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Pathogen involvement in bone marrow failure (BMF). Primary viral or mycobacterial infection occurs in the lower pulmonary system where pathogens infect alveolar cells and macrophages (Mφ), or where Mφ phagocyte mycobacteria containing the infection. Subsequently, Mφ migrate to pulmonary lymph nodes and presents antigens (Ag) to dendritic cells that processed and present Ag to naïve T cells. Once primed, naïve T cells differentiate primarily in T helper (Th) 1 cells releasing pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), interferon-gamma (IFNγ), or interleukins (IL) that, together with type I interferons (IFNs), trigger the activation of effector cytotoxic CD8+ T cells (CTLs). After activation, CTLs directly kill infected cells, and pathogen particles and cellular components are released and likely captured by dendritic cells, processed, and presented as novel antigens. On the other hand, pathogen particles might induce a cross-reactivity with cellular components and start an autoimmune response that might be sustained by Th17 cells and Th17-related cytokines (IL-17 or IL-22). The figure was created in Biorender.com.
Source publication
Acquired bone marrow failure (BMF) syndromes are considered immune-mediated disorders because hematological recovery after immunosuppressive therapies is the strongest indirect evidence of the involvement of immune cells in marrow failure development. Among pathophysiology hypotheses, immune derangement after chronic antigen exposure or cross-react...
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Background
The evolving variants of SARS-CoV-2 may escape immunity from prior infections or vaccinations. It’s vital to understand how immunity adapts to these changes. Both infection and mRNA vaccination induce T cells that target the Spike protein. These T cells can recognize multiple variants, such as Delta and Omicron, even if neutralizing anti...
Citations
... Iatrogenic BMF is subsequent to a direct damage to the hematopoietic stem and progenitor cell (HSPC) compartment by external harmful factors, such as radiation, chemicals, drugs, and chemotherapy [1]. Immune-mediated BMF syndromes comprise four entities: acquired aplastic anemia (AA); paroxysmal nocturnal hemoglobinuria (PNH); hypoplastic myelodysplastic syndromes (MDSs); and large granular lymphocyte leukemia (LGL) [4]. However, these syndromes share numerous clinical, biological, and molecular features, and often coexist. ...
... This clinical and biological overlap underlies common pathogenic mechanisms, mainly an immune response dysregulation, albeit with differences, and a similar risk to progress to acute myeloid leukemia (AML) [6]. BMF syndromes are also a continuum of clinical entities that fade into other clonal hematological conditions, because they can harbor somatic mutations in AML-related genes, such as ASXL1 or DNMT3A [1][2][3][4][5][6]. ...
... The normalization of blood counts after immunosuppression is the main indirect evidence of the immune-mediated origin of this entity [7]. One of the first and still the most supported pathogenetic hypothesis assumes that an unknown viral infection affecting stem cells could cause a cross-reactivity with self-antigens and the subsequent expansion of an autoimmune clone [4]. Infected cells preferentially activate Th1 cells, which are the predominant CD4 + T lymphocytes involved in viral clearance through the activation of CTLs via interferon-γ (IFNγ) or tumor necrosis factor-α (TNF-α) [6,8]. ...
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.
... For long time, infectious causes have been supposed to be the triggers of the AA immune derangement, and with the application of sequencing platforms to characterize T cell receptor (TCR) repertoires, this hypothesis has been raising attention [5,35]. Autoreactivity driven by chronic antigen stimulation remains a key mechanistic feature of many autoimmune and immune dysfunctional contexts (e.g. ...
... The most paradigmatic example of the role of infectious agents is the case of post-hepatitis AA [50], whereby AA ontogeny is associated with a viral etiology, including major and minor hepatitis viruses (hepatitis A [51], hepatitis B [52], and hepatitis C [53], E and G [54]) and other viral agents, such as parvovirus B19 [55], human herpesvirus 6 (HHV-6) [56] and Epstein Barr (EBV) [57]. Furthermore, an infectious-driven TCR signature can be identified in subjects with AA, with a patient-specific expansion of Influenza-A, cytomegalovirus, EBV or mycobacterium-related T-cell specificities that may be responsible for cross reactivity with self-antigens, sharing similar physiochemical characteristics with pathogen-associated epitopes [5,35]. For instance, EBV reactive class II HLA-restricted CD4+ lymphocytes, with killing potential against autologous CD34+ cells, have been isolated from AA patients [8]. ...
Clonal evolution to secondary paroxysmal nocturnal hemoglobinuria (PNH) or myeloid neoplasia (MN) represents one of the long-term complications of patients with aplastic anemia (AA). The recent evidence in the field of immunology and the application of next-generation sequencing have shed light on the molecular underpinnings of these clonal complications, revealing clinical and molecular risk factors as well as potential immunological players. Particularly, whether MN evolution represents a failed tumor surveillance or a maladaptive recovery is still a matter of controversy in the field of bone marrow failure syndromes. However, recent studies have explored the precise dynamics of the immune-molecular forces governing such processes over time, generating knowledge useful for potential early therapeutic strategies. In this review, we will discuss the immune pathophysiology of AA and the emergence of clonal hematopoiesis with regard to the adaptive and maladaptive mechanisms at the basis of secondary evolution trajectories operating under the immune pressure.
... CTL kills directly to target cells via granzyme B (GzmB) and perforin (PFN). In addition, Th17 cells induce the selection of effector memory CD8+T cells (Tem) sustaining HSC apoptosis and reducing regulatory T cell (Treg) functions and number [4,5]. Recent improvement in the pathogenesis of AA is genetic alteration, including telomerase genetic mutations and somatic mutation [6,7]. ...
Objectives
The immune-induced aplastic anemia (AA) mouse model has been used for the study of AA. However, there were no uniform conditions for establishing a model and no assessment of immunological homeostasis. Our study aimed to identify the conditions of establishing a model and assess the AA model in immunology and pathology.
Methods
We induced an AA mouse model by the combination between sublethal irradiation and spleen-thymus lymphocyte infusion. The success of establishing the AA model was identified by blood routine tests and pathology of bone marrow. The frequency of Th17 and Treg cells was measured by flow cytometry. The frequency of CD34+ and CD41+ cells was detected by immunohistochemical technique.IL-6, IL-8, IL-17, TNF-α and IFN-γ were evaluated by ELISA.
Results
The ¹³⁷Cs sublethal irradiation (5 Gy) and spleen-thymus lymphocyte infusion (5 $\times$× 106) induced the AA mouse model successfully. The AA mice had a long lifetime and manifested pancytopenia and bone marrow failure. The percentage of Th17 cells increased and the percentage of Treg cells decreased distinctly in AA mice. The area of hematopoietic tissues and count of CD34+ cells and CD41+ cells were significantly reduced in AA mice.The level of cytokines, IL-6, IL-8, IL-17, TNF-α and IFN-γ, was increased significantly in peripheral blood and bone marrow.
Conclusion
Our data suggest that the improved AA mouse model conforms to the diagnosis standard of AA and simulates the immune internal environment of human AA. The AA mouse model has a longer lifetime and unbalances of Th17/Treg cells caused the destruction of CD34+ cells and CD41+ cells, which was immune-mediated pathogenesis to adapt to long-term research.
... Immune-mediated BMF syndromes are initiated by an autoimmune attack against HSPCs, and four clinical entities are included: acquired aplastic anemia (AA); hypoplastic myelodysplastic syndrome (MDS); large granular lymphocyte leukemia (LGL); and paroxysmal nocturnal hemoglobinuria (PNH) [1][2][3][4] . AA is characterized by peripheral blood cytopenia(s) secondary to a progressive BM depletion of the stem cell compartment, while PNH, a disease caused by somatic mutations in the X-linked phosphatidylinositol glycan class A ( PIGA ) gene, presents with the clinical triad of hemolytic anemia, marrow failure, and increased risk of thromboembolic events [13][14][15] . Hypoplastic MDS shows both MDS and AA features with BM hypocellularity and peripheral blood cytopenia(s) as observed in AA, and simultaneously showing dyspoiesis, chromosomal and genetic abnormalities, and increased risk of acute myeloid leukemia (AML), as described in normo-and/or hypercellular MDS [ 4 , 16-19 ]. ...
... The immune system plays a pivotal role in BM destruction; however, immune signatures differ between early stage and nonsevere AA and late stage or severe AA [1][2][3][4] . The inciting event remains still unknown although viral or bacterial infection, such as cytomegalovirus (CMV) or Mycobacterium tuberculosis , have been proposed as the initiating event [13] . Once infected, cells expose pathogen-derived particles and unmodified or chemically and/or genetically modified cellular components on their surface, and tissue-resident macrophages activate and directly phagocyte pathogens at the entry site [7][8] . ...
... The presence of intracellular pathogens induces the release of high amount of type I IFNs, and macrophages can either go to apoptosis or migrate to local lymph nodes where they prime antigen presenting cells (APCs) [51] . Processed epitopes are then mounted on the major histocompatibility complex (MHC) and presented to antigen specific naïve CD4 + T cells that differentiate toward Th1 phenotype in the presence of interleukin(IL)-6 and IL-2 [13] . Subsequently, naïve T cells produce large amount of IFN-γ , TNF α, and other type I IFN cytokines that activate CTLs and macrophages [52] . ...
Bone marrow failure (BMF) syndromes are a heterogeneous group of benign hematological conditions characterized by uni- or multi-lineage marrow and/or peripheral blood cytopenia(s), and can be classified in constitutional or acquired syndromes based on pathophysiology. In inherited diseases, germline mutations occur in the hematopoietic stem and progenitor cell (HSPC) compartment causing a progressive loss of normal hematopoiesis, while in acquired syndromes, HPSC compartment disruption can be caused by an extrinsic direct damage by external cytotoxic agents on the stem cell pool or by an autoimmune attack against HSPCs. Aplastic anemia is an acquired immune-mediated BMF syndrome where marrow disruption is driven by a cytotoxic T cell-mediated autoimmune attack against HSPCs sustained by type I interferons that polarize the immune system toward T helper 1 responses in early phases and then toward T helper 17 and effector memory CD8⁺ T cell in late stage and severe disease. Cytokines and chemokines also play a crucial role in driving immune responses and HSPC growth inhibition and apoptosis, as described for interferon-γ and tumor necrosis factor α. In this review, we summarize current knowledge on acquired aplastic anemia pathophysiology.
Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.
Nano-vesicular carriers are promising tissue-specific drug delivery platforms. Here, biomimetic proteolipid vesicles (BPLVs) were used for delivery of glycosylphosphatidylinositol (GPI)-anchored proteins to GPI deficient paroxysmal nocturnal hemoglobinuria (PNH) cells. BPLVs were assembled as single unilamellar monodispersed (polydispersity index, 0.1) negatively charged (ζ-potential, −28.6 ± 5.6 mV) system using microfluidic technique equipped with Y-shaped chip. GPI-anchored and not-GPI proteins on BPLV surface were detected by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy and PNH subjects were treated with BPLVs (final concentration, 0.5 mg/mL), and cells displayed an excellent protein uptake, documented by flow cytometry immunophenotyping and confocal microscopy. BPLV-treated cells stressed with complement components showed an increased resistance to complement-mediated lysis, both healthy and PNH PBMCs. In conclusion, BPLVs could be effective nanocarriers for protein transfer to targeted cells to revert protein deficiency, like in PNH disease. However, further in vivo studies are required to validate our preclinical in vitro results.
Hematopoiesis is a remarkable system that plays an important role in not only immune cell function, but also in nutrient transport, hemostasis and wound healing among other functions. Under inflammatory conditions, steady-state hematopoiesis switches to emergency myelopoiesis to give rise to the effector cell types necessary to fight the acute insult. Sustained or aberrant exposure to inflammatory signals has detrimental effects on the hematopoietic system, leading to increased proliferation, DNA damage, different forms of cell death (i.e., apoptosis, pyroptosis and necroptosis) and bone marrow microenvironment modifications. Together, all these changes can cause premature loss of hematopoiesis function. Especially in individuals with inherited bone marrow failure syndromes or immune-mediated aplastic anemia, chronic inflammatory signals may thus aggravate cytopenias and accelerate disease progression. However, the understanding of the inflammation roles in bone marrow failure remains limited. In this review, we summarize the different mechanisms found in mouse models regarding to inflammatory bone marrow failure and discuss implications for future research and clinical practice.
