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再生障碍性贫血 免疫发病机制 的探讨

再生障碍性贫血 免疫发病机制 的探讨. 中山大学附属第三医院血液科 胡 婷 硕士研究生. Definition. 再生障碍性贫血 （ Aplastic anemia ） acquired aplastic anemia Bone marrow failure syndromes is characterized by peripheral blood cytopenia and reduced marrow cellularity. seed. soil. bug. 造血干祖细胞缺陷（质和量的异常）. 造血微环境异常. 免疫异常. 传统观点.

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再生障碍性贫血 免疫发病机制 的探讨

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  1. 再生障碍性贫血免疫发病机制的探讨 中山大学附属第三医院血液科 胡 婷 硕士研究生

  2. Definition 再生障碍性贫血（Aplastic anemia） • acquired aplastic anemia • Bone marrow failure syndromes • is characterized by peripheral blood cytopenia and reduced marrow cellularity.

  3. seed soil bug 造血干祖细胞缺陷（质和量的异常） 造血微环境异常 免疫异常 传统观点

  4. Which comes first? Q Whether there is a causal relationship between the two ? Q Question

  5. Therapy 造血干细胞移植 40岁以下 无感染及其它 并发症 有合适供体的 SAA患者 免疫抑制治疗 抗淋巴/胸腺细胞 球蛋白 环孢素等 促造血治疗 雄激素 造血生长因子

  6. Hot topic 细胞免疫异常是AA的主要发病机制

  7. T 细胞介导的免疫抑制 1 淋巴因子的免疫作用 2 Content

  8. T细胞介导的免疫抑制 TCR – Vβ的CDR3为T细胞克隆的区分标志，AA患者曲线出现数个寡克隆峰。 以CD28为激活的T细胞分选标记， 这群细胞中CDR3优势克隆比例尤其高。 Invivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing.Lancet. 2004

  9. T细胞介导的免疫抑制 • T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood. 2006 Itk PKCθ T-bet IFN-γ Th1细胞激活和扩增 Th1型T细胞反应 干细胞损伤

  10. T细胞介导的免疫抑制 • Increased CD4+ and CD8+ effector memory T cells in patients with aplastic anemia. Haematologica, 2009 (IF5.5) AA患者CD45RA-CCR7-效应T记忆细胞增多 更快更强更有效的免疫应答

  11. T细胞介导的免疫抑制 • Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood. 2007 NFAT1和FOXP3表达水平低 CD4+CD25+FOXP3+调节性T细胞缺陷 与自身免疫性疾病类似

  12. 细胞因子的免疫作用 • 细胞因子的造血负调控作用 造血负调控因子： 白细胞介素-2（IL-2） -干扰素（IFN-） 肿瘤坏死因子-（TNF-）

  13. 细胞因子的免疫作用 • Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TNF-alpha and IFN-gamma. J Immunol ,2009 (IF6.0) 抗膜突蛋白抗体 AA 分泌TNFα和IFNγ 间接抑制 AA骨髓造血

  14. 细胞因子的免疫作用 • 负调控因子的作用机制 • Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia。J Immunol. 2002 IFN - γ和TNF –α 造血干细胞 p38 MAPKK2细胞凋亡

  15. 细胞因子的免疫作用 • Increased inducible nitric oxide synthase expression and nitric oxide concentration in patients with aplastic anemia. Ann Hematol. 2003 IFNγ IRF-1 iNOS NO DNA损伤与细胞凋亡

  16. Reference • Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 • Aplastic anemia: pathogenesis and treatment.Hematology Am Soc Hematol Educ Program.2007

  17. Reference • Perforin gene mutations in patients with acquired aplastic anemia.blood.2007 • Lymphocytes with aberrant expression of Fas or Fas ligand attenuate immune bone marrow failure in a mouse model. JImmunol. 2009

  18. 存在的问题 基础与临床的结合？ 至今也没有按发病机制或病理生理学进行再障分类的建议； 众多的再障免疫异常指标能用于判断疗效和转归者也少。

  19. 无论是重型或非重型再障都有约1/3的患者免疫抑制治疗无效 免疫发病机制仍有许多疑点

  20. Thank You !

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