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GM-CSF is an Essential Factor in the Pathogenesis of Multiple Sclerosis

GM-CSF Pathogenesis Multiple Sclerosis
GM-CSF – Pathogenesis of Multiple Sclerosis

A study by Rasouli et al., published in the Journal of Immunology reports that treatment-naive multiple sclerosis (MS) patients had greater numbers of GM-CSF+ T cells in the peripheral blood, whereas CD4+ and CD8+ T cells in MS brain lesions expressed GM-CSF. In addition, interferon (INF)-β suppressed GM-CSF production by T cells, in vitro conditions.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine.

Granulocyte-macrophage colony-stimulating factor  is a multipotent cytokine that prompts the proliferation of bone marrow-derived macrophages and granulocytes. Reports have identified monocytes as the primary target of GM-CSF.

In addition to its effects as a growth factor, this cytokine plays an important role in chronic inflammatory autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

During the disease course in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE), au-
toreactive T cells facilitate CNS inflammation by secreting a variety of proinflammatory cytokines, such as GM-CSF. This cytokine is essential for the development and progression of EAE. Although various cell types produce it, the cytokine produced from myelin-specific CD4 + T cells is essential to EAE development.

This cytokine first drew attention when a clinical report in 1998, which assessed cytokine concentrations in the cerebral spinal fluid of MS patients with active disease, found that the levels of  the cytokine are significantly increased in MS patients compared to healthy controls.

McQualter and colleagues wanted to determine whether this cytokine played a critical and non-redundant role in promoting EAE pathology. This study is the first to underscore the critical role of GM-CSF in potentiating EAE pathology. Based on their findings and the aforementioned clinical study, McQualter and colleagues posited that this cytokine is a putative therapeutic target for MS treatment.

In the Journal of Immunology study, Rasouli et al. from the Department of Neurology, Thomas Jefferson University, Philadelphia, found significantly greater numbers of GM-CSF-producing CD4+ and CD8+ T cells in peripheral blood (PB) of untreated MS patients compared with patients undergoing IFN-beta therapy and healthy controls. In agreement with this ex vivo analysis, IFN-beta suppressed this cytokine production by T cells in vitro.

According to the authors their observations suggest that the greater frequency of the cytokine–producing T cells may contribute to MS immune pathogenesis, or on the other hand, this may represent only an epiphenomenon of abnormally activated immune cells in MS.

Recent multiple sclerosis (MS) research in animal models showed an important role of granulocyte macrophage colony-stimulating factor. This new study using human samples, by Javad Rasouli and co-workers further reinforces the role of this cytokine .

At BrainImmune, we have recently discussed that GM-CSF-producing CD4+ T cells regulated by the IL-7-STAT5 signaling axis may play a critical role in the pathogenesis of multiple sclerosis. The study may also offer a new explanation for why the INF-β treatment is effective in MS – that is the suppression of this cytokine production by IFN.

An Update

In 2019, Edoardo Galli et al. identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte–macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing–remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. 

Granulocyte-macrophage colony-stimulating factor is increasingly recognized as a pivotal cytokine in the pathogenesis of MS. Its production by multiple immune cell types is increased in MS, and its levels in the CSF correlate with disease activity. Moreover, the cytokine is implicated in the pathological mechanisms of EAE. The blockade of this cytokine signalling prevents or suppresses EAE.

These studies strongly support interventions to block GM-CSF in MS, and results from phase I studies indicate a favourable safety profile of antibodies against this cytokine .

Source: J Immunol. 2015, 194: 5085-5093. Epub 2015 Apr 27.
Read more: jimmunol.org