HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab, 2025, Martín-Martínez et al

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HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab

Eva Martín-Martínez, Sara Gil-Perotin, Karen Giménez-Orenga, Lucas Barea-Moya, Elisa Oltra

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Abstract
This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow up that provided a secondary diagnosis of Multiple Sclerosis (MS) eight years after. The most impactful result being his response to rituximab treatment after the systematic failure of prior treatments.

Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in patients blood supportive of an altered immune system.

Limitations of the study include MRI imaging follow up to monitor lesion progression and reassessment of HERV profiles after rituximab. As an overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered.

Link | PDF (Preprint: Preprints.org) [Open Access]
 
Symptoms/function before and after treatment with Rituximab. Bell went from 10 to 20, so not cured.
The treatment regime consisted of an initial dose of 1 g on days 1 and 15 of the first month, followed by nine monthly doses of 1 g, adjusted based on the repopulation of B cells. This treatment resulted in a significant improvement in fatigue after the third dose, enabling increased mobility and participation in daily activities such as walking and dining out. Prior to treatment, the patient’s condition was as follows:
  • Physically, he was unable to leave the house (only for medical appointments, with significant subsequent deterioration, resulting in an increase in symptoms and increased fatigue requiring continuous rest). He was bedridden most of the day. He was able to perform personal self-care: grooming, dressing, eating at the table, and showering (he had to adapt his bathroom settings and did not do so daily).
  • Cognitively, his computer activity ranged from 10 min to a maximum of one hour a day on days when he felt better.
  • He suffered from a weekly migraine that could last up to three days.
  • He experienced daily symptoms of moderate to severe intensity: dizziness upon standing, feeling immediately tired and unsteady, concentration problems, memory problems, palpitations, and muscle pain.
  • Severe photosensitivity that impaired his vision.
After treatment, the patient’s condition improved at different levels:
  • Physically, he could leave the house 2–3 times a week and take gentle walks for an hour. He could help around the house with simple tasks such as cooking or cleaning, although he could not fully perform these tasks.
  • Cognitively, he could use the computer daily, without the deterioration that used to be triggered, but never for more than an hour at a time.
  • He reported a migraine once a month.
  • The rest of the symptoms persisted, but at a mild to moderate level. He tolerated standing for longer. For muscle pain, he is receiving treatment from a home physiotherapist, and it has almost completely resolved this issue.
  • Photosensitivity persists, and he still requires sunglasses, but it does not impair his vision.
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On the Bell scale for severity assessment, the patient changed from a level of 10 to 20, meaning he doubled his previous capacities. The patient’s neurological condition remains stable, with fatigue stabilized.
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The HERV that has previously been associated with MS, ME/CFS, and LC, HERV-W ENV, wasn't high in this patient. They then looked at HERVs across the whole genome and compared to 8 female ME/CFS and 9 healthy volunteers. The HERV profile clustered closer to ME/CFS than to controls.
In particular, overexpression of the toxic HERV-W ENV protein has been detected in MS patients [33], as well as in ME/CFS and post-COVID conditions [34], indicating a relationship of this protein with post-viral disease chronicity. [...] The results showed that the mean HERV-W ENV level of this patient’s was 1.36 × 105 area under the curve (AUC), which was below the positivity cutoff value (mean AUC: 2.30 × 106), defined as the mean + 2 standard deviations of control samples.
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To further explore potential HERV alterations in this patient, we performed a genome-wide analysis using high-density microarrays, as described in [30]. The results of this study case were compared to those of other age- and BMI-matched ME/CFS cases and healthy volunteers. [...] identified 502 differentially expressed HERV probe sets [...] Hierarchical clustering of HERV expression profiles revealed that the patient’s sample clustered with other ME/CFS cases, despite being from a male subject.
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They looked at the top 29 differentially expressed HERVs between controls and ME/CFS, including this patient, to try to figure out how the HERVs might impact gene function. Some were found to be associated with genes related to the immune system, metabolism, and the nervous system.
To understand the potential cell role of the top overexpressed HERVs in the study case, we first selected those with the highest expression levels in the study case sample with respect to the rest (control or ME/CFS case), which turned out to be 29 out of the 502 differentially expressed (about 6% of them) (Supplementary Table S3), and then searched for their closest annotated genes.[...] The data show that of the 29 HERVs allocated, 10 (34.5%) corresponded with intergenic regions less than 100,000 bp away, while the remaining 19 (65.5%) seemed to be encoded within genes. From the latter, most (thirteen) were encoded within introns (68.4%), four lay within promoter regions (21%), one lay within the 3’UTR region, and one lay within a coding exon (5.3% each). In addition to regulatory lncRNAs and novel transcripts, hit genes were found to be associated with development, infection, metabolism, and neural homeostasis; for example, QKI was involved in myelinization and oligodendrocyte differentiation, and LINGO2 had a role in the glutamatergic synapse.
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The patient also had auto-antibodies against acetylcholine receptors, which might be why Rituximab helped.
The patient displayed auto-antibodies against AchR (AchR-aAbs), which is a typical finding in myasthenia gravis (MG), an autoimmune disease displaying impaired neuromuscular junction transmission with about 85% of patients presenting AchR-aAbs [44]. Thus, a mechanism mediated by AchR-aAbs contributing to patient improvement by rituximab therapy cannot be discarded [45]. However, there are no conclusive studies on the predictive value of these antibodies in asymptomatic patients or those with normal EMG [46]. The patient’s levels were moderately positive, suggesting possible autoimmune disease, but were evaluated in the clinical context. Whether the successful outcome for this patient may be due to other additional factors is presently unknown.
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I haven't looked at this carefully but I suspect they misunderstand what rituximab doe sin MS. It prevents further relapses. If a patient with MS gets better after having rituximab that tells us nothing. It is a relapsing and remitting disease. We only know that rituximab works because of statistical data on the rate of recurrence while B cell depleted in a population. Failure to understand what rituximab is doing is the reason why it took twenty years longer than necessary to get good data on conditions like MS and lupus. It makes one want to tear one's hair out.
 
Jonathan Edwards said:
I haven't looked at this carefully but I suspect they misunderstand what rituximab doe sin MS. It prevents further relapses. If a patient with MS gets better after having rituximab that tells us nothing. It is a relapsing and remitting disease.
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I think they're saying the patient hasn't had a relapse in several years. But also the ME/CFS-like symptoms seem to have slightly improved.
This case report informs of a patient having received an initial diagnosis of ME/CFS (2015), at age 25, and a later diagnosis of MS (2017), at age 27, who, having shown a lack of response to several treatments for the following three years, then showed a striking response to rituximab in 2020, at age 30, continuing in remission until present [...] In this case report, the patient not only showed clear improvement after only three doses of treatment with rituximab, but also his neurological condition remains stable, with reduced fatigue now for some years after the applied 9-month treatment regime.
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forestglip said:
I think they're saying the patient hasn't had a relapse in several years.
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They talk of 'clear improvement after only three doses...' which makes no sense. And people with MS can often go long periods without relapses.

Rituximab îs not going to do anything to MS problems present for three years - because by then the damage will be done and scarred and further recovery will not occur. This is a misunderstanding.
 
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