{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:25:22Z","timestamp":1787610322795,"version":"build-2736575974"},"reference-count":42,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Absence of hematopoietic cells has been recognized from the characteristic morphology for a century; an immune pathophysiology has been inferred from improvement in blood counts with immunosuppressive therapy in the majority of patients. Molecular mechanisms underlying both T cell effector cells and the target marrow stem and progenitor cells are now being identified. Activated type 1 cytotoxic T cells and type 1 cytokines have been implicated in cell culture experiments; clues to the molecular basis of the aberrant immune response include cytokine gene polymorphisms and abnormalities in the regulatory pathways for \u03b3-interferon. For stem cell depletion, mutations in genes of the telomere repair complex are present in some patients with apparently acquired aplastic anemia. Telomerase deficiency is associated with short telomeres and a quantitative reduction in marrow progenitors and likely also a qualitative deficiency in the repair capacity of hematopoietic tissue.<\/jats:p>","DOI":"10.1182\/asheducation-2006.1.72","type":"journal-article","created":{"date-parts":[[2006,11,22]],"date-time":"2006-11-22T18:14:02Z","timestamp":1164219242000},"page":"72-77","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":64,"title":["Pathophysiologic Mechanisms in Acquired Aplastic Anemia"],"prefix":"10.1182","volume":"2006","author":[{"given":"Neal S.","family":"Young","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111704362329100_R1","unstructured":"Young NS, Calado RT, Scheinberg P: Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. In press."},{"key":"2019111704362329100_R2","doi-asserted-by":"crossref","unstructured":"Young NS. Acquired aplastic anemia. In: Young NS, Gerson SL, High K, eds. Clinical Hematology. Philadelphia: Elsevier; 2006:136\u2013157.","DOI":"10.1182\/asheducation-2006.1.72"},{"key":"2019111704362329100_R3","doi-asserted-by":"crossref","unstructured":"Nakao S, Feng X, Sugimori C. Immune pathophysiology of aplastic anemia. Int J Hematol. 2005;82:196\u2013200.","DOI":"10.1532\/IJH97.05116"},{"key":"2019111704362329100_R4","doi-asserted-by":"crossref","unstructured":"Schrezenmeier H, Bacigalupo A. Aplastic Anemia: Pathophysiology and Treatment. Cambridge, UK: Cambridge University Press; 2000.","DOI":"10.1017\/CBO9780511545290"},{"key":"2019111704362329100_R5","doi-asserted-by":"crossref","unstructured":"Choudhry VP, Gupta S, Gupta M, Kashyap R, Saxena R. Pregnancy associated aplastic anemia\u2014a series of 10 cases with review of literature. Hematology. 2002;7:233\u2013238.","DOI":"10.1080\/1024533021000024067"},{"key":"2019111704362329100_R6","doi-asserted-by":"crossref","unstructured":"Lu J, Basu A, Melenhorst J, Young NS, Brown KE. Analysis of T-cell repertoire in hepatitis-associated aplastic anemia. Blood. 2004;103:4588\u20134593.","DOI":"10.1182\/blood-2003-11-3959"},{"key":"2019111704362329100_R7","doi-asserted-by":"crossref","unstructured":"Sutton JF, Stacey M, Kearsey SE, et al. Increased risk for aplastic anemia and myelodysplastic syndrome in individuals lacking GSTT1 gene. Pediatr Blood Cancer. 2004;42:122\u2013126.","DOI":"10.1002\/pbc.10479"},{"key":"2019111704362329100_R8","unstructured":"Dufour C, Syahn J, Bacigalupo A, et al. Genetic polymorphisms of CYP3A4, GSTT1, GSTM1, GSTP1 and NQO1 and the risk of acquired idiopathic aplastic anemia in Caucasian patients. Haematologica. 2005;90:1027\u20131031."},{"key":"2019111704362329100_R9","doi-asserted-by":"crossref","unstructured":"Issaragrisil S, Kaufman D, Anderson T, et al. The epidemiology of aplastic anemia in Thailand. Blood. 2006;107:1299\u20131307.","DOI":"10.1182\/blood-2005-01-0161"},{"key":"2019111704362329100_R10","doi-asserted-by":"crossref","unstructured":"Hirano N, Butler MO, von Bergwelt-Baildon MS, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood. 2003;102:4567\u20134575.","DOI":"10.1182\/blood-2002-11-3409"},{"key":"2019111704362329100_R11","doi-asserted-by":"crossref","unstructured":"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;104:2425\u20132431.","DOI":"10.1182\/blood-2004-05-1839"},{"key":"2019111704362329100_R12","doi-asserted-by":"crossref","unstructured":"Sloand EM, Kim S, Maciejewski JP, et al. Intracellular interferon-\u03b3 in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood. 2002;100:1185\u20131191.","DOI":"10.1182\/blood-2002-01-0035"},{"key":"2019111704362329100_R13","doi-asserted-by":"crossref","unstructured":"Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet. 2004;364:355\u2013364.","DOI":"10.1016\/S0140-6736(04)16724-X"},{"key":"2019111704362329100_R14","doi-asserted-by":"crossref","unstructured":"Chen J, Lipovsky K, Ellison FM, Calado RT, Young NS. Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure. Blood. 2004;104:1671\u20131678.","DOI":"10.1182\/blood-2004-03-1115"},{"key":"2019111704362329100_R15","doi-asserted-by":"crossref","unstructured":"Maciejewski JP, Follmann D, Rivera CE, et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and PNH\/aplastic anemia syndrome. Blood. 2001;98:3513\u20133519.","DOI":"10.1182\/blood.V98.13.3513"},{"key":"2019111704362329100_R16","doi-asserted-by":"crossref","unstructured":"Peng J, Liu C, Zhu K, et al. The TNF2 allele is a risk factor to severe aplastic anemia independent of HLA-DR. Hum Immunol. 2003;64:896\u2013901.","DOI":"10.1016\/S0198-8859(03)00141-1"},{"key":"2019111704362329100_R17","doi-asserted-by":"crossref","unstructured":"Demeter J, Messer G, Schrezenmeier H. Clinical relevance of the TNF-alpha promoter\/enhancer polymorphism in patients with aplastic anemia. Ann Hematol2002;81:566\u2013569.","DOI":"10.1007\/s00277-002-0544-6"},{"key":"2019111704362329100_R18","doi-asserted-by":"crossref","unstructured":"Dufour C, Capasso M, Svahn J, et al. Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol. 2004;126:682\u2013685.","DOI":"10.1111\/j.1365-2141.2004.05102.x"},{"key":"2019111704362329100_R19","doi-asserted-by":"crossref","unstructured":"Solomou EE, Keyvanfar K, Young NS. T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood. 2006;107:3983\u20133991.","DOI":"10.1182\/blood-2005-10-4201"},{"key":"2019111704362329100_R20","doi-asserted-by":"crossref","unstructured":"Xu JL, Nagasaka T, Nakashima N. Involvement of cytotoxic granules in the apoptosis of aplastic anaemia. Br J Haematol. 2003;120:850\u2013852.","DOI":"10.1046\/j.1365-2141.2003.04147.x"},{"key":"2019111704362329100_R21","doi-asserted-by":"crossref","unstructured":"Bacigalupo A, Valle M, Podesta M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol. 2005;33:819\u2013827.","DOI":"10.1016\/j.exphem.2005.05.006"},{"key":"2019111704362329100_R22","doi-asserted-by":"crossref","unstructured":"Zeng W, Kajigaya S, Chen G, et al. Transcript profile of CD4+ and CD8+ cells from the bone marrow of acquired aplastic anemia patients. Exp Hematol. 2004;32:806\u2013814.","DOI":"10.1016\/j.exphem.2004.06.004"},{"key":"2019111704362329100_R23","doi-asserted-by":"crossref","unstructured":"Poggi A, Negrini S, Zocchi MR, et al. Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors. Blood. 2005;106:2399\u20132408.","DOI":"10.1182\/blood-2004-11-4315"},{"key":"2019111704362329100_R24","doi-asserted-by":"crossref","unstructured":"Howe EC, Wlodarski M, Ball EJ, Rybicki L, Maciejewski JP. Killer immunoglobulin-like receptor genotype in immune-mediated bone marrow failure syndromes. Exp Hematol. 2005;33:1357\u20131362.","DOI":"10.1016\/j.exphem.2005.07.005"},{"key":"2019111704362329100_R25","doi-asserted-by":"crossref","unstructured":"Kakagianni T, Giannakoulas NC, Thanopoulou E, et al. A probable role for trail-induced apoptosis in the pathogenesis of marrow failure implications from an in vitro model and from marrow of aplastic anemia patients. Leuk Res. 2006;30:713\u2013721.","DOI":"10.1016\/j.leukres.2005.09.015"},{"key":"2019111704362329100_R26","doi-asserted-by":"crossref","unstructured":"Zeng W, Chen G, Kajigaya S, et al. Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. Blood. 2004;103:325\u2013332.","DOI":"10.1182\/blood-2003-02-0490"},{"key":"2019111704362329100_R27","doi-asserted-by":"crossref","unstructured":"Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS. Interferon-\u03b3-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. Blood. 2006;107:167\u2013175.","DOI":"10.1182\/blood-2005-05-1884"},{"key":"2019111704362329100_R28","doi-asserted-by":"crossref","unstructured":"Fogarty PF, Yamaguchi H, Wiestner A, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362:1628\u20131630.","DOI":"10.1016\/S0140-6736(03)14797-6"},{"key":"2019111704362329100_R29","doi-asserted-by":"crossref","unstructured":"Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352:1413\u20131424.","DOI":"10.1056\/NEJMoa042980"},{"key":"2019111704362329100_R30","doi-asserted-by":"crossref","unstructured":"Savage SA, Calado RT, Lansdorp PM, Chanock SJ, Young NS. Genetic variation In telomeric repeat binding factor 1 but not telomeric repeat binding factor 2 are associated with aplastic anemia. Exp Hematol. 2006;34:664\u2013671.","DOI":"10.1016\/j.exphem.2006.02.008"},{"key":"2019111704362329100_R31","unstructured":"Young NS. Paroxysmal nocturnal hemoglobinuria: current issues in pathophysiology and treatment. Curr Hematol Rep. 2005;4:103\u2013109."},{"key":"2019111704362329100_R32","doi-asserted-by":"crossref","unstructured":"Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59 blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107:1308\u20131314.","DOI":"10.1182\/blood-2005-06-2485"},{"key":"2019111704362329100_R33","doi-asserted-by":"crossref","unstructured":"Takami A, Zeng W, Wang H, Matsuda T, Nakao S. Cytotoxicity against lymphoblastoid cells mediated by a T-cell clone from an aplastic anaemia patient: role of CD59 on target cells. Br J Haematol. 1999;107:791\u2013796.","DOI":"10.1046\/j.1365-2141.1999.01790.x"},{"key":"2019111704362329100_R34","doi-asserted-by":"crossref","unstructured":"Karadimitris A, Notaro R, Koehne G, Roberts IAG, Luzzatto L. PNH cells are as sensitive to T-cell-mediated lysis as their normal counterparts: implications for the pathogenesis of paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2000;111:1158\u20131163.","DOI":"10.1046\/j.1365-2141.2000.02494.x"},{"key":"2019111704362329100_R35","doi-asserted-by":"crossref","unstructured":"Chen G, Kirby M, Zeng W, Young NS, Maciejewski JP. Superior growth of glycophosphatidylinositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo. Exp Hematol. 2002;30:774\u2013782.","DOI":"10.1016\/S0301-472X(02)00811-1"},{"key":"2019111704362329100_R36","doi-asserted-by":"crossref","unstructured":"Chen G, Zeng W, Maciejewski JP, et al. Differential gene expression profile in hematopoietic progenitors form paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis\/immune response in \u2018normal\u2019 phenotype cells. Leukemia. 2005;19:862\u2013868.","DOI":"10.1038\/sj.leu.2403678"},{"key":"2019111704362329100_R37","doi-asserted-by":"crossref","unstructured":"Hanaoka N, Kawaguchi T, Horikawa K, et al. Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Blood. 2006;107:1184\u20131191.","DOI":"10.1182\/blood-2005-03-1337"},{"key":"2019111704362329100_R38","doi-asserted-by":"crossref","unstructured":"Maciejewski JP, Risitano AM, Nunez O, Young NS. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99:3129\u20133135.","DOI":"10.1182\/blood.V99.9.3129"},{"key":"2019111704362329100_R39","doi-asserted-by":"crossref","unstructured":"Sloand EM, Fuhrer M, Risitano A, et al. Preferential suppression of trisomy 8 versus normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood. 2005;106:841\u2013851.","DOI":"10.1182\/blood-2004-05-2017"},{"key":"2019111704362329100_R40","unstructured":"Sloand EM, Chen G, Pfannes L, et al. CD34 cells from trisomy 8 myelodysplastic syndrome (MDS) patients express early apoptotic markers but avoid programmed cell death by upregulation of anti-apoptotic proteins. Blood. In press."},{"key":"2019111704362329100_R41","doi-asserted-by":"crossref","unstructured":"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;100:786\u2013790.","DOI":"10.1182\/blood.V100.3.786"},{"key":"2019111704362329100_R42","unstructured":"Sloand EM, Yong A, Ramkissoon S, Solomou E, Barrett AJ, Young NS. Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells which express a truncated G-CSF receptor isoform. Proc Natl Acad Sci U S A. In press."}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2006\/1\/72\/1091613\/072_077ash.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/hematology\/article-pdf\/2006\/1\/72\/1091613\/072_077ash.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,17]],"date-time":"2019-11-17T04:36:36Z","timestamp":1573965396000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2006\/1\/72\/19811\/Pathophysiologic-Mechanisms-in-Acquired-Aplastic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2006,1,1]]}},"URL":"https:\/\/doi.org\/10.1182\/asheducation-2006.1.72","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,1,1]]}}}