B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.

Metaverse in Healthcare Integrated with Explainable AI and Blockchain: Enabling Immersiveness, Ensuring Trust, and Providing Patient Data Security.

Digitization and automation have always had an immense impact on healthcare. It embraces every new and advanced technology. Recently the world has witnessed the prominence of the metaverse which is an emerging technology in digital space. The metaverse has huge potential to provide a plethora of health services seamlessly to patients and medical professionals with an immersive experience. This paper proposes the amalgamation of artificial intelligence and blockchain in the metaverse to provide better, faster, and more secure healthcare facilities in digital space with a realistic experience. Our proposed architecture can be summarized as follows. It consists of three environments, namely the doctor's environment, the patient's environment, and the metaverse environment. The doctors and patients interact in a metaverse environment assisted by blockchain technology which ensures the safety, security, and privacy of data. The metaverse environment is the main part of our proposed architecture. The doctors, patients, and nurses enter this environment by registering on the blockchain and they are represented by avatars in the metaverse environment. All the consultation activities between the doctor and the patient will be recorded and the data, i.e., images, speech, text, videos, clinical data, etc., will be gathered, transferred, and stored on the blockchain. These data are used for disease prediction and diagnosis by explainable artificial intelligence (XAI) models. The GradCAM and LIME approaches of XAI provide logical reasoning for the prediction of diseases and ensure trust, explainability, interpretability, and transparency regarding the diagnosis and prediction of diseases. Blockchain technology provides data security for patients while enabling transparency, traceability, and immutability regarding their data. These features of blockchain ensure trust among the patients regarding their data. Consequently, this proposed architecture ensures transparency and trust regarding both the diagnosis of diseases and the data security of the patient. We also explored the building block technologies of the metaverse. Furthermore, we also investigated the advantages and challenges of a metaverse in healthcare.

ALAIN01--Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential.

BACKGROUND: Alemtuzumab (Lemtrada®) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers. METHODS/DESIGN: This is a mono center, single arm, explorative phase IV study including 15 patients with highly active RRMS designed for 3 years. Patients will be studied by a high-resolution analysis comprising a repertoire of various immunological assays for the detection of immune cells and their function in peripheral blood as well as the cerebrospinal fluid (CSF). These assays encompass a number of experiments investigating immune cell subset composition, activation status, cytokine secretion, migratory capacity, potential neuroprotective properties and cytolytic activity complemented by instrument-based diagnostics like MRI scans, evoked potentials and optical coherence tomography (OCT). DISCUSSION: Our study represents the first in-depth and longitudinal functional analysis of key immunological parameters in the periphery and the CNS compartment underlying the fundamental effects of alemtuzumab in MS patients. By combining clinical, experimental and MRI data our study will provide a deeper understanding of alemtuzumab's mechanisms of action (MOA) potentially identifying immune signatures associated with treatment response or the development of secondary autoimmunity. After validation in larger cohorts this might help to improve efficacy and safety of alemtuzumab therapy in RRMS patients. TRIAL REGISTRATION: NCT02419378 (clinicaltrials.gov), registered 31 March 2015.

Effects of glatiramer acetate in a spontaneous model of autoimmune neuroinflammation.

Glatiramer acetate (GA) (Copaxone), a well-established drug for the treatment of multiple sclerosis, is believed to modulate numerous pathways including antigen-presenting cells or cytokine responses. A new generation of spontaneous experimental autoimmune encephalomyelitis mouse models has been developed that mimic certain aspects of multiple sclerosis spectrum disorders. We assessed the effects of GA in the opticospinal encephalomyelitis model, which involves MOG35-55 peptide-specific T cells and B cells. A nonsignificant trend toward lower disease incidence was found for GA treatment (started on postnatal day 20). Immunohistochemical evaluations revealed no significant differences for inflammatory lesions and demyelination, cytokine production, proliferation, and cell surface markers of immune cells between GA-treated and PBS-treated (control) mice. Although a good correlation was found between the disease score of individual mice and some readout parameters (eg, immunohistochemical staining), this was not the case for others (eg, IFN-γ production). It seems plausible that a major effect of GA lies on alternative immunological pathways, such as initiating of an immune response that is not sufficiently reflected in this spontaneous experimental autoimmune encephalomyelitis model. Thus, the main advantage of the opticospinal encephalomyelitis model in our hands lies in the elucidation of factors influencing the onset of experimental autoimmune encephalomyelitis (eg, susceptibility factors). The model seems less suitable for investigation of disease severity modifications after therapeutic interventions.

Optimizing immunization services: A Data Envelopment Analysis (DEA) of child immunization facilities in Pakistan.

INTRODUCTION: Child immunization, though cost-beneficial, experiences varying costs influenced by individual facility-level factors. A real-time solution is to optimize resources and enhance vaccination services through proper method to measure immunization facility efficiency using existing data. Additionally, examine the impact of COVID-19 on facility efficiency, with the primary goal of comprehensively assessing child immunization facility efficiency in Pakistan. METHODS: Utilizing survey data collected in four rounds from May 2018 to December 2020, the research focuses on doses administered and stock records for the preceding six months in each phase. In the initial stage, Data Envelopment Analysis (DEA) is utilized to compute facility efficiency, employing two models with varied outputs while maintaining consistent inputs. Model 1 assesses doses administered, encompassing three outputs (pentavalent vaccine 1, 2, and 3). Meanwhile, Model 2, focuses on stock used featuring a single output (total doses used). The inputs considered in both models include stock availability, staff members, cold chain equipment, vaccine carriers, and vaccine sessions. The second stage involves the application of two competing regression specifications (Tobit and Simar-Wilson) to explore the impact of the COVID-19 pandemic and external factors on the efficiency of these facilities. RESULTS: In 12 districts across Punjab and Sindh, we assess 466 facilities in Model 1 and 455 in Model 2. Model 1 shows 59% efficiency, and Model 2 shows 70%, indicating excess stock. Stock of vaccines need to be reduced by from 36% to 43%. In the stage, COVID-19 period reduced efficiency in Model 1 by 10%, however, insignificant in Model 2. CONCLUSIONS: The proposed methodology, utilizing DEA, emerges as a valuable tool for immunization facilities seeking to improve resource utilization and overall efficiency. Model 1, focusing on doses administered indicates facilities low efficiency at average 59% and proves more pertinent for efficiency analysis as it directly correlates with the number of children vaccinated. The prevalent issue of overstocking across all facilities significantly impacts efficiency. This study underscores the critical importance of optimizing resources through the redistribution of excess stock with low efficiency.

Optical coherence tomography angiography suggests different retinal pathologies in multiple sclerosis and Sjögren's syndrome.

BACKGROUND: While retinal vessel changes are evident in the eyes of patients with relapsing-remitting multiple sclerosis (RRMS), changes in the vasculature of possible MS mimics such as primary Sjögren's syndrome (pSS) remain to be determined. We investigated the potential of retinal optical coherence tomography (OCT) angiography (OCTA) as diagnostic tool to differentiate between patients with RRMS and pSS. METHODS: This cross-sectional study included patients with RRMS (n = 36), pSS (n = 36) and healthy controls (n = 30). Participants underwent clinical examination, assessment of visual acuity, retinal OCT, OCTA, and serum markers of glial and neuronal damage. We investigated the associations between OCTA parameters, visual functions, and serum markers. Eyes with a history of optic neuritis (ON) were excluded from analysis. RESULTS: We observed a significant thinning of the combined ganglion cell and inner plexiform layer in the eyes of patients with RRMS but not with pSS, when compared to healthy controls. Retinal vessel densities of the superficial vascular complex (SVC) were reduced in both patients with RRMS and pSS. However, retinal vessel rarefication of the deep vascular complex (DVC) was only evident in patients with pSS but not RRMS. Using multivariate regression analysis, we found that DVC vessel loss in pSS patients was associated with worse visual acuity. CONCLUSIONS: Compared to patients with RRMS, rarefication of deep retinal vessels is a unique characteristic of pSS and associated with worse visual function. Assuming a disease-specific retinal vessel pathology, these data are indicative of a differential affliction of the gliovascular complex in the retina of RRMS and pSS patients.

The Impact of Social Media in Afghanistan: A Multi-Disciplinary Study.

Background: The rapid growth of social media has profoundly transformed communication, community building, and information sharing worldwide. In Afghanistan, the proliferation of social media platforms has significantly impacted the social, cultural, and political landscape, particularly among the youth. Objective: This multi-disciplinary study aims to explore the diverse effects of social media on Afghan youth, focusing on usage patterns, mental health implications, entertainment-driven time allocation, financial expenditures, exposure to explicit content, and academic performance. Methods: A cross-sectional online survey was conducted between September and December 2023, gathering responses from 1556 participants (67% males, 33% females) through various social media platforms. Data were analyzed using SPSS version 26.0, employing statistical tests such as ANOVA and Chi-Square to examine relationships between social media usage and its impacts. Results: The study reveals significant links between social media usage and demographic, behavioral, and mental health factors. Key findings include Facebook as the most used platform (83.6%), with the majority of participants spending 1-3 hours daily on social media. Age differences in time spent were significant (F=15.64, p<0.001). Entertainment was the primary use (45.5%), with gender differences in engagement levels. High anxiety (78.5%) and moderate depression (38.3%) were reported. Significant associations between social media use and mental health were found (eg, χ2=591.87, p<0.001 for nervousness). Excessive use negatively impacted study habits, with 25.7% feeling it hindered their academic performance. Conclusion: This study highlights the multifaceted impacts of social media on Afghan youth, including both positive aspects like enhanced communication and empowerment and negative aspects such as mental health issues and academic challenges. The significant relationships between social media usage and various life aspects underscore the need for targeted interventions to promote healthy digital habits and mitigate adverse effects. Further research is recommended to explore long-term impacts and effective strategies for managing social media use among Afghan youth.

Preventing long-term disability in CIDP: the role of timely diagnosis and treatment monitoring in a multicenter CIDP cohort.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of established biomarkers or risk factors for the development of CIDP and patients' treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy. METHODS: In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy. RESULTS: In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence. CONCLUSION: Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a "hit hard and early" treatment paradigm.

Prevalence of Recurrent Aphthous Ulcers Among Dentistry Students' in Kabul, Afghanistan: A Questionnaire-Based Study.

Introduction: Recurrent aphthous stomatitis (RAS) is the mouth's most common and painful inflammatory ulcerative condition, also called aphthae or canker sores. Its prevalence is about 20% and predisposition factors involve genetics, environmental factors, and immune dysfunctions. Objective: Reviewing the literature and no study was found to show the prevalence and associated factors of recurrent aphthous ulceration in the context of Afghanistan. Therefore, this study aimed to determine the lifetime prevalence and associated factors of recurrent aphthous ulceration among dentistry students at Kabul University of Medical Sciences, Afghanistan. Methods: A cross-sectional questionnaire-based study was carried out among 223 dentistry students. A descriptive and inferential analysis was performed to find the association. Results: The prevalence of (RAS) in our sample group was 30%. (68.7%) of participants had one or more family members who experienced aphthous ulcers and the association was found to be significant (X 2 = 134.940; p < 0, 05). (81%) of participants experienced the condition to eating certain types of food (X 2 = 165.906; p < 0, 05) and (53.7%) of them reported the same about trauma (X 2 = 99.958; p < 0, 05). Regarding stress the difference was also statistically significant (X 2 = 56.830; p < 0, 05). Conclusion: We found that a considerable proportion of the study sample had experienced recurrent aphthous ulceration. Family history, stress, trauma, and dietary factors have an impact on the occurrence of RAS with no association with gender and smoking.

Factors influencing the uptake of short-term contraceptives among women in Afghanistan.

The aim of this study is to assess factors that influence the uptake of short-term contraceptives among married women aged between 15 and 49 years in Afghanistan. The cross-sectional Afghanistan 2015 Demographic and Health Survey provided the dataset for this analysis. We included 22,974 women and applied multivariable logistic regression to investigate the influencing factors for the uptake of short-term contraceptives. 92% of Afghan women knew at least one type of short-term contraception but only 17% were using short term contraceptives. Short term contraceptive use was most prevalent among women in the age group between 30 and 40 who were educated, employed, and rich. Most of the users were living in the western parts of Afghanistan and women from the Balooch and Pashtun ethnic groups were most likely to use short-term contraceptives. Media exposure and women empowerment were also positively associated with the use of short-term contraceptives. We did not find an association with living in urban or rural settings. Contraception promotion in Afghanistan requires multisectoral efforts, tailored to the needs of women from low and middle socioeconomic strata. Health promotion activities, empowering women, strengthening education, and training of service providers on effective counseling are options that should be considered to improve the current situation.

Association of the retinal vasculature, intrathecal immunity, and disability in multiple sclerosis.

Background: Optical coherence tomography angiography (OCT-A) is a novel technique allowing non-invasive assessment of the retinal vasculature. During relapsing remitting multiple sclerosis (RRMS), retinal vessel loss occurs in eyes suffering from acute optic neuritis and recent data suggest that retinal vessel loss might also be evident in non-affected eyes. We investigated whether alterations of the retinal vasculature are linked to the intrathecal immunity and whether they allow prognostication of the future disease course. Material and methods: This study includes two different patient cohorts recruited at a tertiary German academic multiple sclerosis center between 2018 and 2020 and a cohort of 40 healthy controls. A total of 90 patients with RRMS undergoing lumbar puncture and OCT-A analysis were enrolled into a cross-sectional cohort study to search for associations between the retinal vasculature and the intrathecal immune compartment. We recruited another 86 RRMS patients into a prospective observational cohort study who underwent clinical examination, OCT-A and cerebral magnetic resonance imaging at baseline and during annual follow-up visits to clarify whether alterations of the retinal vessels are linked to RRMS disease activity. Eyes with a history of optic neuritis were excluded from the analysis. Results: Rarefication of the superficial vascular complex occured during RRMS and was linked to higher frequencies of activated B cells and higher levels of the pro-inflammatory cytokines interferon-γ, tumor necrosis factor α and interleukin-17 in the cerebrospinal fluid. During a median follow-up of 23 (interquartile range 14 - 25) months, vessel loss within the superficial (hazard ratio [HR] 1.6 for a 1%-point decrease in vessel density, p=0.01) and deep vascular complex (HR 1.6 for a 1%-point decrease, p=0.05) was associated with future disability worsening. Discussion: Optic neuritis independent rarefication of the retinal vasculature might be linked to neuroinflammatory processes during RRMS and might predict a worse disease course. Thus, OCT-A might be a novel biomarker to monitor disease activity and predict future disability.

Skeletal muscle cells actively shape (auto)immune responses.

Histopathological analyses of muscle specimens from myositis patients indicate that skeletal muscle cells play an active role in the interaction with immune cells. Research over the last few decades has shown that skeletal muscle cells exhibit immunobiological properties that perfectly define them as non-professional antigen presenting cells. They are able to present antigens via major histocompatibility complex molecules, exhibit costimulatory molecules and secrete soluble molecules that actively shape the immune response in an either pro- or anti-inflammatory manner. Skeletal muscle cells regulate both innate and adaptive immune responses and are essentially involved in the pathophysiological processes of idiopathic inflammatory myopathies. Understanding the role of skeletal muscle cells might help to identify new therapeutic targets for these devastating diseases. This review summarizes the immunobiological features of skeletal muscle cells, especially in the context of idiopathic inflammatory myopathies, and discusses shortcomings and limitations in skeletal muscle related research providing potential perspectives to overcome them in the future.

Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock?

Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies. Animal models have proven to be tremendously helpful in mechanistic studies and allow researchers to overcome the inevitable restrictions of human research. Although the number of different IIM models has drastically increased over the last few decades, a model that exhibits the phenotypical and histopathological hallmarks of IIM is still missing. Recent publications have shown promising results addressing different pathophysiological issues like mechanisms of onset, chronification or relapse in IIM. However, a standardization of the methodology is critically required in order to improve comparability and transferability among different groups. Here we provide an overview of the currently available IIM models including our own C-peptide based small-peptide model, critically discuss their advantages and disadvantages and give perspectives to their future use.

The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies.

NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naïve CD8+ T cells into highly activated, cytotoxic CD8+NKG2Dhigh T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. CD8+NKG2Dhigh T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68+ macrophages as well as CD4+ T cells, and CD8+NKG2D+ cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.