Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients. ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for the assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a subgroup-specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP). Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Keywords: debilitating disease; immunodeficiencies; immunology; intestinal barrier leakage; mucosal barrier function; myalgic encephalomyelitis/chronic fatigue syndrome; patient stratification; post-viral fatigue.

Figure 1

Patient stratification based on immunological parameters. The information on immunodeficiencies of patients was obtained during medical examinations of already diagnosed ME/CFS patients prior to study participation. All patients were recruited in the doctor’s office of Assoc.-Prof. Eva Untersmayr.

Figure 2

(A) No statistically significant differences in plasma C4a level were found comparing ME/CFS patients with healthy controls. (B) After immunological patient stratification, concentrations of plasma C4a samples are significantly reduced in patients with immunodeficiencies (ME/CFS + ID) compared to patients without immunodeficiencies (ME/CFS − ID) and healthy control participants. LOD: 6 pg/mL; * p < 0.05. ** p < 0.01.

Figure 3

(A) Significantly reduced serum IL-1-beta levels were found when comparing ME/CFS patients without immunodeficiencies to healthy control participants. (B) Serum IL-6 levels were significantly elevated in ME/CFS patients without immunodeficiencies compared to healthy control participants. LOD: 2 pg/mL; * p < 0.05.

Figure 4

(A) When comparing ME/CFS patients to healthy control participants, no statistically significant differences in serum LBP level were found. (B) Only after immunological patient stratification was serum LBP level significantly elevated in patients without immunodeficiencies (ME/CFS − ID) compared to healthy control participants. (C) A similar effect was detected when comparing the LBP/sCD14 ratio of all ME/CFS patients to healthy control participants. (D) Again, only after immunological stratification did ME/CFS patients without immunodeficiencies show a significantly higher LBP/sCD14 ratio compared to the other test groups. LOD (LBP): 0.82 ng/mL; * p < 0.05.