Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Current Concepts of the Pathogenesis of Aplastic Anemia

Author(s): Chunyan Liu, Yingying Sun and Zonghong Shao *

Volume 25, Issue 3, 2019

Page: [236 - 241] Pages: 6

DOI: 10.2174/1381612825666190313113601

Price: $65

Abstract

Abnormal activation of the immune system plays an important role in the pathogenesis of aplastic anemia (AA). Various immune cells and cytokines constitute a complex immune network, leading to bone marrow failure. The known pathogenesis is an increase of the myeloid dendritic cell (mDC)/ plasmacytoid dendritic cell (pDC) ratio, which causes the ratio of T helper (Th)1/Th2 to be skewed in favor of Th1 and eventually leads to an abnormal activation of cytotoxic T lymphocyte (CTL). The antigens that stimulate T cells in the context of AA remain unknown. In this process, regulatory T (Treg), Th17, natural killer (NK) cell, memory T cell and negative hematopoietic regulatory factors are also involved. In addition, genetic background (e.g., chromosomal abnormalities, telomere attrition, somatic cell mutations), abnormal bone marrow hematopoietic microenvironment and viral infection may also contribute to the pathogenesis of AA. This review summarizes the recent studies of the pathogenesis of AA and the current status of AA research.

Keywords: Aplastic Anemia, immunosuppressive therapies, pathogenesis, cytokines, myeloid dendritic cell, bone marrow failure.

[1]
Feng L, Fu R, Wang HQ, et al. Effect of CD8+ effector T cells on the hematopoiesis pathway damage in the patients with severe aplastic anemia. Zhonghua Xue Ye Xue Za Zhi 2011; 32(9): 597-601.
[2]
Liu CY, Fu R, Wang J, et al. Expression of lymphokines in CD8(+)HLA-DR(+) T lymphocytes of patients with severe aplastic anemia. Zhonghua Yi Xue Za Zhi 2012; 92(18): 1240-3.
[3]
Xing L, Liu C, Fu R, et al. CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. . Mol Med Rep 2014; 10(3): 1252.
[4]
Ren J, Hou XY, Ma SH, et al. Elevated expression of CX3C chemokine receptor 1 mediates recruitment of T cells into bone marrow of patients with acquired aplastic anaemia. . J Intern Med 2015; 276(5): 512-24.
[5]
Zeng W, Kajigaya S, Chen G, et al. Transcript profile of CD4+ and CD8+ T cells from the bone marrow of acquired aplastic anemia patients. . Exp Hematol 2004; 32(9): 806-14.
[6]
Shao YQ, Dong HY, Ge ML, et al. Differential expression profiles of MicroRNAs between de novo and complete response severe aplastic anemia. Zhonghua Xue Ye Xue Za Zhi 2018. (1):213-8.
[7]
Qi W, Yan L, Liu C, et al. Abnormal histone acetylation of CD8+ T cells in patients with severe aplastic anemia. Int J Hematol 2016; 104(5): 1-8.
[8]
Sheng W, Liu C, Fu R, et al. Abnormalities of quantities and functions of linker for activations of T cells in severe aplastic anemia. Eur J Haematol 2014; 93(3): 214-23.
[9]
Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic anemia. Blood 2012; 119(9): 2033-43.
[10]
Shi J, Ge M, Lu S, et al. Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia. Blood 2012; 120(8): 1624.
[11]
Yan L, Fu R, Liu H, et al. Abnormal quantity and function of regulatory T cells in peripheral blood of patients with severe aplastic anemia. Cell Immunol 2015; 296(2): 95-105.
[12]
de Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood 2010; 116(20): 4175-84.
[13]
Zheng M, Liu C, Fu R, et al. Abnormal immunomodulatory ability on memory T cells in humans with severe aplastic anemia. Int J Clin Exp Pathol 2015; 8(4): 3659-69.
[14]
Hart DNJ. Dendritic cells: Unique leukocyte populations which control the primary immune response. Blood 1997; 90(9): 3245.
[15]
Inaba K, Turley S, Yamaide F, et al. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 1998; 188(11): 2163-73.
[16]
Xing R, Liu F, Yang Y, et al. GPR54 deficiency reduces the Treg population and aggravates experimental autoimmune encephalomyelitis in mice. Sci China Life Sci 2018; 61(6): 675-87.
[17]
Azad MAK, Sarker M, Wan D. Immunomodulatory effects of probiotics on cytokine profiles. BioMed Res Int 2018; 20188063647
[18]
Shen Y, Liqiang WU, Wang B, et al. B lymphocytes and humoral immunity in patients with aplastic anemia. Zhejiang Zhong Xi Yi Jie He Za Zhi 2017. (1): 5-8.
[19]
Goto M, Kuribayashi K, Takahashi Y, et al. Identification of autoantibodies expressed in acquired aplastic anaemia. Br J Haematol 2013; 160(3): 359-62.
[20]
Liu C, Sheng W, Fu R, et al. Differential expression of the proteome of myeloid dendritic cells in severe aplastic anemia. Cell Immunol 2013; 285(1–2): 141-8.
[21]
Wang J, Shao ZH, Fu R, et al. Study on the dendritic cell subsets in peripheral blood and its relationship with the expressions of T-bet and GATA-3 in lymphocytes in severe aplastic anemia. Zhonghua Xue Ye Xue Za Zhi 2008. 29(11): 733-6.
[22]
Tu MF, Shao ZH, Liu H, et al. Study on the peripheral blood dendritic cells subtypes and the expression of co-stimulating molecules on dendritic cells and B cells in severe aplastic anemia patients. Zhonghua Xue Ye Xue Za Zhi 2006. 27(9): 611-5.
[23]
Wang J, Shao ZH, Fu R, et al. In vitro induction of allo-T lymphocytes proliferation by myeloid dendritic cells in patients with severe aplastic anemia. Zhonghua Nei Ke Za Zhi 2009. 48(12): 1040-3.
[24]
Wei H-J, Gupta A, Kao W-M, et al. Nrf2-mediated metabolic reprogramming of tolerogenic dendritic cells is protective against aplastic anemia. . J Autoimmun 2018; 94: 33-44.
[25]
Li ZS, Shao ZH, Fu R, et al. Percentages and functions of natural killer cell subsets in peripheral blood of patients with severe aplastic anemia. Zhonghua Yi Xue Za Zhi 2011; 91(16): 1084-7.
[26]
Tian Z, Xin Y, Liu C, et al. Decreased TIM-3 expression of peripheral blood natural killer cells in patients with severe aplastic anemia. Cell Immunol 2017; 318: 17.
[27]
Liu C, Li Z, Sheng W, et al. Abnormalities of quantities and functions of natural killer cells in severe aplastic anemia. Immunol Invest 2014; 43(5): 491-503.
[28]
Fu R, Liu H, Zhang J, et al. Expression of NK-activating receptor-NKp46/NCR1 on NK cells in patients with severe aplastic anemia. Clin Lab 2015; 61(9): 1221.
[29]
Galleggiante V, De Santis S, Cavalcanti E, et al. Dendritic cells modulate iron homeostasis and inflammatory abilities following quercetin exposure. Curr Pharm Des 2017; 23(14): 2139-46.
[30]
Feng X, Chuhjo T, Sugimori C, et al. Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood 2004; 104(8): 2425-31.
[31]
Gargiulo L, Zaimoku Y, Scappini B, et al. Glycosylphosphatidylinositol-specific T cells,IFNγ-producing T cells,and pathogenesis of idiopathic aplastic anemia. . Blood 2017; 129(3): 388-92.
[32]
Erie AJ, Samsel L, Takaku T, et al. MHC class II upregulation and colocalization with Fas in experimental models of immune-mediated bone marrow failure. Exp Hematol 2011; 39(8): 837-49.
[33]
Peng H, Tian Z. NK cells in liver homeostasis and viral hepatitis. Sci China Life Sci 2018; 61(12): 1477-85.
[34]
Vijayan V, Shalini K, Yugesvaran V, et al. Effect of paclitaxel-loaded PLGA nanoparticles on MDA-MB type cell lines: Apoptosis and cytotoxicity studies. Curr Pharm Des 2018; 24: 3366-75.
[35]
Abdelwahid E, Stulpinas A, Kalvelyte A. Effective Agents Targeting the Mitochondria and Apoptosis to Protect the Heart. Curr Pharm Des 2017; 23: 1153-66.
[36]
Lin FC, Karwan M, Saleh B, et al. IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation. Blood 2014; 124(25): 3699-708.
[37]
Guan G, Lan S. Implications of antioxidant systems in inflammatory bowel disease. BioMed Res Int 2018; 20181290179
[38]
Bin P, Liu S, Chen S, et al. The effect of aspartate supplementation on the microbial composition and innate immunity on mice. Amino Acids 2017; 49(12): 2045-51.
[39]
Liu G, Yu L, Fang J, et al. Methionine restriction on oxidative stress and immune response in dss-induced colitis mice. Oncotarget 2017; 8(27): 44511-20.
[40]
Shao Z, Feng L, Fu R, et al. Study on the Pathways to Damage Hematopoiesis by CD8+ Effector T Cells of the Patients with Severe Aplastic Anemia. Blood 2011; 118(21): 4371.
[41]
Rehman S, Saba N, Naz M, et al. Single-nucleotide polymorphisms of FAS and FASL genes and risk of idiopathic aplastic anemia. Immunol Invest 2018. 47(5): 484-91.
[42]
Qi W, Fu R, Wang H, et al. Association between serum interleukin-17 level and abnormal cellular immunological status in patients with severe aplastic anemia. Zhonghua Yi Xue Za Zhi 2014; 94(20): 1539.
[43]
Shao Z, Tu M, Wang H, et al. Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia. Int J Hematol 2011; 93(2): 156-62.
[44]
Zeng Y, Katsanis E. The complex pathophysiology of acquired aplastic anaemia. Clin Exp Immunol 2015; 180(3): 361-70.
[45]
Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology (Am Soc Hematol Educ Program) 2006; 108(8): 76-81.
[46]
Liu C, Zheng M, Wang T, et al. PKM2 is required to activate myeloid dendritic cells from patients with severe aplastic anemia. Oxid Med Cell Longev 2018. 2018: 1364165.
[47]
Zonghong S, Rong F. Immunorelated pancytopenia-a newly recognized disease (part 1). Zhongguo Yi Kan 2005; 40(1): 5-8.
[48]
Zonghong S, Rong F. Immunorelated pancytopenia-a newly recognized disease (part 2). Zhongguo Yi Kan 2005; 40(2): 6-9.
[49]
Scheinberg P. A randomized trial of horse versus rabbit antithymocyte globulin in severe acquired aplastic anemia. N Engl J Med 2011; 365(5): 430.
[50]
Zhu X, Guan J, Xu J, et al. Pilot study using tacrolimus rather than cyclosporine plus antithymocyte globulin as an immunosuppressive therapy regimen option for severe aplastic anemia in adults. Blood Cells Mol Dis 2014; 53(3): 157-60.
[51]
Phillip S, Wu CO, Olga N, et al. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica 2009; 94(3): 348.
[52]
Phillip S, Olga N, Barbara W, et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood 2012; 119(2): 345-54.
[53]
Dumitriu B, Feng X, Townsley DM, et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. . Blood 2015; 125(4): 706-9.
[54]
Ishiyama K, Karasawa M, Miyawaki S, et al. Aplastic anaemia with 13q-: a benign subset of bone marrow failure responsive to immunosuppressive therapy. Br J Haematol 2015; 117(3): 747-50.
[55]
Kulasekararaj AG, Jiang J, Smith AE, et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood 2014; 124(17): 2698-704.
[56]
Dezern AE, Brodsky RA. Clinical management of aplastic anemia. . Expert Rev Hematol 2011; 4(2): 221.
[57]
Marsh JCW, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2010; 147(1): 43-70.
[58]
Li Y, Li X, Ge M, et al. Long-term follow-up of clonal evolutions in 802 aplastic anemia patients: a single-center experience. Ann Hematol 2011; 90(5): 529-37.
[59]
Kim SY, Lee JW, Lee SE, et al. The characteristics and clinical outcome of adult patients with aplastic anemia and abnormal cytogenetics at diagnosis. Genes Chromosomes & Cancer 2010; 49(9): 844-50.
[60]
Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe. Aplastic anemia and the Gruppo Italiano Trapiarti di Midolio Osseo (GITMO). Blood 2000; 95(6): 1931-4.
[61]
Kojima S, Ohara A, Tsuchida M, et al. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002; 100(3): 786-90.
[62]
Babushok DV, Duke JL, Xie HM, et al. Somatic HLA mutations expose the role of class I-mediated autoimmunity in aplastic anemia and its clonal complications. Blood Adv 2017; 1(22): 1900-10.
[63]
Nakao S, Takamatsu H, Chuhjo T, et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood 1994; 84(12): 4257.
[64]
Katagiri T, Satootsubo A, Kashiwase K, et al. Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood 2011; 118(25): 6601-9.
[65]
Nakao S, Takami A, Takamatsu H, et al. Isolation of a T-cell clone showing HLA-DRB1*0405-restricted cytotoxicity for hematopoietic cells in a patient with aplastic anemia. Blood 1997; 89(10): 3691-9.
[66]
Sunyang Y, Jiaxiu X, Hongxu M, et al. Advances on the regulation of telomerase. Yi Chuan 2016. 38(4): 289-99.
[67]
Wang T, Mei SC, Fu R, et al. Expression of Shelterin component POT1 is associated with decreased telomere length and immunity condition in humans with severe aplastic anemia. J Immunol Res 2014; 2014439530
[68]
Han B, Liu B, Cui W, et al. Telomerase gene mutation screening in Chinese patients with aplastic anemia. Leuk Res 2010; 34(2): 258-60.
[69]
Sakaguchi H, Nishio N, Hama A, et al. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 2014; 99(8): 1312-6.
[70]
Calado RT, Cooper JN, Padillanash HM, et al. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia. Leukemia 2012; 26(4): 700-7.
[71]
Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304(12): 1358-64.
[72]
Vulliamy TJ, Kirwan MJ, Richard B, et al. Differences in disease severity but similar telomere lengths in genetic subgroups of patients with telomerase and shelterin mutations. PLoS One 2011; 6(9)e24383
[73]
Shtessel L, Ahmed S. Telomere dysfunction in human bone marrow failure syndromes. Nucleus 2011; 2(1): 24-9.
[74]
Young NS. Telomere biology and telomere diseases: implications for practice and research. Hematology Am Soc Hematol Educ Program 2010. 2010: 30-5.
[75]
Calado RT, Yewdell WT, Wilkerson KL, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood 2009; 114(11): 2236-43.
[76]
Saux CJL, Davy P, Brampton C, et al. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis. PLoS One 2013; 8(3)e58423
[77]
Babushok DV, Perdigones N, Perin JC, et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet 2015. 208(4): 115-28.
[78]
Afable MG II, Tiu RV, Maciejewski JP. Clonal evolution in aplastic anemia. Hematology (Am Soc Hematol Educ Program) 2011; 2011(4): 90-5.
[79]
Murakami Y, Kosaka H, Maeda Y, et al. Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood 2002; 100(12): 4116-22.
[80]
Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 2015; 373(1): 35-47.
[81]
Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood 2016; 128(3): 337-47.
[82]
Park M, Park CJ, Cho YW, et al. Alterations in bone marrow microenvironment may elicit defective hematopoiesis: a comparison of aplastic anemia, chronic myeloid leukemia and normal bone marrow. Exp Hematol 2016; 45: 56.
[83]
Füreder W, Krauth MT, Sperr WR, et al. Evaluation of angiogenesis and vascular endothelial growth factor expression in the bone marrow of patients with aplastic anemia. Am J Pathol 2006; 168(1): 123-30.
[84]
Wang H, Dong Q, Fu R, et al. Recombinant human thrombopoietin treatment promotes hematopoiesis recovery in patients with severe aplastic anemia receiving immunosuppressive therapy. Biomed Res Int 2015. 2015(5): 1-6.
[85]
Bacigalupo A. How I treat acquired aplastic anemia. Blood 2017; 129(11): 1428.
[86]
Kaito K, Kobayashi M, Katayama T, et al. Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol 2015; 103(2): 297-303.
[87]
Chao YH, Peng CT, Harn HJ, et al. Poor potential of proliferation and differentiation in bone marrow mesenchymal stem cells derived from children with severe aplastic anemia. Ann Hematol 2010; 89(7): 715-23.
[88]
Li XH, Gao CJ, Da WM, et al. Reduced intensity conditioning, combined transplantation of haploidentical hematopoietic stem cells and mesenchymal stem cells in patients with severe aplastic anemia. PLoS One 2014; 9(3)e89666
[89]
Zhao M, Zhang H, Liu K, et al. Human T-cell immunity against the emerging and re-emerging viruses. Sci China Life Sci 2017; 60(12): 1307-16.
[90]
Wang H, Tu M, Fu R, et al. The clinical and immune characteristics of patients with hepatitis-associated aplastic anemia in China. PLoS One 2014; 9(5)e98142
[91]
Zhang T, Liu C, Liu H, et al. Epstein barr virus infection affects function of cytotoxic T lymphocytes in patients with severe aplastic anemia. BioMed Res Int 2018; 2018(7335): 1-10.
[92]
Qiu J, Söderlund-Venermo M, Young NS. Human parvoviruses. Clin Microbiol Rev 2017; 30(1): 43-113.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy