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Abstract So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35–55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.

Abstract Mental healthcare research increasingly focuses the needs of trans people and, in doing so, acknowledges knowledge and epistemic resources developed in trans communities. In this article, we aim to raise awareness of an ethical issue described by Emmalon Davis that may arise in the context of engaging with community knowledge and epistemic resources: the risk of epistemic appropriation. It is composed of two harms (1) a detachment of epistemic resources developed in the originating community and (2) a misdirection of these epistemic resources for epistemic goals of a dominant community. In this article, we map and discuss the ethical concerns in using knowledge originating in trans communities in terms of epistemic appropriation in the context of mental healthcare research. We first argue that misgendering, failing to reference non-academic sources and a lack of attribution in community authorship are forms of epistemic detachment. Second, we problematize cases of epistemic misdirection of trans epistemic resources, focusing on the examples of detransition and transition regret. We discuss harms related to epistemic appropriation in relationship to risks to safety. The article aims to raise awareness about the risk of epistemic appropriation both in researchers engaging with trans knowledge as well as in mental healthcare workers who seek information on trans.

Abstract Bioethics increasingly recognizes the impact of discriminatory practices based on social categories such as race, gender, sexual orientation or ability on clinical practice. Accordingly, major bioethics associations have stressed that identifying and countering structural discrimination in clinical ethics consultations is a professional obligation of clinical ethics consultants. Yet, it is still unclear how clinical ethics consultants can fulfill this obligation. More specifically, clinical ethics needs both theoretical tools to analyze and practical strategies to address structural discrimination within clinical ethics consultations. Intersectionality, a concept developed in Black feminist scholarship, is increasingly considered in bioethical theory. It stresses how social structures and practices determine social positions of privilege and disadvantage in multiple, mutually co-constitutive systems of oppression. This article aims to investigate how intersectionality can contribute to addressing structural discrimination in clinical ethics consultations with a particular focus on mental healthcare. To this end, we critically review existing approaches for clinical ethics consultants to address structural racism in clinical ethics consultations and extend them by intersectional considerations. We argue that intersectionality is a suitable tool to address structural discrimination within clinical ethics consultations and show that it can be practically implemented in two complementary ways: 1) as an analytic approach and 2) as a critical practice.

Background: Pregnancy in patients with multiple sclerosis (MS) is accompanied by a decline of relapse activity with increased risk of relapses 3 months post-partum, for unknown reasons. Eomesodermin + T-helper cells (Eomes + Th cells) are known to mediate neuroinflammation and disease progression in MS and are induced by prolactin-secreting cells. Objectives: Here, investigated immune cell alterations and the pathophysiological role of Eomes + Th cells for disease activity during pregnancy and post-partum in MS. Methods: We enrolled n = 81 pregnant patients with relapsing-remitting MS (RRMS), n = 27 post-partum RRMS and n = 26 female RRMS control patients under the umbrella of the German Multiple Sclerosis and Pregnancy Registry. Clinical data were collected and immune cell alterations were analysed using flow cytometry. Results: While CD3 + CD4 + Th cells were unaffected, CD3 + CD8 + cytotoxic T-cells were elevated post-partum ( p = 0.02) with reduced B-cell frequencies ( p = 0.01) compared to non-pregnant RRMS patients. NK cells were elevated during first trimester ( p = 0.02) compared to the third trimester. Frequencies of Eomes + Th and Eomes + Tc cells did not differ. There was no correlation of prolactin release and expression of Eomes + Th cells. However, Eomes + Th cells correlated with lower frequencies of regulatory T-cells during second ( r = −0.42; p

IntroductionThe lack of regenerative capacity of the central nervous system is one of the major challenges nowadays. The knowledge of guidance cues that trigger differentiation, proliferation, and migration of neural stem and progenitor cells is one key element in regenerative medicine. The extracellular matrix protein tenascin-C (Tnc) is a promising candidate to regulate cell fate due to its expression in the developing central nervous system and in the adult neural stem cell niches. Of special interest are the alternatively spliced fibronectin type III (FnIII) domains of Tnc whose combinatorial diversity could theoretically generate up to 64 isoforms in the mouse. A total of 27 isoforms have already been discovered in the developing brain, among others the domain combinations A1D, CD, and A124BCD.MethodsIn the present study, these domains as well as the combination of the constitutively expressed FnIII domains 7 and 8 (78) were expressed in Chinese hamster ovary cells as pseudo-antibodies fused to the Fc-fragment of a human immunoglobulin G antibody. The fusion proteins were presented to primary mouse neural stem/progenitor cells (NSPCs) grown as neurospheres, either as coated culture substrates or as soluble additives in vitro. The influence of the domains on the differentiation, proliferation and migration of NSPCs was analyzed.ResultsWe observed that the domain combination A124BCD promoted the differentiation of neurons and oligodendrocytes, whereas the domain A1D supported astrocyte differentiation. The constitutively expressed domain 78 had a proliferation and migration stimulating impact. Moreover, most effects were seen only in one of the presentation modes but not in both, suggesting different effects of the Tnc domains in two- and three-dimensional cultures.DiscussionThis knowledge about the different effect of the Tnc domains might be used to create artificial three-dimensional environments for cell transplantation. Hydrogels spiked with Tnc-domains might represent a promising tool in regenerative medicine.

Summary: Visual processing depends on sensitive and balanced synaptic neurotransmission. Extracellular matrix proteins in the environment of cells are key modulators in synaptogenesis and synaptic plasticity. In the present study, we provide evidence that the combined loss of the four extracellular matrix components, brevican, neurocan, tenascin-C, and tenascin-R, in quadruple knockout mice leads to severe retinal dysfunction and diminished visual motion processing in vivo. Remarkably, impaired visual motion processing was accompanied by a developmental loss of cholinergic direction-selective starburst amacrine cells. Additionally, we noted imbalance of inhibitory and excitatory synaptic signaling in the quadruple knockout retina. Collectively, the study offers insights into the functional importance of four key extracellular matrix proteins for retinal function, visual motion processing, and synaptic signaling.

Abstract Background Sulfated glycosaminoglycan chains are known for their regulatory functions during neural development and regeneration. However, it is still unknown whether the sulfate residues alone influence, for example, neural precursor cell behavior or whether they act in concert with the sugar backbone. Here, we provide evidence that the unique 473HD-epitope, a representative chondroitin sulfate, is expressed by spinal cord neural precursor cells in vivo and in vitro, suggesting a potential function of sulfated glycosaminoglycans for spinal cord development. Results Thus, we applied the widely used sulfation inhibitor sodium chlorate to analyze the importance of normal sulfation levels for spinal cord neural precursor cell biology in vitro. Addition of sodium chlorate to spinal cord neural precursor cell cultures affected cell cycle progression accompanied by changed extracellular signal-regulated kinase 1 or 2 activation levels. This resulted in a higher percentage of neurons already under proliferative conditions. In contrast, the relative number of glial cells was largely unaffected. Strikingly, both morphological and electrophysiological characterization of neural precursor cell-derived neurons demonstrated an attenuated neuronal maturation in the presence of sodium chlorate, including a disturbed neuronal polarization. Conclusions In summary, our data suggest that sulfation is an important regulator of both neural precursor cell proliferation and maturation of the neural precursor cell progeny in the developing mouse spinal cord.

Abstract Background Mental healthcare users and patients were described as a particularly vulnerable group in the debate on the burdens of the COVID-19 pandemic. Just what this means and what normative conclusions can be derived from it depend to a large extent on the underlying concept of vulnerability. While a traditional understanding locates vulnerability in the characteristics of social groups, a situational and dynamic approach considers how social structures produce vulnerable social positions. The situation of users and patients in different psychosocial settings during the COVID-19 pandemic has not yet been comprehensively considered and ethically analyzed under the aspect of situational vulnerability. Methods We present the results of a retrospective qualitative analysis of a survey of ethical challenges in different mental healthcare facilities of a large regional mental healthcare provider in Germany. We evaluate them ethically using a dynamic and situational understanding of vulnerability. Results Difficulties in implementing infection prevention measures, restrictions of mental health services in favor of infection prevention, social isolation, negative health effects on mental healthcare users and patients, and challenges in implementing regulations on state and provider levels within the local specificities emerged across different mental healthcare settings as ethically salient topics. Conclusions Applying a situational and dynamic understanding of vulnerability allows the identification of specific factors and conditions that have contributed to an increased context-dependent vulnerability for mental healthcare users and patients. These factors and conditions should be considered on the level of state and local regulations to reduce and address vulnerability.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

In the mammalian cortex a proper excitatory/inhibitory (E/I) balance is fundamental for cognitive functions. Especially γ-aminobutyric acid (GABA)-releasing interneurons regulate the activity of excitatory projection neurons which form the second main class of neurons in the cortex. During development, the maturation of fast-spiking parvalbumin-expressing interneurons goes along with the formation of net-like structures covering their soma and proximal dendrites. These so-called perineuronal nets (PNNs) represent a specialized form of the extracellular matrix (ECM, also designated as matrisome) that stabilize structural synapses but prevent the formation of new connections. Consequently, PNNs are highly involved in the regulation of the synaptic balance. Previous studies revealed that the formation of perineuronal nets is accompanied by an establishment of mature neuronal circuits and by a closure of critical windows of synaptic plasticity. Furthermore, it has been shown that PNNs differentially impinge the integrity of excitatory and inhibitory synapses. In various neurological and neuropsychiatric disorders alterations of PNNs were described and aroused more attention in the last years. The following review gives an update about the role of PNNs for the maturation of parvalbumin-expressing interneurons and summarizes recent findings about the impact of PNNs in different neurological and neuropsychiatric disorders like schizophrenia or epilepsy. A targeted manipulation of PNNs might provide an interesting new possibility to indirectly modulate the synaptic balance and the E/I ratio in pathological conditions.

Objective: Discriminatory practices in mental health care undermine the right to health of marginalized service users. Intersectional approaches enable consideration of multiple forms of discrimination that occur simultaneously and remain invisible in single-axis analyses. The authors reviewed intersectionality-informed qualitative literature on discriminatory practices in mental health care to better understand the experiences of marginalized service users and their evaluation and navigation of mental health care. Methods: The authors searched EBSCO, PubMed, MEDLINE, and JSTOR for studies published January 1, 1989–December 14, 2022. Qualitative and mixed-methods studies were eligible if they used an intersectional approach to examine discrimination (experiences, mechanisms, and coping strategies) in mental health care settings from the perspective of service users and providers. A qualitative evidence synthesis with thematic analysis was performed. Results: Fifteen studies were included in the qualitative evidence synthesis. These studies represented the experiences of 383 service users and 114 providers. Most studies considered the intersections of mental illness with race, sexual and gender diversity, or both and were performed in the United States or Canada. Four themes were identified: the relevance of social identity in mental health care settings, knowledge-related concerns in mental health care, microaggressions in clinical practice, and service users' responses to discriminatory practices. Conclusions: Discriminatory practices in mental health care lead to specific barriers to care for multiply marginalized service users. Universities and hospitals may improve care by building competencies in recognizing and preventing discrimination through institutionalized training. [ABSTRACT FROM AUTHOR]

Abstract Background Self-binding directives (SBDs) are psychiatric advance directives that include a clause in which mental health service users consent in advance to involuntary hospital admission and treatment under specified conditions. Medical ethicists and legal scholars identified various potential benefits of SBDs but have also raised ethical concerns. Until recently, little was known about the views of stakeholders on the opportunities and challenges of SBDs. Aims This article aims to foster an international exchange on SBDs by comparing recent empirical findings on stakeholders’ views on the opportunities and challenges of SBDs from Germany, the Netherlands, and the United Kingdom. Method Comparisons between the empirical findings were drawn using a structured expert consensus process. Results Findings converged on many points. Perceived opportunities of SBDs include promotion of autonomy, avoidance of personally defined harms, early intervention, reduction of admission duration, improvement of the therapeutic relationship, involvement of persons of trust, avoidance of involuntary hospital admission, addressing trauma, destigmatization of involuntary treatment, increase of professionals’ confidence, and relief for proxy decision-makers. Perceived challenges include lack of awareness and knowledge, lack of support, undue influence, inaccessibility during crisis, lack of cross-agency coordination, problems of interpretation, difficulties in capacity assessment, restricted therapeutic flexibility, scarce resources, disappointment due to noncompliance, and outdated content. Stakeholders tended to focus on practical challenges and did not often raise fundamental ethical concerns. Conclusions Stakeholders tend to see the implementation of SBDs as ethically desirable, provided that the associated challenges are addressed.

Although the understanding of secondary progressive multiple sclerosis (SPMS) is evolving, early detection of relapse-independent progression remains difficult. This is further complicated by superimposed relapses and compensatory mechanisms that allow for silent progression. The term relapsing multiple sclerosis (RMS) subsumes relapsing-remitting multiple sclerosis (RRMS) and SPMS with relapses. The latter is termed ‘active’ SPMS, for which disease-modifying therapies (DMTs) approved for either RMS or active SPMS can be used. However, the level of evidence supporting efficacy and safety in SPMS differs between drugs approved for RMS and SPMS. Our review aims to identify current evidence from published clinical trials and European public assessment reports from the marketing authorization procedure on the efficacy, especially on progression, of DMTs approved for RMS and SPMS. To identify relevant evidence, a literature search has been conducted and European public assessment reports of DMTs approved for RMS have been screened for unpublished data specific to SPMS. Only two clinical trials demonstrated a significant reduction in disability progression in SPMS study populations: the EXPAND study for siponimod, which included a typical SPMS population, and the European study for interferon (IFN)-beta 1b s.c., which included patients with very early and active SPMS. Both DMTs also achieved significant reductions in relapse rates. Ocrelizumab, cladribine, ofatumumab, and ponesimod are all approved for RMS – ocrelizumab, ofatumumab, and ponesimod based on an RMS study, cladribine based on an RRMS study. Data on efficacy in SPMS are only available from post hoc analyses of very small subgroups, representing only up to 15% of the total study population. For these DMTs, approval for RMS, including active SPMS, was mainly based on the assumption that the reduction in relapse rate observed in patients with RRMS can also be applied to SPMS. Based on that, the potential of these drugs to reduce relapse-independent progression remains unclear.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tremendous implications for the management of patients with autoimmune conditions such as multiple sclerosis (MS) under immune therapies targeting CD20 + B cells (aCD20). Objectives: Here, we investigated humoral and cellular immune responses, including anti-spike titers, neutralization against SARS-CoV-2 wild-type (WT), delta, and omicron variant and T cell responses of aCD20-treated relapsing–remitting MS patients following SARS-CoV-2 vaccination compared with healthy controls. Methods: Blood samples were collected within 4–8 weeks following the second vaccination against SARS-CoV-2. Sera were analyzed for anti-SARS-CoV-2 spike antibodies and neutralization capacity against pseudovirus for wild-type (WT), delta, and omicron variant. Peripheral blood mononuclear cells (PBMCs) were stimulated with a SARS-CoV-2 peptide pool and analyzed via flow cytometry. Results: The aCD20-treated MS patients had lower anti-SARS-CoV-2-spike titers, which correlated with B cell repopulation. Sera of aCD20-treated patients had reduced capacity to neutralize WT, delta, and omicron pseudoviruses in vitro . On the contrary, PBMCs of aCD20-treated patients elicited higher frequencies of CD3 + T cells and CD4 + T cells and comparable response of cytotoxic T cells, while Th1 response was reduced following restimulation with SARS-CoV-2. Conclusion: In summary, aCD20-treated patients have a reduced humoral immune response, depending on B cell repopulation, in accordance with preserved cellular immune response, suggesting partial cellular protection against SARS-CoV-2.

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.

Oligodendrocyte precursor cells (OPCs) are the exclusive source of myelination in the central nervous system (CNS). Prior to myelination, OPCs migrate to target areas and mature into myelinating oligodendrocytes. This process is underpinned by drastic changes of the cytoskeleton and partially driven by pathways involving small GTPases of the Rho subfamily. In general, the myelination process requires migration, proliferation and differentiation of OPCs. Presently, these processes are only partially understood. In this study, we analyzed the impact of the guanine nucleotide exchange factor (GEF) Vav3 on the migration behavior of OPCs. Vav3 is known to regulate RhoA, Rac1 and RhoG activity and is therefore a promising candidate with regard to a regulatory role concerning the rearrangement of the cytoskeleton. Our study focused on the Vav3 knockout mouse and revealed an enhanced migration capacity of Vav3−/− OPCs on the extracellular matrix (ECM) glycoprotein tenascin-C (TnC). The migration behavior of individual OPCs on further ECM molecules such as laminin-1 (Ln1), laminin-2 (Ln2) and tenascin-R (TnR) was not affected by the elimination of Vav3. The migration process was further investigated with regard to intracellular signal transmission by pharmacological blockade of downstream pathways of specific Rho GTPases. Our data suggest that activation of RhoA GTPase signaling compromises migration, as inhibition of RhoA-signaling promoted migration behavior. This study provides novel insights into the control of OPC migration, which could be useful for further understanding of the complex differentiation and myelination process.

ObjectiveRegarding pathogenesis, clinical manifestations, at-risk individuals, and diagnostic methods for stratifying patients for therapeutic approaches, our understanding of post-COVID syndrome is limited. Here, we set out to assess sociodemographic and clinical aspects in patients with the long-COVID and post-COVID syndrome.MethodsWe performed a cross-sectional analysis of patients presenting at our specialized university hospital outpatient clinic. We assessed patients' clinical presentation, fatigue, symptoms of depression and anxiety, and impairment of smell.ResultsA total of 101 patients were included (73.3% female), of whom 78.2% had a mild course of COVID-19. At presentation, 93.1% suffered from fatigue, 82.2% from impaired concentration, and 79.2% from impaired memory, 53.5% had impaired sleep. The most common secondary diagnosis found in our cohort was thyroid disease. Fatigue analysis showed that 81.3% of female and 58.8% of male patients had severe combined fatigue. Female gender was an independent risk factor for severe fatigue (severe cognitive fatigue OR = 8.045, p = 0.010; severe motor fatigue OR = 7.698, p = 0.013). Males suffered from more depressive symptoms, which correlated positively with the duration of symptom onset. 70.3% of patients with anamnestic smell impairment had hyposmia, and 18.9% were anosmic.InterpretationMost long-COVID patients suffered from severe fatigue, with the female sex as an independent risk factor. Fatigue was not associated with symptoms of depression or anxiety. Patients with long-COVID symptoms should receive an interdisciplinary diagnostic and therapeutic approach depending on the clinical presentation.

Abstract Background Since the coronavirus disease 2019 (COVID-19) has risen, several risk factors have been identified, predicting a worse outcome. It has been speculated that patients with Multiple sclerosis (MS) have an increased risk for a severe course of COVID-19 due to a suspected higher vulnerability. Therefore, we aimed to analyze the impact of comorbid MS on the outcome of patients with COVID-19 in Germany. Methods We conducted a retrospective cross-sectional study using the administrative database of all hospitalized patients diagnosed with PCR-confirmed COVID-19 (n = 157,524) in Germany during 2020. The cohort was stratified according to the presence (n = 551) or absence (n = 156,973) of comorbid MS, including discrimination of MS subtypes. Primary outcome measures were admission to the intensive care unit (ICU), use of invasive or non-invasive ventilation, and in-hospital mortality. Differences were investigated using rates and odds ratios as estimates. Pooled overall estimates, sex-stratified estimates, age-group stratified estimates, and MS subtype stratified estimates were calculated for all outcomes under the random-effects model. Results Among 157,524 patients hospitalized with COVID-19, 551 had a concurrent MS diagnosis (0.3%). Overall, univariate analysis showed lower rates of ICU admission (17.1% versus 22.7%, p

ObjectiveThe pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.MethodsWe here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.ResultsWe show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).InterpretationIn summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.

Background: The role of neuroinflammation and autoimmune processes in neurodegenerative diseases is not fully understood. Activation of microglia with expression of proinflammatory cytokines supports the hypothesis that immune processes may play an important role in the pathophysiology of Huntington’s disease (HD) and thus, immunomodulating therapies might have potential neuroprotective properties. Until now, no disease-modifying therapy (DMT) is available for HD. Objective: The aim of this research was to characterize a cohort of patients suffering from both HD and autoimmune demyelinating diseases of the central nervous system (classified as G35-37 in ICD-10; ADD-CNS) in comparison to HD cases without ADD-CNS. In particular, we were interested to investigate potential modulating effects on disease manifestation and progression of HD over time of prescribed immunomodulating medications (DMT). Methods: We analyzed the course of HD regarding motoric, functional, and cognitive aspects, using longitudinal data of up to 2 years from the worldwide registry study ENROLL-HD. Additional cross-sectional data in the largest cohort worldwide of HD patients was analyzed using demographic and molecular genetic parameters. Data were analyzed using analysis of variance (ANOVA) for cross-sectional and repeated-measures ANOVA for longitudinal parameters in IBM SPSS Statistics V.27. Results: Within the ENROLL-HD database, we investigated N = 21,116 participants and identified n = 60 participants suffering from ADD-CNS. Molecular, genetic, and demographic data did not differ between groups. The subgroup of n = 32 participants with motor-manifest HD revealed better cognitive performance in five out of eight cognitive tests at baseline with less progression over time in two tests (all p < 0.05). Differentiation between DMT-treated and untreated patients revealed better cognitive and motor performance in the DMT group; those patients, however, tended to be younger. Pre-manifest HD patients simultaneously diagnosed with ADD-CNS ( n = 12) showed lower functional scores and more decline over time when compared with other pre-manifest HD ( p < 0.05). Conclusion: Patients suffering from motor-manifest HD and simultaneously from ADD-CNS have better cognitive capacities compared with other motor-manifest HD patients. Moreover, DMTs might have beneficial effects on progression of neurodegeneration including the motor phenotype. However, this effect might have been biased by younger age in DMT-treated patients. Pre-manifest HD patients showed more functional impairment as expected due to their additional ADD-CNS disease.

Abstract Predator-induced phenotypic plasticity describes the ability of prey to respond to an increased predation risk by developing adaptive phenotypes. Upon the perception of chemical predator cues, the freshwater crustacean Daphnia longicephala develops defensive crests against its predator Notonecta spec. (Heteroptera). Chemical predator perception initiates a cascade of biological reactions that leads to the development of these morphological features. Neuronal signaling is a central component in this series, however how the nervous system perceives and integrates environmental signals is not well understood. As neuronal activity is often accompanied by functional and structural plasticity of the nervous system, we hypothesized that predator perception is associated with structural and functional changes of nervous tissues. We observe structural plasticity as a volume increase of the central brain, which is independent of the total number of brain cells. In addition, we find functional plasticity in form of an increased number of inhibitory post-synaptic sites during the initial stage of defense development. Our results indicate a structural rewiring of nerve-cell connections upon predator perception and provide important insights into how the nervous system of prey species interprets predator cues and develops cost–benefit optimized defenses.

Fast-spiking parvalbumin interneurons are critical for the function of mature cortical inhibitory circuits. Most of these neurons are enwrapped by a specialized extracellular matrix (ECM) structure called perineuronal net (PNN), which can regulate their synaptic input. In this study, we investigated the relationship between PNNs, parvalbumin interneurons, and synaptic distribution on these cells in the adult primary visual cortex (V1) of quadruple knockout mice deficient for the ECM molecules brevican, neurocan, tenascin-C, and tenascin-R. We used super-resolution structured illumination microscopy (SIM) to analyze PNN structure and associated synapses. In addition, we examined parvalbumin and calretinin interneuron populations. We observed a reduction in the number of PNN-enwrapped cells and clear disorganization of the PNN structure in the quadruple knockout V1. This was accompanied by an imbalance of inhibitory and excitatory synapses with a reduction of inhibitory and an increase of excitatory synaptic elements along the PNNs. Furthermore, the number of parvalbumin interneurons was reduced in the quadruple knockout, while calretinin interneurons, which do not wear PNNs, did not display differences in number. Interestingly, we found the transcription factor Otx2 homeoprotein positive cell population also reduced. Otx2 is crucial for parvalbumin interneuron and PNN maturation, and a positive feedback loop between these parameters has been described. Collectively, these data indicate an important role of brevican, neurocan, tenascin-C, and tenascin-R in regulating the interplay between PNNs, inhibitory interneurons, synaptic distribution, and Otx2 in the V1.

γδ T cells are unconventional T cells, distinguished from αβ T cells in a number of functional properties. Being small in number compared to αβ T cells, γδ T cells have surprised us with their pleiotropic roles in various diseases. γδ T cells are ambiguous in nature as they can produce a number of cytokines depending on the (micro) environmental cues and engage different immune response mechanisms, mainly due to their epigenetic plasticity. Depending on the disease condition, γδ T cells contribute to beneficial or detrimental response. In this review, we thus discuss the dichotomous nature of γδ T cells in cancer, neuroimmunology and infectious diseases. We shed light on the importance of equal consideration for systems immunology and personalized approaches, as exemplified by changes in metabolic requirements. While providing the status of immunotherapy, we will assess the metabolic (and other) considerations for better outcome of γδ T cell-based treatments.