Tag: Mella

Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystemic disorder mostly triggered by viral infections, with core symptoms including post-exertional malaise (PEM), fatigue, pain, and cognitive dysfunction. Its prevalence has increased significantly in the context of the coronavirus disease 2019 (COVID-19) pandemic. Despite its severity and impact on patients’ quality of life, ME/CFS remains poorly understood.

On May 12 and 13, 2025, the 3rd International Conference hosted by the Charité Fatigue Center brought together nearly 200 researchers from various disciplines on-site, and around 3,700 participants online to discuss recent advances in ME/CFS research, diagnostics, clinical care, and therapeutic trials. The program featured 33 lectures by international experts on key topics such as post-COVID syndrome (PCS), care structures, and pathophysiological mechanisms including cardiovascular dysregulation, immune dysregulation, autoimmune mechanisms, and metabolic dysfunction.

In addition, results from clinical trials addressing disease mechanisms, including those specifically targeting autoantibodies, were presented. While public awareness and funding opportunities have increased in the wake of the pandemic and the emergence of PCS, ME/CFS remains severely underresearched. Sustained and adequately funded research efforts are urgently required to advance understanding, identify diagnostic markers, and develop targeted therapeutic interventions.

Source: Fehrer A, Windzio L, Schoening S, Steiner S, Aschenbrenner AC, Babel N, Behrends U, Bellmann-Strobl J, Cammà G, Cash A, Doehner W, den Dunnen J, Fluge Ø, Franke C, Hoffmann K, Kedor C, Kim L, Löhden W, Mella O, Mihatsch LL, Peluso MJ, Puta C, Putrino D, Ramoji A, Sato W, Sawitzki B, Schlieper G, Schoenfeld Y, Seifert M, Sigurdsson F, Slaghekke A, Sommerfelt K, Sotzny F, Stein E, Steinacker JM, Stingl M, Systrom DM, Tronstad KJ, Wirth K, Wörmann B, Wüst RCI, Yamamura T, Scheibenbogen C. Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center. Autoimmun Rev. 2026 Mar 25:104043. doi: 10.1016/j.autrev.2026.104043. Epub ahead of print. PMID: 41895458. https://www.sciencedirect.com/science/article/pii/S1568997226000571 (Full text)

Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition often triggered by infections, with unclear mechanisms and no established biomarkers or treatments. We apply aptamer-based serum proteomics to 50 ME/CFS patients and 29 healthy controls, analyzing 7,326 protein targets.

We identify 1,823 aptamers with significant differences between the groups (845 after false discovery rate [FDR] correction). Distinct patterns of tissue- and process-specific changes are seen. There is a broad increase in secreted proteins, while intracellular proteins, e.g., from skeletal muscle, particularly show reduction. Immune cell-associated signatures indicate immune reprogramming, including a distinct reduction in proteins secreted by activated neutrophils. Focused secretome analysis supports intensified regulatory interactions related to immune activity, inflammation, vasculature, and metabolism.

Validation of measurements using antibody-based methods confirms findings for a selection of proteins. The uncovered serum proteome patterns in ME/CFS patients may contribute to understanding the pathophysiology and inform future biomarker research and therapeutic development.

Source: Hoel A, Hoel F, Dyrstad SE, Chapola H, Rekeland IG, Risa K, Alme K, Sørland K, Brokstad KA, Marti HP, Mella O, Fluge Ø, Tronstad KJ. Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights. Cell Rep Med. 2026 Mar 4:102647. doi: 10.1016/j.xcrm.2026.102647. Epub ahead of print. PMID: 41785863. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00064-9?rss=yes (Full text)

Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells.

The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls.

Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses.

Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 %CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 %CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 %CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 %CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 %CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

Source: Ramadan DJ, Kichula KM, Tao S, Porfilio T, Lande A, Fluge Ø, Mella O, Strand EB, Saugstad OD, Norman PJ, Lie BA, Viken MK. Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Brain Behav Immun. 2025 Aug 31:106098. doi: 10.1016/j.bbi.2025.106098. Epub ahead of print. PMID: 40897283. https://www.sciencedirect.com/science/article/pii/S0889159125003332 (Full text)

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Abstract:

Background: Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods: A case-control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors-vildagliptin, saxagliptin, and linagliptin-on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results: ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions: SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

Note: See Correction: SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Source: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I, Moezzi A, Leveau C, Rompré P, Godbout C, Mella O, Fluge Ø, Moreau A. SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis. J Transl Med. 2025 Jul 7;23(1):748. doi: 10.1186/s12967-025-06829-0. PMID: 40624584; PMCID: PMC12236014. https://pmc.ncbi.nlm.nih.gov/articles/PMC12236014/ (Full text)

Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) -a clinical pilot study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) entails low quality of life for patients and massive societal costs. There is an urgent need for elucidation of disease mechanisms and for rational treatment. Our working hypothesis is that ME/CFS in a subgroup of patients is associated with functional autoantibodies emerging after an infection, and that plasma-cell depletion with transient reductions in serum immunoglobulins will have a beneficial effect on symptoms.

Objective: To evaluate feasibility and toxicity of plasma-cell targeting treatment using subcutaneous anti-CD38 antibody daratumumab (Darzalex) in moderate to severe ME/CFS, and to assess the clinical course through 12-24 months follow-up. Methods: We performed an open-label pilot trial (EudraCT 2022-000281-18). Ten female patients were enrolled. Following 12 weeks run-in, six patients received four daratumumab injections. The next four patients received four, followed by three additional injections from week 20.

Results: All planned treatments were administered, and there were no serious adverse events. Four patients had no significant clinical changes. Six patients experienced marked improvement. For all ten patients, mean SF-36 Physical Function (SF-36 PF) increased from 25.9 to 55.0 at eight to nine months (p=0.002). In six responders, mean SF-36 PF increased from 32.2 to 78.3. Five of these had major and sustained improvement with a mean SF-36 PF of 88 (range 80 to 95) toward end of follow-up. Mean steps per 24 hours was 3359 (range 1493 to 6277) at baseline. At eight to nine months, the mean number of steps was 5862, and 7392 in the six responders. All five patients with sustained improvement reached a mean step count above 10000/24h for some weeks, and above 15000 on individual days. Relative reduction of serum IgG levels was 54% in patients with clinical improvement, and 40% in those with no benefit. Low baseline NK-cell count in blood was associated with lack of clinical response.

Conclusion: Subcutaneous daratumumab was well tolerated. In six ME/CFS patients, treatment was associated with clinical improvement and concurrent transient reduction of serum IgG levels, indicating pathomechanistic roles for long-lived plasma cells and functional autoantibodies. No definite conclusions should be drawn before a randomized study has been performed.

See: Correction

Source: Øystein Fluge, Ingrid Gurvin Rekeland, Kari Sørland, Kine Alme. Kristin Risa, Ove Bruland, Karl Johan Tronstad, Olav Mella. Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) -a clinical pilot study.
Front. Med., Sec. Infectious Diseases: Pathogenesis and Therapy, Volume 12 – 2025 | doi: 10.3389/fmed.2025.1607353  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1607353/abstract

Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.

Objective: In this study, we aimed to characterize gastric motility and gastric symptoms in response to a liquid meal.

Methods: We included 20 patients with ME/CFS with abdominal complaints who were recruited to a double-blind randomized placebo-controlled trial of Rituximab. The patients of this sub study were examined with an ultrasound drink test, and gastrointestinal symptoms were evaluated using the Rome III questionnaire and Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) questionnaire.

Results: We found that patients commonly reported fullness/bloating (75%), abdominal pain (45%) and nausea (35%). Ultrasound measurements revealed lower proximal measurements of the stomach after a meal (p < 0.01) and larger fasting antral area (p = 0.019) compared to healthy controls. The patients had a stronger symptomatic response to the liquid meal compared to healthy controls regarding epigastric pain, discomfort and nausea (p < 0.05). Ninety percent of the patients reported bowel movement frequencies within the normal range but scored high on bowel habit dissatisfaction and life disruption.

Conclusion: The patients presented with fullness/bloating, nausea and epigastric pain, showed signs of impaired gastric accommodation and visceral hypersensitivity, showing that the gastrointestinal symptoms of ME/CFS patients are similar to functional dyspepsia.

Key summary:

  • Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.

  • In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal.

  • Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test.

  • Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome.

Source: Steinsvik EK, Hausken T, Fluge Ø, Mella O, Gilja OH. Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. Scand J Gastroenterol. 2023 Feb 2:1-8. doi: 10.1080/00365521.2023.2173533. Epub ahead of print. PMID: 36728717. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280942 (Full text)

Endothelial dysfunction in ME/CFS patients

Abstract:

Objective: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.

Study design: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures.

Results: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline.

Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

Source: Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø. Endothelial dysfunction in ME/CFS patients. PLoS One. 2023 Feb 2;18(2):e0280942. doi: 10.1371/journal.pone.0280942. PMID: 36730360; PMCID: PMC9894436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894436/ (Full text)

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).

Materials and methods: In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire-Short Form (DSQ-SF).

Results: The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%-79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.

Conclusion: Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.

Source: Rekeland IG, Sørland K, Bruland O, Risa K, Alme K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. PLoS One. 2022 Sep 19;17(9):e0274472. doi: 10.1371/journal.pone.0274472. PMID: 36121803. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274472 (Full text)

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants.

We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10-8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls).

We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

Source: Ueland M, Hajdarevic R, Mella O, Strand EB, Sosa DD, Saugstad OD, Fluge Ø, Lie BA, Viken MK. No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Transl Psychiatry. 2022 Jul 11;12(1):277. doi: 10.1038/s41398-022-02046-1. PMID: 35821115. https://www.nature.com/articles/s41398-022-02046-1 (Full text)

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci

Highlights:

• Largest ME/CFS genetic study to date.

• Three different cohorts totaling >2500 patients.

• First Immunochip study in ME/CFS.

• Possible implication of TPPP genetic region.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date.

In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance.

In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

Source: Hajdarevic R, Lande A, Mehlsen J, Rydland A, Sosa DD, Strand EB, Mella O, Pociot F, Fluge Ø, Lie BA, Viken MK. Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci. Brain Behav Immun. 2022 Mar 19:S0889-1591(22)00078-2. doi: 10.1016/j.bbi.2022.03.010. Epub ahead of print. PMID: 35318112. https://www.sciencedirect.com/science/article/pii/S0889159122000782 (Full study)