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Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy. [ABSTRACT FROM AUTHOR]

Peripheral central nervous system (CNS)–infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (TRM) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible for diagnostics, we evaluated whether human CSF, apart from infiltrating cells, also contains TRM cells and CNS-resident myeloid cells draining from the parenchyma or border tissues. Using deep generative models, we integrated 41 CSF and 14 CNS parenchyma single-cell RNA sequencing (scRNAseq) samples from eight independent studies, encompassing 120,629 cells. By comparing CSF immune cells collected during multiple sclerosis relapse with cells collected during therapeutic very late antigen–4 blockade, we could identify immune subsets with tissue provenance across multiple lineages, including CNS border–associated macrophages, CD8 and CD4 TRM cells, and tissue-resident natural killer cells. All lymphocytic CNS-resident cells shared expression of CXCR6 but showed differential ITGAE expression (encoding CD103). A common signature defined CD4 and CD8 TRM cells by expression of ZFP36L2, DUSP1, and ID2. We further developed a user interface–driven application based on this analysis framework for atlas-level cell identity transfer onto new CSF scRNAseq data. Together, these results define CNS-resident immune cells involved in multiple sclerosis pathology that can be detected and monitored in CSF. Targeting these cell populations might be promising to modulate immunopathology in progressive multiple sclerosis and other neuroinflammatory diseases. Identifying immunity: The central nervous system (CNS) and cerebrospinal fluid (CSF) are infiltrated by peripheral immune cells in healthy individuals and in the context of diseases such as multiple sclerosis (MS). However, the characterization of CNS-infiltrating cells in humans has lagged behind their characterization in other tissues. Here, Ostkamp et al. developed a framework to analyze immune cells in the CSF or CNS with samples from patients with MS, including patients treated with natalizumab. As natalizumab blocks cell entry into the CNS, this allowed the authors to determine whether cells likely originated in the periphery or in CNS tissue. Finally, the authors developed an application to allow other researchers to identify CNS- and CSF-infiltrating immune cells in their own datasets. -CM [ABSTRACT FROM AUTHOR]

Background: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone–use and –abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. Case presentation: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. Conclusion: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone. [ABSTRACT FROM AUTHOR]

There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56bright NK cells have been suggested to play a major role in controlling T cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immunoprotective role of NK cells in MS. Here, we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK cell/T cell interactions in MS and discuss how disease-modifying treatments for MS affect NK cells. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56bright NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in themigratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4+ T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4+ T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/ CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MSassociation studies, and up-regulation of the receptor's ligand CD155 on CD4+ T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4+ T cells and the cytolytic activity of NK cells. [ABSTRACT FROM AUTHOR]

Objective. We investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis (ALS) patients compared to controls free of neurological disorders (CTRL) and patients with dementia (DEM) or primary progressive multiple sclerosis (PPMS) to elucidate whether compartment-specific inflammation contributes to ALS pathophysiology. Methods. Conventional cerebrospinal fluid (CSF) parameters were examined in 308 patients including 132 ALS patients. In a subgroup of 41 ALS patients, extensive flow-cytometric immune cell profiling in peripheral blood (PB) and CSF was performed and compared with data from 26 CTRL, 57 DEM and 27 PPMS patients. Results. ALS patients presented with significantly altered proportions of monocyte subsets in PB and increased frequencies of CD4+ and CD8+ T cells expressing the activation marker HLA-DR in PB and CSF compared to CTRL. The increased intrathecal levels of T-cell activation were comparable to DEM and PPMS and resulted from in situ differentiation rather than trans-migration from the PB. Moreover, peripheral CD4+ and CD8+ T cell HLA-DR expression significantly exceeded DEM and PPMS. While T-cell activation did not correlate with clinical measures, patients with high disease disability and rapid progression showed reduced intrathecal levels of immune-regulatory CD56bright natural killer (NK) cells. The integration of these parameters into a composite score facilitated the differentiation of patients with high ALS severity and rapid disease progression from patients from all other cohorts. Conclusion. Increased peripheral and intrathecal activation of CD4+ and CD8+ T cells concomitant with diminished immune regulation by CD56bright NK cells suggest an involvement of these immune cells in ALS pathophysiology. [ABSTRACT FROM AUTHOR]

• Skin-resident γδT-cells are mostly Vδ1+, non-activated, and predominantly localized in/around distal hair follicles in human scalp skin. • Vδ1+T-cells are significantly increased in/around the hair bulb of lesional, and around non-lesional alopecia areata (AA) hair follicles. • Vδ1+T-cells infiltrating in/around AA hair follicles are pro-inflammatory. • Skin-resident Vδ1+T-cells represent previously overlooked, but potentially important, innate immunity protagonists in AA pathobiology. • Vδ1+T-cells may be involved in the early stages of human AA, and may thus deserve therapeutic targeting for optimal AA management. It is widely accepted that NKG2D+cells are critically involved in alopecia areata (AA) pathogenesis. However, besides being expressed in CD8+T-cells and NK cells, NKG2D is also found in human γδT-cells. AA lesional hair follicles (HFs) overexpress NKG2D and γδTCR activating ligands, e.g. MICA and CD1d, and chemoattractants for γδT-cells, such as CXCL10. To investigate whether abnormal activities of γδT-cells may be involved in AA pathogenesis. We analyzed the number and activation status of γδT-cells in human healthy, lesional and non-lesional AA scalp biopsies by FACS and/or quantitative (immuno-)histomorphometry. In healthy human scalp skin, the few skin-resident γδT-cells were found to be mostly Vδ1+, non-activated (CD69−NKG2Ddim) and positive for CXCL10, and CXCL12 receptors. These Vδ1+T-cells predominantly localized in/around the HF infundibulum. In striking contrast, the number of Vδ1+T-cells was significantly higher around and even inside the proximal (suprabulbar and bulbar) epithelium of lesional AA HFs. These cells also showed a pro-inflammatory phenotype, i.e. higher NKG2D, and IFN-γ and lower CD200R expression. Importantly, more pro-inflammatory Vδ1+T-cells were seen also around non-lesional AA HFs. Lesional AA HFs also showed significantly higher expression of CXCL12. Our pilot study introduces skin-resident γδT-cells as a previously overlooked, but potentially important, mostly (auto-)antigen-independent, new innate immunity protagonist in AA pathobiology. The HF infiltration of these activated, IFN-γ-releasing cells already around non-lesional AA HFs suggest that Vδ1+T-cells are involved in the early stages of human AA pathobiology, and may thus deserve therapeutic targeting for optimal AA management. [ABSTRACT FROM AUTHOR]