Mood symptoms and chronic fatigue syndrome due to relapsing remitting multiple sclerosis are associated with immune activation and aberrations in the erythron

Abstract

Background: Multiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood. Objectives: The current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS. Material and Methods: We recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables and used a bio-plex assay to measure 27 serum cytokines. Results: A significant part of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, T helper (Th)1 and Th-17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels. Conclusions: Around 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS.

In major depression, complex intersections between adverse childhood experiences and negative life events impact neuroticism, brooding, suicidal tendencies, insomnia, and cognitive interference

“…A factor extracted from physical and emotional maltreatment and neglect as well as family problems had a substantial, significant direct effect on the phenome, according to this analysis. These results build upon the conclusions drawn by Almulla et al, 22 which indicated that ACEs could predict the phenome of depression. Consistent with previous research (e.g., Hein et al; 50 Peckins et al; 51 Gizdic et al 52 ), our findings demonstrate that distinct subtypes of ACEs are associated with psychopathology in unique ways.…”

“…23,24,73 Furthermore, increased NLEs were found to partially mediate the effects of ACEs on rumination, SB, neuroticism, and the phenome of depression, according to the current study. Almulla et al 22 discovered that NLEs combined with ACEs substantially predict the manifestation of very severe MDD, as well as the lifetime and current suicidal behaviors. These results build upon those of Almulla et al 22 The effects of ACEs on the increases in affective symptoms during the COVID -19 pandemic are partially mediated by increased NLE scores.…”

“…Almulla et al 22 discovered that NLEs combined with ACEs substantially predict the manifestation of very severe MDD, as well as the lifetime and current suicidal behaviors. These results build upon those of Almulla et al 22 The effects of ACEs on the increases in affective symptoms during the COVID -19 pandemic are partially mediated by increased NLE scores. 74 Maes and Almulla 27 identified a similar pattern to the present study:…”

“…17,18 Cognitive dysfunction and emotional dysregulation, as well as an increased risk of developing psychopathology and late-life cognitive impairment, such as major depressive disorder (MDD), may result from daily hassles and exposure to NLEs . [19][20][21][22][23][24][25] MDD was predicted by increased daily hassles in a 14-24-year-old cohort. 23 Maybery 26 identified a correlation between perceived distress among university students and adverse interpersonal (e.g., financial, and familial) and noninterpersonal (e.g., academic) events.…”

Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 82 studies comprising 58 cytokines/chemokines/growth factors

“…The cytokines and chemokines belonging to the neurotoxicity profile all show a potential to damage the function or structure of neuronal cells or affect neuroplasticity or neurogenesis (Maes and Carvalho 2018, Almulla, Abbas Abo Algon et al 2023, Almulla, Abdul Jaleel et al 2023, Sreenivas, Maes et al 2024.…”