Fatigue Is Not Associated with Impaired Function of Regulatory T Cells in Untreated Patients with Multiple Sclerosis

Abstract

Background: The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients. Methods: In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls. Results: Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25– cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity. Conclusions: Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients.

Is there a link between inflammation and fatigue in multiple sclerosis?

“…However, given the existence of some conflicting data in this domain, such an association merits further investigation. Finally, concerning T-cell population (ie, CD3 + CD4 + T lymphocytes 50 or regulatory T cells 57 ) or peripheral markers of inflammation (ie, CRP, erythrocyte-sedimentation rate, and soluble ICAM1), 45 , 58 , 59 few data were available, and these studies failed to find a link between MS fatigue and these measures. It is also worth noting that studies differed greatly in the clinical characteristics of their cohorts, especially concerning treatment profiles.…”

“…Fatigued and unfatigued MS patients did not differ with regards to the amount of IFNγ-producing CD3 + CD4 + T lymphocytes in one study 50 or the number of leukocyte and lymphocyte subsets including regulatory T cells and its suppressive function in another study. 57 …”

Fatigue in Multiple Sclerosis Is Associated with Reduced Expression of Interleukin-10 and Worse Prospective Disease Activity

“…In particular, in MS patients with fatigue, higher production capacity, increased mRNA expression, and serum levels of specific inflammatory molecules such as IL-6 and TNF have been reported [ 8 , 10 , 11 ]. However, the association between fatigue in MS and peripheral inflammatory molecules is still unclear; in fact, some investigations have not reported significant associations, and most studies have been conducted on small samples [ 12 , 13 , 14 , 15 , 16 ]. Assessment of intrathecal cytokine levels may help to identify markers of fatigue directly related to MS-specific mechanisms [ 17 ].…”

Fatigue in A sample of Egyptian Multiple Sclerosis Patients: A Cross Sectional Study

“…Although the available evidence was restricted, serum proinflammatory cytokines [i.e., IL6, TNF, and IFN] appeared to be linked to MS fatigue [5] . Finally, a few data were available on the T-cell population [CD3+, CD4+ T lymphocytes] [11] or regulatory-T cells [12] or peripheral markers of inflammation [CRP, ESR, and soluble ICAM1] [13][14][15] , and such studies failed to find a correlation between MS fatigue and these measures [5] .…”