Analysis on the activated T-cells in lymphoproliferative diseases

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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