ME/CFS Research Foundation invests €2.4 million in new research projects 

Growing scientific evidence suggests that autoantibodies and dysregulated B cells play a significant role in a subset of ME/CFS patients. In studies—including those conducted at Charité – Universitätsmedizin Berlin — immunoadsorption (the removal of circulating antibodies from the blood) led to marked, though only temporary, clinical improvement in some treated patients; this is likely because the procedure has only a limited effect on the antibody-producing B cells themselves. The targeted elimination of antibody-producing cells using therapeutic monoclonal antibodies is an established treatment strategy for various autoimmune diseases. The TAME project is investigating the CD19 antibody tafasitamab as a potential new treatment for ME/CFS. Tafasitamab targets B cells and plasmablasts involved in the production of disease-relevant autoantibodies. Tafasitamab is being administered as a direct follow-up treatment in a study succeeding the PIONEER trial (funded by the Federal Ministry for Research, Technology and Space, BMFTR), in which the CD19 antibody inebilizumab was used. The aim is to determine whether tafasitamab can achieve or maintain B-cell depletion and clinical remission as effectively as inebilizumab. While tafasitamab is significantly less expensive than inebilizumab, data regarding its use in autoimmune diseases remain limited. The TAME study will involve 38 patients who previously participated in the PIONEER trial. Depending on their original PIONEER study arm, patients receive tafasitamab under different treatment regimens—either as an initial B-cell-depleting therapy or as maintenance therapy following prior treatment with inebilizumab. The study aims to provide important insights into whether CD19-targeted B-cell therapy is a promising therapeutic approach for an immunologically defined subgroup of ME/CFS.

This project addresses an important gap in ME/CFS research by focusing on families in which several members are affected. Such familial clustering suggests that inherited genetic factors may contribute to disease susceptibility. The project will establish a deeply characterised cohort of 50 families with at least two affected members. Participants will undergo standardised clinical, neurological, and neuropsychological assessments, and severely affected individuals will be included through home visits. Blood samples will undergo state-of-the-art long-read whole-genome sequencing (WGS) to identify complex genetic variation, structural variants, repeat expansions, and DNA methylation patterns that may contribute to disease susceptibility. Additional biospecimens will be stored in the Hannover Unified Biobank to enable future studies of immune function and other molecular mechanisms. By combining comprehensive clinical phenotyping with advanced genomic technologies, the project aims to identify genetic susceptibility factors for post-infectious ME/CFS, improve disease stratification, and establish a sustainable resource for future research. Ultimately, the findings are expected to support the development of improved biomarkers, more precise diagnostics, and targeted therapeutic strategies.

Children and young people living with post-infectious conditions such as ME/CFS or Long COVID are usually treated as if they were all suffering from the same condition. However, it is reasonable to assume that different biological processes underlie these similar symptoms. STRAT4PAIS is systematically investigating this hidden diversity for the first time. The starting point is four post-infectious clinical presentations: abnormal circulatory and cardiac rhythm responses; a persistent immune response to viral infections; autoimmune processes; and headaches in which, amongst other things, increased intracranial pressure can be detected. The aim is to determine whether these four clinical presentations are underpinned by four distinct biological mechanisms. To clarify this, the immune systems of the affected children and adolescents will be examined using state-of-the-art single-cell analysis methods (single-cell technologies). At the heart of this is single-cell transcriptome analysis (scRNA-seq): following targeted cell sorting, the gene activity of each individual immune cell is analysed, supplemented by the individual immune receptors of the T and B cells (TCR/BCR repertoire) and selected surface proteins. This enables the identification of exhausted antiviral T-cell states and autoreactive B-cell programmes; in parallel, the innate immune system is analysed (NK cells, monocytes, dendritic cells). High-dimensional flow cytometry verifies findings across the entire cohort, whilst a broad protein multiplex analysis (~250 mediators) captures the inflammatory response. Furthermore, the test screens for traces of reactivated herpesviruses (e.g. Epstein-Barr virus) and autoantibodies. Measurements are taken at various stages of the disease course: during periods of stability, during post-exertional malaise (PEM) and during a febrile infection. It is precisely these critical moments, when the body is under stress, that could reveal correlations which remain hidden at rest. And because the same patients are compared with themselves in different states, it may be possible to identify the disease-driving changes with particular clarity. Using all this data, the aim is to determine which patients are biologically similar to one another and can be assigned to common endotypes. The aim is to highlight what distinguishes these children and young people from one another biologically, and to pave the way for future treatments to target the specific underlying cause. STRAT4PAIS is linked, amongst other projects, to the PEDNET-LC project funded by the Federal Ministry of Health (BMG).

Programmed cell death is a key bodily defence mechanism following infections such as SARS-CoV-2; as part of the immune response, it enables the targeted elimination of infected cells, thereby limiting the spread of pathogens. However, programmed cell death can simultaneously release pro-inflammatory molecules and signals that damage tissue. This process triggers sustained immune activation, which may contribute to the pathogenesis of post-viral illnesses and the development of characteristic long-term sequelae. Yet, it remains unclear how these cell death mechanisms sustain disease-relevant chronic inflammatory responses, in which organs these processes occur, and how they contribute to the multisystemic symptoms of ME/CFS. The aim is to characterise the causal links between virus-induced cell death, chronic inflammation, and disease-specific symptoms. To this end, the investigators combine a preclinical in-vivo model of post-COVID syndrome with genetic functional analyses, advanced whole-body and intravital imaging, and the analysis of longitudinal blood samples from patients with post-COVID ME/CFS. This approach links molecular processes at the cellular level with organ changes, functional effects, and clinical courses, thereby enabling the differentiation of causal signalling pathways from correlative findings. The focus lies on signalling pathways involved in programmed cell death and associated inflammatory responses linked to post-COVID ME/CFS. A two-stage imaging approach allows, for the first time, the systematic mapping of cell death and inflammation signatures throughout the entire organism. The identification of these signatures is being validated in a clinical ME/CFS cohort to pinpoint disease-relevant blood and tissue markers as well as potentially druggable signalling pathways. The project aims to provide fundamental mechanistic insights into the pathogenesis of post-infectious diseases. It lays the foundation for mechanism-based diagnostics, improved patient stratification, and the targeted repurposing of cell-death-modulating and anti-inflammatory treatments for ME/CFS and post-COVID syndrome.

The investigators hypothesise that the initiating event in post-COVID ME/CFS is damage to the inner lining of blood vessels (endothelium): once the virus attaches to the blood vessel walls, it disrupts their protective barrier, exposing signalling proteins on the vessel surface to the immune system. They further hypothesise that the immune system, in attempting to respond, generates antibodies that mistakenly target these proteins — and that these G-protein coupled receptor (GPCR) autoantibodies are not innocent bystanders but active drivers of cardiovascular injury. By causing blood vessels to constrict, promoting scarring of the heart muscle, and making vessel walls leaky, they reduce the volume of blood circulating in the body and stiffen the heart. The heart compensates by beating faster, but its capacity to respond to physical effort becomes critically limited — a pattern similar to a form of heart failure in which the muscle is stiff rather than weak.

The MYOFLAME-19 trial tested whether this cascade could be interrupted using two complementary treatments: losartan, to relax blood vessels and reduce scarring, and low-dose prednisolone, to calm the immune response driving antibody production. With the results of MYOFLAME-19 still being processed, this new project asks, for the first time in a context of controlled clinical trial, whether the treatment reduced the levels of these self-targeting antibodies and whether any such reduction explains the improvements in symptoms and heart function seen in patients who received active treatment. Using blood samples already collected from all MYOFLAME-19 participants, this study — as a sub-study to MYOFLAME-19 — will aim to provide direct evidence linking targeted treatment to a reduction in these harmful antibodies: a meaningful step forward in understanding and treating the immune underpinnings of ME/CFS with heart involvement.

Current evidence suggests that autoimmunity plays an important role in ME/CFS and post-COVID-Syndrome (PCS) and the similarity of symptoms suggests that both share a common pathophysiology. Detection of functional GPCR autoantibodies correlated with fatigue in PCS patients but so far, it is unclear why only subgroups of patients responded to autoantibody targeting treatments. Therefore, additional biomarkers are needed to delineate the role of autoimmunity in ME/CFS and PCS and to monitor the effectiveness of immunomodulatory treatments. One promising strategy in this context is the analysis of B-cell receptor (BCR) and T-cell receptor (TCR) repertoire of ME/CFS and PCS patients to detect potentially expanded or autoreactive clones that can be targeted. In contrast to bulk sequencing, single-cell RNA sequencing (scRNA-seq) is much more sensitive for the detection of clonally expanded immune cell receptors (IRs) as it allows the delineation of the complete BCR and TCRs in single cells and can provide information regarding the differentiation state and the metabolic activity of cells with distinct BCRs and TCRs. The investigators hypothesise that scRNA-Seq of the immune receptor repertoire could be a sensitive biomarker to assess the pathogenesis of ME/CFS and PCS and to monitor the response to immunomodulatory treatments. Within this project, they seek to identify clonally expanded and potentially autoreactive BCRs and TCRs in the peripheral blood from ME/CFS and PCS patients and map these to epitopes. BCR epitope pairs will furthermore be validated in-vitro and clonally expanded immune receptors will be compared between ME/CFS and PCS patients and healthy controls. Additionally, they plan to analyse the effect of treatments such as BC007 and corticosteroids on the TCR and BCR repertoire of ME/CFS and PCS patients regarding the potential elimination or functional attenuation of expanded and potentially autoreactive immune receptors.

The diagnosis of ME/CFS is currently based on established clinical criteria; objective diagnostic biomarkers are not yet available. However, biomarkers could complement clinical diagnosis by enabling standardised patient classification, reducing diagnostic uncertainty and delays, and serving as objective measures for clinical trials. Biomarkers are also gaining importance as research indicates biological heterogeneity in ME/CFS, with immunological dysregulation and autoimmune mechanisms playing a central role in a subset of patients. The project aims to develop minimal biomarker panels for the diagnosis and biological stratification of ME/CFS patients. Building on existing high-dimensional immune and proteomics data, machine learning methods will be used to identify biomarker combinations that offer the highest possible diagnostic performance. Complex biological signatures will be reduced to a small number of informative biomarkers, and the study will assess whether these panels enable reliable diagnosis and allow for biological stratification into clinically relevant endotypes (patient groups characterised by distinct biological disease mechanisms). This approach aims to lay the groundwork for more objective diagnostics and more targeted treatment decisions. The project results are intended to form the basis for further analytical and clinical validation, as well as for regulatory development into an in-vitro diagnostic (IVD) product. In doing so, the project aims to make a significant contribution to improving diagnostics and to establish a foundation for future personalised treatment of ME/CFS.