Biology subjects

Hamann, J.

Publications and source records attributed to Hamann, J..

4 recordsLinked to original sources

bioRxiv2024

Microglial states determine lesion dynamics in multiple sclerosis

Summary paragraphMultiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system, characterized by demyelinating lesions 1. Lesion expansion contributes to progression and increased disability, while remyelination can recover neurological deficits. However, mechanisms driving lesion dynamics are largely unclear, hindering the development of effective therapeutics. We propose that distinct states of microglia are involved in lesion expansion and remyelination 2,3. Using Stereo-seq, an RNA capture based high-resolution spatial transcriptomics technology with single-cell resolution, on post-mortem human brain tissue, we compared mixed active/inactive lesions with lipid-laden foamy microglia with lesions containing ramified microglia. We identified distinct cellular and molecular mechanisms underlying lesion activity and remyelination, linked to microglia phenotypes and states. Lesions with foamy microglia were characterized by elevated immune activation, increased lymphocyte densities, upregulated immunoglobulin production (IGHG1, IGHG3), increased complement system activity, indication of iron dysregulation (FTL, FTH1), and increased demyelination. In contrast, lesions with ramified microglia exhibited gene expression profiles indicative of myelin stability (ABCA2, QKI) and neuro-axonal protection, fostering an environment conducive to repair and remyelination. Our findings highlight the role of microglial states in lesion expansion and repair in MS and offer promising avenues for the development of therapeutic approaches aimed at preventing MS disability progression.

neuroscience↗

bioRxiv2024

Relationship as resource or burden? Associations of attachment style, relationship quality and dyadic coping with acute psychosocial stress in the presence of the romantic partner

Stress is a wide-spread phenomenon and associated with various detrimental health effects. A significant resource for stress buffering is social support. How social support is perceived, however, depends on a multitude of individual and interindividual factors. This study aimed to explore the stress-reducing properties of relationship-inherent variables. We investigated the association of attachment style, relationship quality and dyadic coping, with subjective and physiological stress responses to a psychosocial laboratory stressor in romantic partners. Seventy-nine couples participated, with one partner ("target") undergoing the Trier Social Stress Test and the other ("observer") observing the situation. Besides examining the role of targets relationship variables, we also assessed the link between observers relationship variables and targets stress reactivity. We found that both targets and observers insecure-avoidant attachment scores were associated with targets stress reactivity. In detail, while targets insecure-avoidant attachment scores were negatively associated with targets subjective stress experience, observers insecure-avoidant attachment scores were positively associated with targets heart rate reactivity. Further, higher insecure-avoidant attachment scores linked to lower psycho-endocrine covariance, i.e., a lower accordance between self-reported and cortisol stress responding. On the one hand, these data may suggest that under stress, insecure-avoidantly attached individuals suppress their experience of stress to preserve a sense of independence as part of their deactivating attachment strategy. The presence of an insecure-avoidantly attached partner during a stressful experience, on the other hand, seems to be a stressor rather than a source of support. Long-term, an insecure-avoidantly attached partner may negatively impact an individuals stress-related health and wellbeing. Highlights- In a situation in which one romantic partner experienced stress ("target") while being ob- served by their partner ("observer"), insecure-avoidant attachment of both predicted the tar- gets stress response - Targets insecure-avoidant attachment was associated with lower subjective stress in the tar- gets - Observers insecure-avoidant attachment was related to higher heart rate reactivity in the targets - Insecure-avoidant attachment was associated with lower psycho-endocrine covariance

neuroscience↗

bioRxiv2024

CD4+ Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Therapeutic options against multiple sclerosis (MS) preventing T cell migration to the central nervous system (CNS) have remarkable clinical effects against the relapsing-remitting (RRMS) form of the disease, while they are poorly effective against its progressive form (PMS). Disability progression in PMS is thought to result from an interplay between smoldering local inflammation and neurodegeneration. We postulated that an ongoing inflammatory process mediated by CNS-resident memory CD4+ T cells (CD4+ Trm) could contribute to promote disease chronicity independently of de novo recruitment of peripheral autoreactive T cells. Indeed, our results revealed the presence of bona fide CD4+ Trm expressing CD69, CXCR6, P2RX7, CD49a and the transcription factor Hobit in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in the brain of persons with PMS. Single-cell transcriptional analysis uncovered their transcriptional heterogeneity and inflammatory potential and, accordingly, CD4+ Trm preferentially localized within inflammatory lesions. Finally, depletion of both the recirculating and the CNS-resident CD4+ T cell compartments was required to alleviate neurological signs during the chronic phase of EAE. Our results, therefore, indicate that CD4+ Trm actively contribute to maintain a chronic inflammatory state in the CNS, promoting damage and/or preventing repair, and suggest that new therapeutic strategies for the treatment of PMS should consider targeting the CNS-resident T cell compartment.

immunology↗

bioRxiv2023

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

Clusters of ramified HLA-DR+ cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.

neuroscience↗