IL‐17‐producing CD4⁺ T cells, pro‐inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome

Abstract

Summary Immunological responses are increasingly recognised as being important in the initiation and progression of myelodysplastic syndrome (MDS). Indeed, autoimmune diseases commonly occur in association with MDS, particularly in subtypes with a low risk of leukaemic transformation. This study showed for the first time that the numbers of CD3+ CD4+ IL‐17 producing T cells (Th17) were markedly increased in low risk MDS compared with high risk MDS (P < 0·01). An inverse relationship between the numbers of Th17 cells and naturally occurring CD4+CD25high FoxP3+ regulatory T cells (Tregs) were also described. The Th17:Tregs ratio was significantly higher in low risk disease (P < 0·005) compared with high risk MDS and was correlated with increased bone marrow (BM) apoptosis (P < 0·01). Tregs from MDS patients suppressed interferon‐γ (IFN‐γ) secretion by effector CD4+ T cells but had no effect on interleukin (IL)‐17 production. In addition, the serum levels of IL‐7, IL‐12, RANTES and IFN‐γ are significantly elevated in low risk MDS, while inhibitory factors, such as IL‐10 and soluble IL‐2 receptor, are significantly higher in high risk disease. The ‘unfavourable’ Th17:Tregs ratio in low risk MDS may explain the higher risk of autoimmunity and the improved response to immune suppression in patients with low risk MDS compared to those with high risk disease.

The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome

“…We have previously shown that the number of regulatory T cells (Treg) is significantly increased in high-risk and intermediate-2 MDS, whereas in 'low-risk' MDS interleukin (IL)-17-producing CD4 + T cells (Th17 cells) are increased, suggesting a correlation between the number of Treg, Th17 and disease severity. 14,15 The expression of forkhead box p3 (FOXP3), the master switch for Treg, has been demonstrated to be epigenetically regulated with complete demethylation of its CpG rich promoter in Treg, whereas in naïve and effector T cells the FOXP3 promoter is methylated. 16,17 The effect of 5-azaC on activated CD4 + T cells and induction of "lupus like" autoimmunity has been shown previously.…”

Th17 immune responses contribute to the pathophysiology of aplastic anemia

“…5 In mice, the differentiation program of Th17 cells from naive CD4 ϩ T cells requires the activation of the transcription factor, orphan nuclear receptor ROR␥t, 6 and the presence of IL-6 and transforming growth factor-␤ (TGF-␤). 7,8 In humans, Th17 differentiation is under the control of IL-1␤, 10 Several studies have reported the association of IL-17 with inflammatory disorders, such as rheumatoid arthritis, asthma, multiple sclerosis, and lupus, 11 as well as hematologic disorders, such as myelodysplastic syndrome 12,13 and acute myeloid leukemia. 14 Aplastic anemia (AA), a disease characterized by peripheral blood pancytopenia and bone marrow (BM) hypoplasia, 15 is an immunemediated disorder in most cases with active destruction of hematopoietic cells by effector T lymphocytes.…”

Optic Neuritis Associated with Myelodysplastic Syndrome Accompanied by Eosinophilic Crisis

“…AIMs are thought to be caused by a T-cell response to abnormal antigen presentation or abnormal B-and T-cell interactions (7)(8)(9). In these patients, increased levels of inflammatory cytokines or chemokines, such as interleukin (IL)-2, IL-17, interferon (IFN)-γ and regulated on activation, normal T cell expressed and secreted (RANTES), have been described (10). In the present case, late leakage and vasodilatation of both optic discs were observed on fluorescein angiography, and inflammatory cells in the anterior chamber were seen on slit-lamp microscopy.…”