Joona Sarkkinen and al.

The authors characterized the immune landscape of deep cervical lymph nodes (dcLNs) in newly diagnosed untreated patients with MS (pwMS) using fine-needle aspirations. By combining single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing, they report increased memory B cells and reduced germinal center B cells with decreased clonality in pwMS. Double-negative memory B cells were increased in pwMS that transcriptionally resembled B cells with a lytic EBV infection. Moreover, EBV-targeting memory CD8 T cells were detected in a subset of pwMS. Finally, increased EBV DNA in dcLNs and elevated viral loads were detected in patient saliva. These findings suggest that EBV-driven B cell dysregulation is a critical mechanism in MS pathogenesis.

Somnath Tagore and al.

Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC). Here the authors performed multimodal transcriptomic analyses of brain metastases and primary tumors in patients with treatment-naive NSCLC. Chromosomal instability was found to be a distinguishing genomic feature of brain metastases compared with primary tumors. Also, transcriptional neural-like programs were strongly enriched in cancer cells from brain metastases. These results were confirmed in an independent cohort using multiplexed immunofluorescence. It is concluded that brain metastases from NSCLC are strongly enriched in a cancer cell population characterized by neural features.

Jing Zhou and al.

Anti-NMDA receptor encephalitis frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific mAb during a critical developmental period (from postnatal day 3 to day 12) in mice. The authors observed long-lasting sensory-motor deficits along with permanent changes in callosal axons within the primary somatosensory cortex in adulthood, including increased terminal branch complexity. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons.

Sara Perrotta and al.

Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. The authors report that in mice, cardiac left ventricle pressure overload recruits a brainstem neural circuit to stimulate the splenic sympathetic nervous system and induce the secretion of placental growth factor (PlGF). During hypertensive stress, PlGF drives the proliferation of self-renewing cardiac resident macrophages expressing its receptor, neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to heart failure. In humans, circulating PlGF correlates with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs.

Irving Estevez and al.

In this study, the authors show that during flavivirus infection the kinase RIPK3 preserve neuronal survival through the suppression of excitatory neurotransmission. These effects occur independently of the traditional functions of RIPK3 in promoting necroptosis and inflammatory transcription. Instead, RIPK3 promotes phosphorylation of the neuronal regulatory kinase CaMKII, which in turn activates the transcription factor CREB to drive a neuroprotective transcriptional program and to suppress deleterious glutamatergic signaling.

Lynn van Olst and al.

The authors used spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. They compared actively immunized patients with AD with non-immunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. They uncovered spatially distinct microglial responses that vary by brain region. However, upregulation of TREM2 and APOE in microglia across immunization approaches, which correlated positively with antibody responses and Aβ removal. Furthermore, they show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization.