scholarly journals Upregulated Expression of Profilin1 on Dendritic Cells in Patients With Severe Aplastic Anemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong Yu ◽  
Yang Zhao ◽  
Xiaofeng Pan ◽  
Chunyan Liu ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Cell Movement ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells ◽  
Life Threatening ◽  
Movement Ability ◽  
Antigen Presenting

Severe aplastic anemia (SAA) is a life-threatening form of bone marrow failure that is associated with very high mortality. Dendritic cells (DCs) are antigen presenting cells (APCs) with powerful movement ability, which is an important factor affecting immune function. The expression of profilin1 (Pfn1) plays an important role in the regulation of cell movement ability. We detected the expression of Pfn1 mRNA in the bone marrow (BM) myeloid dendritic cells (mDCs) from patients with SAA using RT-PCR. Next, we examined Pfn1 expression on mDCs using flow cytometry (FCM). We also assessed the relationship between Pfn1 expression and cytokine levels. Our data showed increased Pfn1 mRNA expression in patients with SAA. The expression of Pfn1 in BM mDCs increased in SAA patients. The expression of Pfn1 on mDCs and cytokines (TNF-α and IFN-γ) were positively correlated in the serum of untreated patients with SAA. Taken together, we found that the expression of Pfn1 on mDCs of SAA patients increased, which may affect the function of mDCs. Profilin 1 may be involved in the immunopathogenesis of SAA.

scholarly journals PKM2 Is Required to Activate Myeloid Dendritic Cells from Patients with Severe Aplastic Anemia

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Chunyan Liu ◽  
Mengying Zheng ◽  
Ting Wang ◽  
Huijuan Jiang ◽  
Rong Fu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Immune Status ◽  
Bone Marrow Failure ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells ◽  
Protein Levels ◽  
Immune Mediated ◽  
Normal Controls

Severe aplastic anemia (SAA) is an autoimmune disease in which bone marrow failure is mediated by activated myeloid dendritic cells (mDCs) and T lymphocytes. Recent research has identified a strong immunomodulatory effect of pyruvate kinase M2 (PKM2) on dendritic cells in immune-mediated diseases. In this study, we aimed to explore the role of PKM2 in the activation of mDCs in SAA. We observed conspicuously higher levels of PKM2 in mDCs from SAA patients compared to normal controls at both the gene and protein levels. Concurrently, we unexpectedly discovered that after the mDC-specific downregulation of PKM2, mDCs from patients with SAA exhibited weakened phagocytic activity and significantly decreased and shortened dendrites relative to their counterparts from normal controls. The expression levels of the costimulatory molecules CD86 and CD80 were also reduced on mDCs. Our results also suggested that PKM2 knockdown in mDCs reduced the abilities of these cells to promote the activation of CD8+ T cells (CTLs), leading to the decreased secretion of cytotoxic factors by the latter cell type. These findings demonstrate that mDC activation requires an elevated intrinsic PKM2 level and that PKM2 improves the immune status of patients with SAA by enhancing the functions of mDCs and, consequently, CTLs.

scholarly journals Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Kamran Qureshi ◽  
Usman Sarwar ◽  
Hicham Khallafi
Keyword(s):  
Bone Marrow ◽  
Liver Injury ◽  
Acute Hepatitis ◽  
Aplastic Anemia ◽  
Viral Infections ◽  
Anabolic Steroids ◽  
Bone Marrow Failure ◽  
Young Male ◽  
Severe Aplastic Anemia ◽  
Successful Outcome

Hepatitis associated aplastic anemia (HAAA) is a rare syndrome in which severe aplastic anemia (SAA) complicates the recovery of acute hepatitis (AH). HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT). The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST) and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

Erythrocytosis after Allogeneic Bone Marrow Transplantation in the Patients with Severe Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5327-5327
Author(s):  
Soo-Jeong Park ◽  
Chi-Wha Han
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Severe Aplastic Anemia ◽  
Allogeneic Bone ◽  
Laboratory Findings ◽  
Normal Ranges ◽  
Serum Erythropoietin Level

Abstract Severe aplastic anemia (sAA) is a bone marrow failure disorder which is mostly a consequence of immunologically mediated stem cell destruction. Stem cell transplantation (SCT) from a histocompatible sibling is a treatment of choice for this disease but major obstacles in success of allogeneic SCT include graft-versus-host disease (GVHD), graft rejection and treatment related toxicities. We describe two cases of post-transplant erythrocytosis in severe aplastic anemia. About 5 years later, following HLA-matched sibling transplantation, the patients (45-year-old male and 43-year-old male) developed a sustained increase in hemoglobin (>17 g/dL) and hematocrit (> 50%), an increase in the frequency of headache, and new onset of dizziness and malaise. Laboratory findings demonstrated normal ranges of other blood components and serum erythropoietin level, and they did not have smoking or other drugs. Also, they did not have a hepatosplenomegaly or other organ diseases. We initiated a therapeutic phlebotomy program (400 ml q 2–4 weeks and then q 2–3 months for 5 years) in order to lower the hematocrit to available values (Hb < 14.5 g/dL), and to induce iron deficiency (Fig 1). Repeated phlebotomy resulted in a decrease in symptoms and a total volume of blood venesection is about 9,200 – 11,200 ml so far. Figure 1. Hemoglobin change after bone marrow transplantations. Figure 1. Hemoglobin change after bone marrow transplantations.

Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia

2011 ◽  
Vol 93 (2) ◽  
pp. 156-162 ◽  
Author(s):  
Shao Zonghong ◽  
Tu Meifeng ◽  
Wang Huaquan ◽  
Xing Limin ◽  
Wang Jun ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells

scholarly journals A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1861-1869
Author(s):  
N Young ◽  
P Griffith ◽  
E Brittain ◽  
G Elfenbein ◽  
F Gardner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Antithymocyte Globulin ◽  
Bone Marrow Failure ◽  
Multicenter Trial ◽  
Severe Aplastic Anemia ◽  
Transfusion Independence ◽  
Group I ◽  
Significant Difference ◽  
To Receive

One hundred fifty patients with bone marrow failure were treated in three groups with antithymocyte globulin (ATG; Upjohn, Kalamazoo, MI) in a multicenter trial. Patients were assessed at 3, 6, and 12 months after initiation of treatment by three criteria: transfusion independence, clinical improvement, and blood counts. Group I consisted of 77 patients with acute severe aplastic anemia, randomized to receive either ten or 28 days of ATG. There was no significant difference between the two arms of this protocol: 47% of all patients were clinically improved and 31% were transfusion independent at 3 months. Of the severely affected patients, 27% died before 3 months; most deaths occurred early in treatment. Factors associated with survival in severely affected patients included male sex, age less than 40 years, absolute neutrophil count greater than 200/microL, and idiopathic etiology. Neutrophil counts generally increased by 8 weeks after treatment, but patients continued to show improvement to 1 year posttreatment. In Group II, 44 patients with moderate or chronic severe aplastic anemia were randomized to receive either ten days of ATG or 3 months of high-dose nandrolone decanoate. No patient initially treated with androgens recovered, but 28% of ATG-treated cases achieved transfusion independence at 3 months. Group III consisted of patients with a variety of bone marrow failure syndromes. Patients with pancytopenia and cellular bone marrow showed response rates similar to those of patients with chronic or moderate aplastic anemia.

Recurrent 6pLOH Is the Most Common Somatic Lesion in Refractory Cytopenia of Childhood and Occurs Very Infrequently in Severe Aplastic Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 644-644 ◽  
Author(s):  
Marcin W Wlodarski ◽  
Shinsuke Hirabayashi ◽  
Brigitte Strahm ◽  
Sandra Urbaniak ◽  
Brigitte Schlegelberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Telomere Length ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Good Prognosis ◽  
Severe Aplastic Anemia ◽  
Diamond Blackfan Anemia ◽  
Immune Mediated ◽  
Somatic Aberrations

Abstract Abstract 644 Refractory cytopenia of the childhood (RCC) and severe aplastic anemia (SAA) are the most common causes of acquired hypoplastic bone marrow failure (BMF) in children. Although predisposing genetic factors and inciting immunological events had been implicated, little is known about the molecular origins of these conditions. Whole-genome scanning using single nucleotide polymorphism arrays (SNP-A) can complement standard cytogenetics in terms of the detection of submicrocopic aberrations and regions with copy number neutral loss of heterozygosity (CN-LOH). Here we present the results of an analysis of 181 children with bone marrow failure: MDS, n=106; SAA, n=41; and for hematological control, 34 patients with Diamond Blackfan anemia (DBA). To enrich for the myeloid lineage, we used granulocytes from bone marrow as source for DNA. We employed Affymetrix 6.0 arrays and used CNAG v3.3 and Genotyping Console v4.0 platforms for data analysis. To identify somatic aberrations that might have been missed by standard metaphase cytogenetics (MC), we initially looked at cases with abnormal MC, presenting as RCC or advanced MDS (n=25, median age 12.4 years). While SNP-A generally confirmed the cytogenetic lesions identified by MC, no novel recurrent somatic aberrations with pathogenic character were discovered. In the next step we focused on the analysis of RCC patients with normal karyotype (N=81, median age 10.2 years). In one case a small monosomy 7 clone was identified using SNP-A, that has been missed by standard MC. Most strikingly, 11 patients (14%) carried clones with a terminal CN-LOH of the short arm of chromosome 6 (6pLOH), with a length of 30–42Mb and various clonal size. The somatic myeloid origin was confirmed by the analysis of CD4+/CD8+ sorted T-cells in several cases. The 6pLOH lesion encompasses the HLA gene cluster leading to the loss of one HLA haplotype, has previously been reported in adults with SAA diagnosed in USA and Japan (Afable/Wlodarski, and Katagiri 2011), and was generally associated with a good prognosis. Regarding treatment modalities in RCC patients, the 6pLOH clone was overrepresented in the watch and wait (W&W) cohort: 10/55 (18%) of W&W cases carried this clone, as compared to 1/26 (4%) patient who received therapy within 6 months from diagnosis. Out of the 10 W&W patients with 6pLOH clone, only two required later therapeutic interventions (stem cell transplantation) due to progressive cytopenia at 10 and 11 months after diagnosis. The remaining 8/10 patients are still under W&W strategy with a median FUP of 6.6 (1.6.-12.2) years. In summary, all 11 RCC 6pLOH patients are alive with a median FUP of 6.6 years without disease progression. Interestingly, the 6pLOH clone survives over a long period of time, as confirmed in 2 patients in different bone marrow samples obtained 7 years apart. To answer the question if the persistence of the 6pLOH clones has an effect on telomere maintenance in the hematopoietic cell compartment, we measured telomere length using a quantitative PCR-based approach. All 11 RCC cases with 6pLOH studied had normal telomere length as compared to age-matched controls. Since the immune-mediated attack is the main operating mechanism of BMF in SAA, we next asked whether the 6pLOH clone can also arise in the bone marrow of children with SAA. We SNP-A genotyped a cohort of 41 SAA patients (median age 10.4 years) including 5 hepatitis-associated SAA (HSAA) cases. While no genomic copy number alterations were found, the somatic 6pLOH clone was discovered in only one HSAA patient, in whom the SAA developed 6 months after onset of hepatitis. When compared to the SAA patients, the 6pLOH clone is significantly more frequent in the RCC W&W cohort (P <0.04). Finally, to compare the results to a “non-immune-mediated” BMF, we analyzed 34 children with Diamond Blackfan anemia in whom no 6pLOH clone or other somatic defects were identified. In summary, 6pLOH is the most common somatic lesion found in the myeloid compartment in RCC patients and correlates with a very good prognosis. The absence of 6pLOH in children with SAA with no other associated pathologies supports the concept that RCC and SAA are two distinct entities in children. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Effects of Shikonin on the Functions of Myeloid Dendritic Cells in a Mouse Model of Severe Aplastic Anemia

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Mengying Zheng ◽  
Bingnan Liu ◽  
Yuanyuan Shao ◽  
Luogang Hua ◽  
Rong Fu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mouse Model ◽  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Survival Rates ◽  
Severe Aplastic Anemia ◽  
High Survival ◽  
Myeloid Dendritic Cells ◽  
Cd8 Cells

This study is aimed at investigating the effects of shikonin, a pyruvate kinase M2 (PKM2) inhibitor, on the functions of myeloid dendritic cells (mDCs) in a mouse model of severe aplastic anemia (AA) generated by total body irradiation and lymphocyte infusion. Flow cytometry and qPCR were used to determine the proportions of PKM2+ mDCs and other immune indicators in the AA mice. Glucose consumption level, pyruvate generation level, and ATP content were used to determine the level of glycolytic metabolism in the mDCs. The survival rates of AA mice were evaluated after the administration of shikonin or the immunosuppressive agent cyclosporin A. The AA mice displayed pancytopenia, decreased CD4+/CD8+ cell ratio, increased perforin and granzyme levels in CD8+ cells, increased costimulatory CD80 and CD86 expressions, and inadequate regulatory T cell number. In vivo animal experiments showed that the shikonin-mediated inhibition of the PKM2 expression in mice was associated with high survival rates. In addition, the administration of cyclosporin A or shikonin decreased the expression of cytotoxic molecules and costimulatory CD80 and CD86 on CD8+ cells. Taken together, the results of this study indicated that shikonin could inhibit the activation and proliferation of mDCs as well as the activation of downstream cytotoxic T cells by reducing the PKM2 level in mDCs.

scholarly journals A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1861-1869 ◽  
Author(s):  
N Young ◽  
P Griffith ◽  
E Brittain ◽  
G Elfenbein ◽  
F Gardner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Antithymocyte Globulin ◽  
Bone Marrow Failure ◽  
Multicenter Trial ◽  
Severe Aplastic Anemia ◽  
Transfusion Independence ◽  
Group I ◽  
Significant Difference ◽  
To Receive

Abstract One hundred fifty patients with bone marrow failure were treated in three groups with antithymocyte globulin (ATG; Upjohn, Kalamazoo, MI) in a multicenter trial. Patients were assessed at 3, 6, and 12 months after initiation of treatment by three criteria: transfusion independence, clinical improvement, and blood counts. Group I consisted of 77 patients with acute severe aplastic anemia, randomized to receive either ten or 28 days of ATG. There was no significant difference between the two arms of this protocol: 47% of all patients were clinically improved and 31% were transfusion independent at 3 months. Of the severely affected patients, 27% died before 3 months; most deaths occurred early in treatment. Factors associated with survival in severely affected patients included male sex, age less than 40 years, absolute neutrophil count greater than 200/microL, and idiopathic etiology. Neutrophil counts generally increased by 8 weeks after treatment, but patients continued to show improvement to 1 year posttreatment. In Group II, 44 patients with moderate or chronic severe aplastic anemia were randomized to receive either ten days of ATG or 3 months of high-dose nandrolone decanoate. No patient initially treated with androgens recovered, but 28% of ATG-treated cases achieved transfusion independence at 3 months. Group III consisted of patients with a variety of bone marrow failure syndromes. Patients with pancytopenia and cellular bone marrow showed response rates similar to those of patients with chronic or moderate aplastic anemia.

Changes of Subsets of DC 1 in the Bone Marrow of Severe Aplastic Anemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3712-3712
Author(s):  
Guangsheng He ◽  
Zhonghong Shao ◽  
De Pei Wu ◽  
Xiao Ma ◽  
Aining Sun
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Stable Form ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Cd8 Cells ◽  
Normal Controls

Abstract Objective To measure the changes of subsets of dendritic cells 1 (DC1) in the bone marrow of severe aplastic anemia (SAA) patients and evaluate the relationships between the CD11c+CD83+cells and Th1 cells, CD3+CD8+ cells or hematopoietic function. Methods By FACS, the quantity and ratio of CD11c+CD1a+ cells, CD11c+CD83+ cells, Th1 cells, and CD3+CD8+ cells in the bone marrow of SAA patients and normal controls were detected respectively. The relationships between CD3+CD8+ cells and Ret or ANC, between Th1 cells and CD3+CD8+ cells, Ret or ANC, between CD11c+CD83+ cells, and Th1 cells, CD3+CD8+ cells, Ret or ANC were evaluated. Results In normal control’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells, CD11c+CD83+ cells and ratio of CD11c+CD83+ /CD11c+CD1a+ was 0.42±0.30%, 0.38±0.29%, 0.37±0.32% and 1.07±0.10 respectively. In the untreated SAA patient’s bone marrow, they were 4.87±0.54%, 1.73±0.24%, 3.38±0.56% and 2.21±0.32 respectively, and increased markedly(p<0.01). In recovering SAA patient’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells and CD11c+CD83+ cells decreased significantly[0.53±0.22%, 0.61±0.23%, 0.65±0.22%, respectively (p<0.01)]. The ratio of CD11c+CD83+/CD11c+ CD1a+ of recovering SAA patients was 1.37±0.25 which was similar to that of normal controls (p>0.05). The percentages of CD3+CD8+ cells of untreated SAA patients was 32.32±10.22%, and that of recovering SAA patients decreased to 13.67%±5.24 significantly (p<0.01). The percentages of CD3+CD8+ cells of SAA patients were correlated to their Ret and ANC (P<0.05) negatively. Their Th1 cell percentages were correlated to their CD3+CD8+ cells positively (P<0.01), but to their Ret and ANC negatively(p<0.01). SAA patient’s CD11c+CD83+ cell percentages were correlated to their Th1 cell and CD3+CD8+ cells positively (P<0.01, P<0.05), but to their Ret and ANC negatively(p<0.01). Conclusion Both immature DC1 and activated DC1 increased in the bone marrow of SAA patients, and the balance of subsets of DC1 shifted from stable form to active one, which might promote Th0 cells to polarize to Th1 cells, then cause the over-function of T lymphocytes and hematopoietic failure in SAA.

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