Pathophysiology 5: immune dysregulation in Long COVID with ME/CFS

Pathophysiology 5: immune dysregulation in Long COVID with ME/CFS

Some of the most severely affected individuals amongst Long COVID patients are those who suffer from encephalomyelitis/chronic fatigue symptom (ME/CFS). A recent study focused on the immunological differences of this particular subgroup and people who fully recovered from COVID-19.

In the blog series pathophysiology, we address new findings regarding the mechanisms in one’s body that change during Long COVID. So far, we took a closer look at the immune system, biomarkers, the microbiome and a proposition for characterizing different sub phenotypes of the disease.

Moreover, in an interview with the scientist Dr. Carlo-Cervia Hasler, we discussed, what could be the impact of new pathomechanistic findings such as the identification of new biomarkers.

In a recently published study researchers assessed the differences in the immune system of a particularly affected subgroup of Long COVID patients: patients with confirmed myalgic encephalomyelitis/chronic fatigue symptom (ME/CFS) diagnosis.


Study Pooulation Immunological Dysregulation Saito Et Al

Study population; red = male participants, blue = female participants.


Study population

The study comprised 2 cohorts. In the first cohort, 33 healthy controls, 57 Long COVID patients with ME/CFS and 41 people who fully recovered from COVID-19 were included. The second cohort, a validation cohort, comprised 34 Long COVID patients with ME/CFS and 34 recovered patients. While participants in cohort 1 have not been vaccinated at the time of sample acquisition, around two thirds of participants in cohort 2 have been vaccinated. However, most of them were infected with SARS-CoV-2 prior to their vaccination against the virus.

Moreover, all participants in cohort 1 with a confirmed SARS-CoV-2 infection had been infected with the original virus variant from 2020, while participants in the second cohort were mainly infected with the delta or omicron variants of the virus.

ME/CFS was confirmed using the De Paul Symptom Questionnaires assessing the frequency and severity of the symptoms. Eligible patients for the Long COVID with ME/CFS group had to score a high frequency of at least moderate symptoms over the last 6 months across 6 symptom categories (fatigue, post-excertional malaise, sleep difficulties, pain neurological/cognitive manifestations and other).

In both cohorts the groups of recovered people and Long COVID patients were age and sex matched with a ~70% of participants in each group being female. The majority of participants had a mild course during the acute COVID-19 infection and around three quarters of patients were under the age of 57.


Key immunological findings

The blood samples of patients suffering from Long COVID with ME/CFS and of fully recovered people were analyzed 12 months after confirmed SARS-CoV-2 infection. Significant differences in the expression of proteins related to immunological dysregulation, chronic inflammation, and erythropoiesis were observed between participants with Long COVID and ME/CFS versus recovered participants.

The researchers observed reduced lymphocytes (white blood cells that are responsible for the response of the adaptive immune systems) but increased neutrophils (white blood cells that are crucial in the innate immune systems response to infections), monocytes (white blood cells that are part of the innate immune system; monocytes differentiate into macrophages and dendritic cells and help digesting pathogens) and CD71+ erythroid cells (CECs; immature red blood cells) in patients with Long COVID and ME/CFS compared to recovered participants.

These changes in the composition of blood cells suggest that the development of stem cells into different blood cell types (hematopoiesis) is impaired in patients suffering from Long COVID with ME/CFS.

A dysregulated hematopoiesis could be a result of impaired antiviral response and an increased response of the innate immune system. This hypothesis is supported by the finding, that cytokines and chemokines such as several interleukins, tumor necrosis factor a (TNF-a), monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein (CRP) as well as Galactin-9 (Gal-9; a protein that helps regulate inflammation, supports immune cell signaling and can induce cell death (apoptosis)) were significantly elevated in both Long COVID cohorts.

Consistent with the observed immune dysregulation, levels of the cytokine transforming growth factor b1 (TGF-b1; a protein that controls cell growth, cell proliferation, cell differentiation, and apoptosis) were increased in Long COVID patients.

Furthermore, a decline in mucosal-associated invariant T (MAIT) cells was observed, which could be caused by the increase in Gal-9. MAIT cells are T lymphocytes that are primarily found in mucosal tissue (e.g., lungs, liver, gastrointestinal) and are susceptible to Gal-9-induced apoptosis.

Interestingly, most of the mentioned factors were also altered in recovered patients 12 months after infection compared to healthy controls (people that have never been infected with SARS-CoV-2). However, the differences were less pronounced than the differences between Long COVID patients and healthy controls.

An impaired antiviral response as suggested by the increase in cytokines/chemokines, can increase antigen persistence and promote chronic inflammation. This may lead to enhanced T cell differentiation, which is supported by the observed decrease of naïve T cells in Long COVID patients. Changes in T cell differentiation have been reported previously and were discussed in more detail in one of our previous blog posts.

In addition to these alterations, the increase in neutrophils and CECs could enhance oxidative stress since they are a potential source for reactive oxygen species (ROS). Moreover, CECs have been reported to express artemin (ARTN). This relates well with the observed higher levels of ARTN in Long COVID patients with ME/CFS as compared to recovered controls.

ARTN has been shown to play a role in osteoarthritic pain. Indeed, the researchers found a correlation between ARTN levels and pain indexes reported by Long COVID patients. An additional correlation was found between ARTN levels and cognitive impairment scores, which supports a potential role of ARTN in the pathogenesis of Long COVID.

Similar to previous reports, the study showed that females are more prone to develop Long COVID than males, potentially due to the more robust immune responses in females.

Finally, the authors of the study were able to reliably discriminate between the Long COVID group and the recovered group using a regression model based on the expansion of two types of T cells (TIM-3+CD160+ and 2B4+CD160+ CD8+). Moreover, the regression model could distinguish between the two groups by an increase in CD4TE and CD8TE T cells, ARTN, CECs, Gal-9, and the cytokine MCP1, coupled with a decrease in TGF-β1 cytokine and MAIT cells.


Results Immunological Dysregulation Saito Et Al

Overview of observed immunological differences between Long COVID patients with ME/CFS and recovered controls.



The study shows significant immunological differences between Long COVID patients with ME/CFS and participants who have recovered from COVID-19 as well as those who have never been infected with SARS-CoV-2.

The immunological insights add to the growing body of evidence supporting the role of the innate and adaptive immune system, hematopoietic dysregulation, T cell exhaustion, and chronic inflammation in Long COVID with ME/CFS. Understanding these pathophysiological mechanisms is crucial for clear diagnosis and development of effective treatments.