on B cells expressing lymphotoxin (LTβ) to maintain CD169+ marginal metallophilic macrophages (MMMs). We further discovered, via ligand‒receptor interaction analyses, that the communication between MMMs and Langerin+ cDC1s was mediated via the VCAM1–ITGA4/ITGB1 interaction. Thus, our data reveal that B cells regulate the development of MMMs in the spleen via LTβ expression and consequently sustain Langerin+ cDC1 homeostasis for effective initiation of an antiviral CD8+ T-cell response. Overall, our study offers a new perspective on how B cells maintain the homeostasis of antigen-presenting cells in the splenic marginal zone and thus indirectly affect the virus-specific CD8+ T-cell response, which could be extended to other infectious and autoimmune diseases as well as tumors.

A specific and accurate blood test for acute brain injury could help monitor infarct growth in ischemic stroke and serve as a surrogate end point in clinical trials. Using a single-molecule detection assay, we assessed plasma brain-derived tau (BD-tau), a marker selectively quantifying tau protein from the central nervous system, in a prospective cohort of 502 patients with acute ischemic stroke with serial blood sampling from admission to day 7. Higher BD-tau concentrations at admission were associated with more extensive early brain injury on computed tomography and predicted larger final infarct volumes. BD-tau increases from admission to day 2 were related to infarct growth. BD-tau concentrations rose until day 7 and were higher in patients with secondary events, including recurrent stroke. After thrombectomy, the rise of BD-tau was smaller in patients with complete versus incomplete recanalization. BD-tau outperformed other blood markers and imaging metrics in predicting 90-day functional outcome across infarct size strata and time points. In an independent multicenter prospective cohort (N = 519), BD-tau showed higher performance than magnetic resonance imaging-derived final infarct volume in predicting functional outcomes at 3, 12, and 36 months. In the biomarker substudy of a phase 3 trial assessing nerinetide in patients with ischemic stroke (N = 193), BD-tau showed predictive performance comparable to the other cohorts, mediated the relationship between recanalization and functional outcome, and showed a 49% smaller increase in the nerinetide group versus placebo. Overall, plasma BD-tau tracked ischemic brain injury over time, outperformed other biomarkers in predicting functional outcomes, and identified possible treatment responses.

The guidelines ´Viral meningoencephalitis´ emphasize early and aggressive management, including rapid diagnosis through cerebrospinal fluid (CSF) analysis and neuroimaging (MRI).Treatment focuses on supportive care, with specific antiviral therapy (like acyclovir for herpes encephalitis) available for certain viral causes. These Guidelines also address the importance of prompt antibiotic treatment for bacterial meningitis when suspected, and the use of dexamethasone alongside antibiotics in some cases.

Abstract Langerhans cells (LC) are specialized antigen-presenting cells that form a dense immune surveillance network within the oral epithelium. There, they continuously interact with epithelial cells and the resident microbiota to maintain mucosal homeostasis. A defining feature of LC is their highly dendritic morphology, which enables efficient sampling of the environment at barrier surfaces. Although E-cadherin–mediated adhesion has been implicated in LC–epithelial cell interactions, its role in oral LC biology and periodontal immune homeostasis remains elusive. Here, we investigated the function of E-cadherin on oral LC using CD11c-specific E-cadherin–deficient (CD11c-Ecad DEL ) mice. Loss of E-cadherin profoundly altered LC morphology throughout the oral mucosa, resulting in reduced dendrite formation and impaired dendrite extension towards the epithelial surface, thereby disrupting interaction with the oral microbiota. While the total number of LC remained unchanged, E-cadherin deficiency significantly altered the relative distribution of LC subsets, characterized by reduced LC1 and increased LC2 populations. E-cadherin–deficiency was associated with pronounced oral dysbiosis, characterized by increased bacterial burden and microbial diversity, as well as a shift away from the commensal-dominated community, particularly through the loss of protective lactobacilli. Transcriptome analysis of gingival tissue revealed inflammatory reprogramming marked by enrichment of NF-κB, TNF, IL-17, Toll-like receptor, and MAPK signaling pathways. Consistently, CD11c-Ecad DEL mice exhibited increased IL-17A production in the gingiva, expansion of αβ and γδ T cells, spontaneous age-dependent alveolar bone loss, and exacerbated inflammatory bone destruction in a model of ligature-induced periodontitis. In summary, our findings reveal that E-cadherin preserves oral LC dendrite organization and microbiota-dependent immune homeostasis, thereby limiting dysbiosis-driven inflammation and periodontal bone loss.

Abstract Background Syphilis is a multifaceted disease caused by Treponema pallidum. It has re-emerged as a public health concern and represents a potentially treatable cause of cerebrovascular disease. Neurosyphilis (NS) can involve the central nervous system at any stage of infection, with meningovascular syphilis leading to ischemic or, less frequently, hemorrhagic stroke. Diagnosis remains challenging due to heterogeneous clinical presentations and challenging serological diagnostics. Methods We report a case of ischemic stroke as the first manifestation of syphilis and performed a systematic review of the literature on syphilis-associated stroke. A structured search of PubMed, the COCHRANE Library, and secondary sources was conducted for studies published from 1972 onward. Results The reported case describes a 44-year-old HIV-negative man presenting with ischemic stroke due to presumed small-vessel meningovascular syphilis, supported by CSF pleocytosis and positive treponemal serology in serum and CSF. The patient improved substantially following ceftriaxone therapy. The systematic review identified 98 relevant publications, including 73 individual cases and 36 cohort studies. Stroke frequently led to the initial diagnosis of syphilis and predominantly affected younger male patients. Ischemic stroke was the most common presentation, mainly due to large-vessel disease. Penicillin was the most frequently used therapy, with ceftriaxone as an effective alternative. Discussion Syphilis is an important and underrecognized risk factor for stroke, particularly in younger patients. NS should be considered in cases of cryptogenic stroke, and standardized diagnostic and therapeutic approaches are needed to improve recognition and outcomes. Few data on the specific stroke treatment in syphilis exist.

Abnormal brain oscillatory activity is a well-established hallmark of bradykinesia and motor impairment in Parkinson's disease (PD), yet its molecular underpinnings remain unclear. To address this gap, we analyzed over 100,000 single-cell RNA transcriptomes from fresh dorsolateral prefrontal cortex tissue of individuals with PD and non-PD controls, undergoing deep brain stimulation-2 cohorts, which open up an unprecedent window to the characterization of human cortical brain tissue, aiming to uncover the molecular mechanisms of abnormal brain oscillatory activity in PD. Fresh brain tissue samples offer a unique opportunity to precisely elucidate the molecular underpinnings of known, clinically relevant electrophysiological hallmarks of neurodegeneration, which can be used to inform targeted therapeutic strategies. We depicted in microglia and astrocytes enrichment of mitochondrial electron transport and oxidative phosphorylation pathways, which were directly linked to the increase of pathological brain activity and the decrease of prokinetic brain activity. Additionally, the abnormal phase-amplitude coupling of beta-gamma brain activity was related to the dysfunction of oligodendrocyte precursor cells and inflammasome activation mediated by lymphocyte-driven adaptive immunity. We identified a distinct set of dysregulated genes from the mitogen-activated protein kinase phosphorylation pathways, mitochondrial electron transport at the intersection of neuroinflammation and neurodegeneration, suggesting pivotal roles in PD pathology. This unique dataset provides unprecedented insights into the immune and metabolic dysregulation underlying PD, offering a mechanistic framework for understanding invasive transcriptomic biomarkers related to prokinetic and pathologic brain activity in PD.

Background: The utilisation of emergency departments (ED) by patients with non-life-threatening conditions poses an increasing challenge. The aim of this study was to examine the reasons for ED visits, subjective urgency, prior use of primary care services, awareness of the 116117 (urgent care telephone number in Germany), and willingness to use digital self-assessment among patients in Bavarian EDs. Methods: In a multicentre cross-sectional survey, patients in 18 Bavarian EDs were surveyed using a standardized questionnaire between September and November 2024. Results: Of 7527 patients surveyed, 49.7% were female and 32.6% had a higher education. The main reasons for ED visits were symptom severity (49.6%) and health-related anxiety (23.9%). In all, 88.0% assessed their concern as at least "urgent" or "emergency", and 39.7% of respondents had previously attempted to reach a physician's practice. The telephone number 116117 was known to 61.8% of respondents, with significant differences regarding age, education, migration background, and online research; 23.7% were generally open to digital self-assessment. Discussion: The results show that subjectively perceived symptom severity and health-related anxieties are central motives for ED consultations. The moderate awareness level of 116117 with pronounced sociodemographic disparities indicates untapped potential for patient flow-management. Conclusion: The study emphasises the potential and the need to improve awareness of 116117 and the implementation of digital decision support tools for more efficient allocation of patients within emergency care services.

Die Inanspruchnahme von Notaufnahmen durch Patienten mit nichtlebensbedrohlichen Beschwerden stellt eine zunehmende Herausforderung dar. Ziel der Studie war es, die Beweggründe zur Notaufnahmevorstellung, die subjektive Dringlichkeit, die vorherige Nutzung vertragsärztlicher Angebote, die Bekanntheit der 116117 sowie eine Bereitschaft zur digitalen Selbsteinschätzung unter Patienten in bayerischen Notaufnahmen zu untersuchen. In einer multizentrischen Querschnittserhebung wurden zwischen September und November 2024 Patienten in 18 bayerischen Notaufnahmen standardisiert mittels Fragebogen befragt. Von 7.527 befragten Patienten waren 49,7

Fever elevates body temperature to enhance immune response; however, intracellular temperature can fluctuate by up to 15 °C, suggesting a previously unrecognized layer of thermal regulation. While hyperthermia has long been exploited in medicine, how localized temperature gradients influence cellular fate remains poorly understood. Here, a dual-function nanodiamond platform is introduced that integrates optically detected magnetic resonance (ODMR) thermometry with croconium-dye-based photothermal heating to precisely modulate temperature within endo-lysosomal compartments of macrophages. Controlled intracellular hyperthermia triggers oxidative stress, transcriptional reprogramming, and polarization toward a pro-inflammatory phenotype, as confirmed by immunofluorescence, flow cytometry, and transcriptomics. These findings reveal intracellular thermal gradients as active regulators of immune signaling and gene expression. By establishing a direct subcellular thermal trigger for immune activation, independent of the canonical heat-shock pathway. This work introduces a quantum-enabled strategy for probing and programming cellular thermodynamics at the nanoscale.

Description of a patient with multiple sclerosis (MS) who underwent immunotherapy with ocrelizumab and suffered a severe course of tick-borne encephalitis (TBE): A 33-year-old man presented with acute cerebellitis with tonsillar herniation. The initial suspected diagnosis of TBE was confirmed after a significant diagnostic delay, likely caused by negative serological testing due to B-cell depletion from ocrelizumab treatment for underlying MS. TBE diagnosis was made using polymerase chain reaction (PCR) and oligo-hybrid capture metagenomic next-generation sequencing (mNGS) of cerebral spinal fluid and brain biopsy samples which yielded a near-full length TBE Virus (TBEV) genome.