Analysis on the activated T-cells in lymphoproliferative diseases

淋巴细胞增殖性疾病中活化的 T 细胞分析

• 批准号: 13670814
• 负责人: OHGA Shouichi
• 金额: $ 1.86万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670814/
• 关键词: lymphoproliferative diseases (disorders); perforin; activated T cell; Fas; activation-induced cell death (AICD); hemophagocytic lymphohistiocytosis (HLH); autoimmune lymphoproliferative syndrome (ALPS); hyper-IgE syndrome (HIES); 血球貧食リンパ組織球症(HLH)

Lymphoproliferative disease (LPD) is defined as a clonal disorder of lymphocytes without histopathological evidence of malignancy. Epstein-Barr virus (EBV) is reactivated and associated with the development of B-cell LPD in immunodeficient patients. This virus infects T/NK cells in immunocompetent subjects and induces EBV^+ T-cell LPD including chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). On the other hand, there is a group of inherited LPD caused by the defective functional molecule of T cells. Patients with primary HLH or autoimmune lymphoproliferative syndrome (ALPS) show hypercytokinemia or autoimmunity, because the cytotoxcity and activation-induced cell death (AICD) are impaired by the defects of perforin and Fas, respectively. Hyper-IgE syndrome (HIES) is a congenital immunodeficiency characterized by recurrent infections, marked IgE elevation, and increase of activated T cells. The defective IFNγ production is implicated in the pathogenesis … More of HIES. The present study revealed that the cytokines released from persistently activated T cells could contribute to the pathophysiology of these diseases.1) primary HLH: Perforin gene defects were found in 2/8 Japansese patients with familial HLH (FHL), and 1/7 patients without affected siblings (4 novel mutations). The protein was not expressed in CD8^+/CD56^+ cells of the patient. The frequency of mutation was 〜20% of FHL in Japan.2) ALPS: Patients with CD4^-CD8^- double negative (DN) αβT-cell expansion showed high serum IL-10 levels. IL-10-expressing DNT cells were increased in patients with lymphoproliferation. Real-time PCR revealed 〜100 times higher IL-10, but not, IFNγ or TGFβ in DN than in single positive T-cells. IL-10 was exclusively expressed in DN αβ but not γδ-cells. Circulating DN αβT-cells may constitutively express IL-10 and contribute to the ALPS phenotype.3) HIES: Cytokine profile of HLA-DR^+ and DR^- T-cells was analyzed. IFNγ/IL-4 or IFNγ/IL-10 ratio in DR^+ T-cells of HIES was lower than each of chronic granulomatous disease (CGD). TGFβ/IL-4 ratio in DR^+ T-cells of HIES was lower than that of atopy or CGD. TGFβ/IL-4 in DR^- T-cells of HIES was also lower than that of atopy. The statistical analysis revealed that TGFβ/IL-4 ratios in DR^+ or DR^- T-cells were the most powerful parameters to distinguish HIES from atopy and/or CGD. The in vivo activated T-cells of HIES might not sufficiently express IFNγ and TGFβ genes to counteract on the IL-4 dependent IgE production. The reduced TGFβ expression may imply the indigenous T-cell defects of HIES. Less

淋巴细胞增生性疾病（LPD）是指一种无恶性组织病理学证据的淋巴细胞克隆性疾病。EB病毒（EBV）被重新激活，并与免疫缺陷患者的B细胞LPD的发展有关。该病毒感染免疫活性受试者的T/NK细胞，并诱导EBV^+ T细胞LPD，包括慢性活动性EBV感染（CAEBV）和噬血细胞性淋巴组织细胞增多症（HLH）。另一方面，存在一组由T细胞功能分子缺陷引起的遗传性LPD。原发性HLH或自身免疫性淋巴组织增生综合征（ALPS）患者表现出高细胞因子血症或自身免疫，因为穿孔素和Fas的缺陷分别削弱了细胞毒性和激活诱导的细胞死亡（AICD）。高IgE综合征（hyper-IgE syndrome，HIES）是一种以反复感染、IgE显著升高和活化T细胞增多为特征的先天性免疫缺陷。IFNγ产生缺陷与发病机制有关 ...更多信息 的他。目前的研究表明，从持续活化的T细胞释放的细胞因子可能有助于这些疾病的病理生理学。1）原发性HLH：穿孔素基因缺陷被发现在2/8例日本家族性HLH（FHL）患者和1/7例无受累同胞（4个新突变）。该蛋白在患者的CD 8 ^+/CD 56 ^+细胞中不表达。在日本，突变频率为FHL的约20%。2）ALPS：CD 4 ^-CD 8 ^-双阴性（DN）αβ T细胞扩增的患者显示高血清IL-10水平。IL-10表达的DNT细胞在淋巴细胞增生患者中增加。Real-time PCR显示DN中IL-10的表达比单个阳性T细胞高100倍，而IFNγ或TGFβ的表达则无明显差异。IL-10仅表达于DN αβ细胞，而不表达于DN γδ细胞。循环DN αβ T细胞可能组成性表达IL-10并参与ALPS表型。3）HIES：分析HLA-DR^+和DR^-T细胞的细胞因子谱。HIES组DR^+ T细胞中IFNγ/IL-4、IFNγ/IL-10比值均低于慢性肉芽肿病组（CGD）。HIES组DR^+ T细胞中TGFβ/IL-4比值低于过敏症组和CGD组。HIES组DR^-T细胞中TGFβ/IL-4比值也低于特应性组。统计学分析显示，DR^+或DR^-T细胞中TGFβ/IL-4比值是区分HIES与特应性和/或CGD的最有力参数。HIES的体内活化T细胞可能不充分表达IFNγ和TGFβ基因以对抗IL-4依赖性IgE的产生。TGFβ表达的降低可能暗示HIES的固有T细胞缺陷。少

项目成果

Ishizaki Y, et al.: "Quantification of circulating varicella zoster virus-DNA for the early diagnosis of visceral varicella"J Infect. (in press).

Ishizaki Y 等人：“循环水痘带状疱疹病毒 DNA 的定量用于内脏水痘的早期诊断”J Infect。

Ohga S, Nomura A, Takahata Y, Ihara K, Takada H, Wakiguchi H, Kudo Y, Hara T:: "Dominant expression of IL-10 but not IFN-γ in CD4^- CD8^- αβ T cells of autoimmune lymphoproliferative syndrome."Br J Haematol. 119. 535-538 (2002)

Ohga S、Nomura A、Takahata Y、Ihara K、Takada H、Wakiguchi H、Kudo Y、Hara T：：“自身免疫性淋巴细胞增殖性 CD4^- CD8^- αβ T 细胞中 IL-10 的显性表达，而非 IFN-γ 的显性表达综合征。”Br J Haematol. 119. 535-538 (2002)

Kogawa K, Kudoh J, Nagafuchi S, Katsuta H, Ohga S, et al.: "Phenotype of autoimmune polyglandular syndrome type I and genotype of AIRE gene in a Japanese family"Clinical Immunology. 103. 277-283 (2002)

Kokawa K，Kudoh J，Nagafuchi S，Katsuta H，Ohga S，等：“日本家族中自身免疫性多腺体综合征 I 型表型和 AIRE 基因的基因型”临床免疫学。

Takada H, Nomura A, Ohga S, Hara T: "IL-18 in hemophagocytic lymphohistiocytosis"Leukemia and Lymphoma. 42. 21-28 (2001)

Takada H、Nomura A、Ohga S、Hara T：“噬血细胞性淋巴组织细胞增多症中的 IL-18”白血病和淋巴瘤。

大賀正一, 稲葉頌一: "小児輸血療法-安全で有効な輸血のために-(II.新生児の輸血 D.顆粒球輸血)"南江堂. 75~83 (2001)

Shoichi Ohga、Shoichi Inaba：“小儿输血疗法 - 安全有效的输血 - (II.新生儿输血 D. 粒细胞输血)” Nankodo 75~83 (2001)。