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All Roads Lead to Interferon-γ: From Known to Untraveled Pathways in Acquired Aplastic Anemia - PubMed

  • ️Sun Jan 01 2023

Review

All Roads Lead to Interferon-γ: From Known to Untraveled Pathways in Acquired Aplastic Anemia

Bianca Serio et al. Medicina (Kaunas). 2023.

Abstract

Bone marrow failure (BMF) syndromes are a heterogeneous group of benign hematological conditions with common clinical features including reduced bone marrow cellularity and peripheral blood cytopenias. Acquired aplastic anemia (AA) is caused by T helper(Th)1-mediated immune responses and cytotoxic CD8+ T cell-mediated autologous immune attacks against hematopoietic stem and progenitor cells (HSPCs). Interferon-γ (IFNγ), tumor necrosis factor-α, and Fas-ligand are historically linked to AA pathogenesis because they drive Th1 and cytotoxic T cell-mediated responses and can directly induce HSPC apoptosis and differentiation block. The use of omics technologies has amplified the amount of data at the single-cell level, and knowledge on AA, and new scenarios, have been opened on "old" point of view. In this review, we summarize the current state-of-art of the pathogenic role of IFNγ in AA from initial findings to novel evidence, such as the involvement of the HIF-1α pathway, and how this knowledge can be translated in clinical practice.

Keywords: acquired aplastic anemia; bone marrow failure syndromes; interferon-γ.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Pathophysiology of acquired aplastic anemia (AA). Apoptotic and/or infected hematopoietic stem and progenitor cells (HSPCs) can release unmodified or chemically and/or genetically modified antigens (self-Ags) that are phagocyted by macrophages (Mφs) and presented to antigen-presenting dendritic cells (DCs). These cells process and present Ags to naïve CD4+ T cells, that differentiate toward T helper (Th) 1 phenotype under interleukin (IL)-2, IL-4, tumor necrosis factor alpha (TNF-α), and interferon-gamma (IFNγ), mainly through STAT and HIF-1α signaling pathway activation. DCs via Ag presentation to T-cell receptor (TCR) and Th1 cells sustain effector cytotoxic CD8+ T lymphocyte (CTL) activation through STATs, HIF-1α, and mTORC1/2 signaling. Activated CTLs induce growth inhibition and apoptosis of HSPCs by directly killing cells via granzyme B and perforin release, and by paracrine inhibitory effects of TNF-α, IFNγ, Fas ligand (Fas-L), activation of inducible nitric oxide (NO, *) synthase, and NO release, they also exert cytotoxicity near cells. HSPC growth inhibition is also caused by a decoy receptor function of IFNγ, that binds to growth factors (GFs), such as thrombopoietin, and interferes with their binding to surface receptors. Persistent Ag stimulation induces Th17 differentiation of naïve T cells under IL-6, IL-21, and IL-23 stimulation. Th17 cells also reduce T regulatory cell (Treg) function and numbers because IL-17 and IFNγ augment HIF-1α stabilization which blocks the master transcription factor FOXP3 of Treg. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (

https://creativecommons.org/licenses/by/3.0/

) (accessed on 15 November 2023).

Figure 2
Figure 2

Thrombopoietin (TPO) axis and ruxolitinib-related changes in AA mouse model. (A) Circulating plasma levels of TPO and its receptor c-MPL from [28] were extracted. TPO/c-MPL ratio was calculated for each healthy control (HC), complete (CR), partial (PR), and non-responder (NR) group before (pre) and after (post) immunosuppressive therapy + eltrombopag, and levels compared by one-way ANOVA. All comparisons corrected with Tukey’s multiple comparisons test were statistically significant, except between HC and CR post-treatment (p = 0.8303). (B) Putative gene network interactions using dysregulated genes in CD8+ T cells from ruxolitinib-treated BMF mice from [51] were interpolated by also including HIF-1α, and (C) protein pathways were identified by STRING database. ns, not statistically significant.

Figure 3
Figure 3

Protein pathway analysis in acquired aplastic anemia (AA). Proteins from an aptamer-based high-throughput proteomic analysis [28] were extracted, and those whose levels changed >1.5 fold change after immunosuppressive therapies in complete (CR), partial (PR), and non-responders (NRs) were interpolated. (A) Proteins that showed >1.5 fold changes (n = 11) and (B) that did not change after treatment in PR and NR (n = 11) nor in NR only (n = 15). (C) Those 11 proteins were used for protein pathway analysis by STRING database, and the first top 15 represented networks are reported, as well as (D) those networks enriched using those 15 unmodified proteins in NR only.

Figure 4
Figure 4

Protein pathway analysis in large granular lymphocytic leukemia (LGL). Genes from a single-cell TCR coupled with RNA sequencing of CD3+ T cells from LGL [65] were extracted, and those upregulated or downregulated (A) at diagnosis and (B) after alemtuzumab treatment were used for protein pathway analysis using the STRING database and by also adding HIF-1α. First 15 that better represented networks are reported for (C) diagnosis and (D) after treatment.

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