Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-β Therapy

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Studies in animal models of MS have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by T cells is necessary for development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients, and to determine the effect of interferon-beta (IFN-β) therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-β were characterized in samples of untreated and IFN-β-treated MS patients vs. healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF+ CD4+ and CD8+ T cells in PB compared to healthy controls and IFN-β-treated MS patients. IFN-β significantly suppressed GM-CSF production by T cells in vitro. A number of CD4+ and CD8+ T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-β therapy, namely suppression of GM-CSF production.

Interleukin‐17‐ and interleukin‐22‐secreting myelin‐specific CD4+ T cells resistant to corticoids are related with active brain lesions in multiple sclerosis patients

“…11 Some other studies have demonstrated high serum levels of IL-22 in MS during clinical relapses. Interleukin-22, along with IL-21 and IL-17, is considered part of the Th17 signature.…”

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

“…Consistent with this report, in our study, AxD astrocytes from patient iPSCs exhibited increased amounts of secreted GM-CSF, IL5, IL6, and TNFα. GM-CSF, IL6, and TNFα are well known as proinflammatory cytokines and are upregulated in various kinds of white matter diseases, including multiple sclerosis (MS) and neuromyelitis optica (NMO) [25][26][27][28]. IL-5 is a Th2 cell-type cytokine that is secreted by astrocytes and microglia [29], turning on the switch of inflammatory response by activating microglia to upregulate inflammatory response in the brain, cooperating with GM-CSF [30,31].…”

T Cell-Derived GM-CSF, Regulation of Expression and Function

“…Outside of incidence, the frequency of GM-CSF-producing CD4 + in MS is also associated with disease severity [27]. IFN-β, a drug prescribed to control MS progression, may function in part through suppressing GM-CSF expression by peripheral blood T cells of MS patients [28]. Of note, however, there is a discrepancy in these reports as to whether the frequency of GM-CSF-producing CD8 + T cells was also elevated in MS patients [27,28].…”

“…IFN-β, a drug prescribed to control MS progression, may function in part through suppressing GM-CSF expression by peripheral blood T cells of MS patients [28]. Of note, however, there is a discrepancy in these reports as to whether the frequency of GM-CSF-producing CD8 + T cells was also elevated in MS patients [27,28]. Nevertheless, it is likely that CD4 + T cell-derived GM-CSF plays a pivotal role in the pathogenesis of MS and might be a promising target for therapeutic intervention.…”