Background
Myelodysplastic syndrome (MDS) is a clonal disease that originates from hematopoietic stem cells. It is characterized by low hematopoietic function, dysplasia and peripheral blood cytopenia [
1,
2]. Abnormal cloned cells exhibit impaired differentiation and maturation in the bone marrow, pathological or ineffective hematopoiesis, and a high risk of transformation into acute myeloid leukemia. Different clinical treatments are chosen for patients with varying levels of risk. Increased apoptosis of hematopoietic precursors is a key feature of MDS [
3,
4]. This phenomenon may be influenced by both genetic and epigenetic alterations [
5], as well as immune mechanisms. Some studies have suggested that the interaction between malignant clones and the bone marrow microenvironment causes clonal expansion and apoptotic responses in MDS [
6]. Various bone marrow stromal cells work collaboratively in the bone marrow niche, regulating the differentiation, development, and self-renewal of bone marrow hematopoietic stem cells and maintaining a dynamic balance in the hematopoietic microenvironment [
7‐
9]. These stromal cells include endothelial cells, macrophages, adipocytes, fibroblasts, osteoblasts, and chondrocytes [
10]. Autocrine production of angiogenic molecules is associated with the self-renewal of bone marrow monocyte precursors and promotes the production of oncogenic cytokines [
3]. These cells can regulate hematopoiesis by secreting cytokines. Both the innate and adaptive immune systems are active in the ecological niche of MDS and play an important role in its pathogenesis [
11].
The World Health Organization prognostic scoring system (WPSS), International Prostate Symptom Score (IPSS-R), and Revised International Prostate Symptom Score (IPSS-R) can be used to evaluate the prognosis of MDS patients by monitoring age, sex, neutrophil count, hemoglobin, platelet count, cytopenia series, bone marrow primitive cell ratio, and karyotype, as well as predict the risk grade of MDS patients and propose related treatment strategies [
12‐
15]. The percentage of blasts, the number of cytopenic lines, and the cytogenetic indications of bone marrow, are all included in the classification criteria, but immune indicators prognosis are not. In MDS patients with different types (RA/RARS/RCMD/RAEB/RAEB-T), the ratio of Th1/Th2 will vary to different degrees. However, there is no relevant research on the correlation between the expression levels of Th1/Th2 immune indicators and the prognosis of MDS patients with various risk grades [
16‐
18]. In our study, we focused on MDS-associated TB cell subsets and cytokine assay results, with the goal of identifying a specific immune indicator. Following identification, we investigated the variation in this indicator in newly diagnosed MDS patients, and subsequently examining the influence of its content on the survival of MDS patients. Given the significant differences in serum IL-4 levels between low-risk and medium- to high-risk patients, it may be used as an independent risk factor for predicting MDS patient survival. Moreover, this index may be included in the prognostic scoring system.
Discussion
Immune dysregulation is closely associated with the pathogenesis of MDS. Firstly, dysregulation of T cell response and innate immune activation and its mediated bone marrow suppression are important causes of MDS, and apoptosis is often considered as a marker of low-risk MDS. In MDS, naive T cells (CD3+) exhibit shorter telomeres and significantly reduced proliferative potential [
19]. MDS tumor cell immune escape occurs through dysfunctional T cell and cytokine expression and matrix changes in the hematopoietic niche [
20]. Immune checkpoint inhibitors, such as PD-1 and its ligand, PD-L1, and CTLA-4, play an active role in the evasion of tumor surveillance and therapeutic resistance of MDS cells [
21,
22]. Second, innate immunity consists of humoral and cellular immune mechanisms, which typically rely on Toll-like receptors (TLRS) for microbial recognition in mammals. The TLR signaling pathway leads to the activation of nuclear factor K-light chain enhancer and mitogen-activated protein kinase pathways in activated B cells, which then induce the transcription of proinflammatory cytokines [
23]. In many MDS cases, TLR signaling is severely overactive due to the overexpression of activators (e.g., myeloid differentiation primary response 88, TIR Domain Containing Adaptor Protein, interleukin-1 receptor-associated kinase 4, and Tumor necrosis factor receptor-associated factor) and downregulation of repressors (e.g., miR145 and miR146a). Both MiR145 and miR146a are lost in 5Q-MDS, and these patients have a greater risk of dysplasia and transformation to acute myeloid leukemia [
24‐
26]. Lastly, cytokines also play an important role in immune dysregulation in MDS.
In our study, we surprisingly identified immune index having significant differences between low-risk and medium- to high-risk MDS patients, and serum IL-4 showed great effects on the survival of MDS patients in different prognostic scoring systems. We suspected it as an immune index and speculate that it can be used as an important prognostic factor in patients with middle- to high-risk MDS.
Cytokines play critical roles in the circulatory system [
27‐
32]. In lymphoid progenitor cells, IL-2 stimulates the differentiation of T cells [
33], and IL-4 and IL-6 stimulate the differentiation of B cells [
17]. As the most primitive hematopoietic stem cells, IL-3 drives the production of blood cell progeny [
17,
21,
34]. Granulocyte–macrophage colony-stimulating factor (stimulates granulocyte–macrophage progenitors and promotes cell differentiation in erythroid pedigree lines, while G-CSF and M-CSF stimulate the most differentiated bone marrow progenitors to produce granulocytes and monocytes/macrophages, respectively [
35,
36]. It is because of the existence of these hematopoietic factors that the blood system can constantly renew and self-regulate to maintain the homeostasis of the hematopoietic microenvironment. Studies have shown that the expression of at least 30 kinds of cytokines can be detected in the bone marrow and peripheral blood of MDS patients, among which the increased levels of TNF-a, IFN-γ, TGF-β, IL-6 and IL-8 directly reflect the serious dysregulation of inflammatory signal conduction and bone marrow differentiation [
11,
37‐
39]. The levels of cytokines in the innate and adaptive immune responses are different, and the levels of cytokines in MDS patients with different risks are also significantly different [
7]. In innate immunity, since NK cells can mediate the cytotoxicity of bone marrow precursor cells, macrophages are more cytotoxic to bone marrow precursor cells in low-risk MDS patients. As a result, higher frequencies of NK cells and macrophages were observed in low-risk MDS patients than in high-risk MDS patients, and DCS expression was low in both low-risk and medium- to high-risk MDS patients. In the adaptive immune response, the bone marrow mesenchymal cells of MDS patients lose the potential to differentiate into B-cell progenitors, so the expression of B-cell-related factors and Treg cells is reduced. However, cytotoxic CD8+ T cells, NK T cells, and Th17 cells are all highly expressed in low-risk MDS patients and poorly expressed in medium- and high-risk MDS patients [
40,
41]. In terms of pathogenesis, low-risk MDS is usually characterized by elevated apoptosis, whereas high-risk MDS has been shown to be associated with more aggressive clonal expansion [
4]. IFN-γ and IL-6 levels are closely related to the induction of apoptosis in MDS patients’ BM; thus, higher secretion of IFN-γ and IL-6 is usually associated with low-risk MDS [
42]. However, immunosuppressive cytokines, such as IL-10, are more strongly secreted in high-risk MDS patients [
33,
43].
IL-4, IL-3, IL-5, IL-9, IL-13, and transcription factor GATA3 belong to the Th2 cytokine family, which plays important immunomodulatory roles and have corresponding effects on a variety of immune cells. These include B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Th2 cells are one of the major sources of IL-4 due to their ability to amplify antigens [
44]. Other sources of IL-4 include follicle-helper Th (Tfh) cells located in lymph node B-cell follicles, a unique subset of T cells called NKT cells, and certain innate immune cells, such as mast cells, basophils, and eosinophils [
11,
44,
45]. There are two main types of receptors that specifically bind to interleukin-4. Type I receptors are composed of receptors that only bind to interleukin-4, while type II receptors are composed of receptors that can bind to both interleukin-4 and interleukin-13 [
11]. Many reports have shown that IL-4 plays an important role in mediating inflammatory reactions and can play an important role in type I allergic reactions. Interleukin-4 polymorphism is widely correlated with rheumatoid arthritis/atopic dermatitis/allergic rhinitis [
27,
46,
47] and other diseases. In addition, IL-4 can also cause capillary leakage syndrome and IL-4 associated hematuria and gastroduodenal lesions; however, there are few studies on the mechanism of IL-4 in MDS patients and its impact on prognosis. We hope that future clinical studies will enrich the content of this review.
Meanwhile, we found that age ≥ 65 is also an important risk factor for the prognosis of MDS patients. Reinhard Stauder et al
. showed that anemia is particularly common in the elderly and is a key indicator of various reactive and clonal diseases. Many underlying diseases with anemia as the main presentation, such as myelodysplastic syndrome (MDS), develop preferentially in the elderly [
48,
49]. Due to advanced age, comorbidities, and a lack of histocompatible donors, patients with MDS have lost the opportunity for allogeneic hematopoietic stem cell transplantation [
50]. MDS is a chronic disease. Comorbidities must be considered in the elderly because they are often accompanied by other basic diseases and present with more clinical symptoms, resulting in a worse prognosis.
In the diagnosis of MDS, we often monitor a series of immune indicators, but few people pay attention to the correlation between the expression level of these immune indicators and the survival of low-risk and medium- to high-risk MDS patients. Considering the important role of IL-4 in the diagnosis of MDS, we speculate that IL-4 can be used as an important part of the prognostic scoring system to predict the survival of MDS patients. However, our study has some limitations. Our study was a retrospective study on clinical case data, rather than a prospective study, which has certain limitations. Moreover, due to the limited follow-up time and the small number of people screened in the group, there may be bias. There is a 30% chance that MDS will progress to leukemia [
51,
52]; therefore, studies often use conversion to leukemia as an important clinical parameter to determine the prognosis of MDS. In our study, the small number of patients enrolled and the fact that most patients were lost to follow-up after treatment makes it more difficult to study patients with conversion to leukemia; therefore, this important indicator is not reflected in this study. In 2022, an updated prognostic scoring system for MDS was proposed called the new Molecular International Prognostic Scoring System (IPSS-M) [
53,
54]. In this new scoring system, patients are stratified more finely in terms of risk from a molecular perspective [
55]. In this study, we should have also studied the patients in relation to the IPSS-M, but we were unable to perform an IPSS-M-related analysis because the patients were not tested at enrollment and because of the limitations of the current testing methods, and a large number of clinical trials are needed to confirm our hypothesis.
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