Impaired regulatory function in circulating CD4+CD25highCD127low/− T cells in patients with myasthenia gravis

Abstract

Previous studies have reported alterations in numbers or function of regulatory T cells (Tregs) in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous “Treg” populations. In this study, we used surface CD4, CD25high, and CD127low/− expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg-mediated suppression of responder T cells (Tresp) was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target.

AChR-specific immunosuppressive therapy of myasthenia gravis

“…CD4 + CD25 + FoxP3 + regulatory T cells have a key role in controlling autoimmunity and maintaining immunologic selftolerance [105]. Recent studies have reported functional defects of CD4 + CD25 + regulatory T cells from thymuses of MG patients and reduction in peripheral regulatory T cell population in untreated MG patients [106][107][108][109][110][111][112]. Impairment of suppressive activity of regulatory T cells and reduction in frequency of regulatory T cells in the spleen and peripheral blood were also demonstrated in EAMG rats [113,114].…”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…An extension of these observations is that defects in Treg number or function may underlie the development of human autoimmune disorders. Importantly, Tregs have been implicated in preventing autoantibody production by self-reactive B cells [75][76][77], and dysfunction or deficiencies of Tregs have been demonstrated in MG [63,[78][79][80][81].…”

The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics

“…Multiple sclerosis, psoriasis, Type I diabetes and also AChR-MG patients show a significant decrease in the suppressive function of Tregs compared with HC [10,[67][68][69]. This section focuses on discussing the several studies that have been undertaken on characteristic, quantitative and qualitative changes of Tregs in MG patients.…”

“…Several studies have demonstrated that Tregs from AChR-MG have a severe defect in their suppressive function, suggesting a role for Tregs abnormalities in MG pathogenesis [10][11][12]. Once T/B cells are activated, one could expect their activation status to be regulated by Tregs; but, since AChR-MG Tregs are dysfunctional, they cannot suppress the pathological responses of those cells that lead to the high level of autoreactive cells, which can extend inflammation and autoimmunity.…”