Katsuji Sugie

Impaired natural killer activity and expression of interleukin‐2 receptor antigen in familial erythrophagocytic lymphohistiocytosis

A 1‐month‐old boy with familial erythrophagocytic lymphohistiocytosis (FEL) had a barely detectable natural killer (NK) activity of 0% to 7% (median, 0.5%) with an effector/target ratio of 20:1. The number of Leu7+ and Leu11+ cells was within normal range. In terms of interleukin‐2 (IL‐2) receptor antigens, IL‐2R/p55 (Tac) was marginally expressed whereas IL‐2R/p75‐related antigen recognized by YTA‐1 monoclonal antibody (MAb), i.e., YTA‐1 antigen, was moderately expressed on the patients mononuclear cells. Since the NK activity was restored in vitro by IL‐2 stimulation, insufficient in vivo IL‐2 production or altered cooperation of IL‐2R/p75 and IL‐2R/p55 (Tac) in the IL‐2 mediated immune response was suspected to be present. The induction of IL‐2R/p55 (Tac) in vitro was found to be impaired after stimulation with IL‐2, or YTA‐1 MAb. When the patient attained remission, the IL‐2R/p55 (Tac) induction had normalized, but low NK activity persisted. The results indicate that the IL‐2/IL‐2R system may play an important role in the etiology and pathogenesis of FEL.

Induction of the 2B9 antigen/dipeptidyl peptidase IV/CD26 on human natural killer cells by IL-2, IL-12 or IL-15.

Activation of human natural killer (NK) cells involves sequential events including cytokine production and induction of cell surface molecules, resulting in the enhancement of cytolytic activity. To delineate the activation process of NK cells, we generated murine monoclonal antibodies (mAbs) against YT, a human large granular lymphocyte/natural killer (LGL/NK) cell line. Among the mAbs reactive with YT cells, one mAb, termed 2B9, was noted because of the lack of reactivity with most of the human T‐ and B‐cell lines tested. In fresh peripheral blood mononuclear cells (PBMC), however, the majority of cells expressing this antigen (Ag) were T cells but not CD16+ nor CD56+ NK cells. Since YT cells showed an activated phenotype expressing interleukin‐2 (IL‐2) receptor α chain, we examined whether 2B9 Ag could be induced on normal human peripheral blood NK cells by cytokines known to activate NK cells. The 2B9 Ag was induced on NK cells by IL‐2, IL‐12 or IL‐15 while no induction was observed by interferon‐γ (IFN‐γ). Biochemical analysis showed that anti‐2B9 mAb recognized a 115 kDa molecule in YT cells. A cDNA clone encoding the 2B9 Ag was isolated from a cDNA expression library of YT cells and its sequence was identical to CD26 cDNA although it was not of full length. Transient expression of the 2B9 cDNA on COS‐7 cells revealed that this cDNA encodes the antigenic epitope(s) recognized by anti‐2B9 mAb as well as Ta1, an anti‐CD26 mAb. These results showed that the 2B9 Ag is identical to CD26, and demonstrated that CD26 is an activation antigen on CD16+ CD56+ NK cells inducible by IL‐2, IL‐12 or IL‐15.

Activation of human natural killer cells by the protein-bound polysaccharide PSK independently of interferon and interleukin 2

The protein-bound polysaccharide PSK was tested for the ability to activate human natural killer (NK) cells. When blood lymphocytes and purified CD3-CD16+ large granular lymphocytes (LGL) were treated in vitro overnight with PSK, they demonstrated enhanced NK cell activity against K562. The PSK-activated killer cells also lysed NK-resistant targets and freshly isolated autologous and allogeneic tumor cells. The PSK effect was observed with concentrations that could be obtained in the blood of cancer patients receiving oral administration of PSK. PSK-induced enhancement of NK activity was not abrogated by monoclonal antibodies (mAb) that neutralized interferon (IFN) alpha, IFN gamma, or interleukin-2 (IL-2). In addition, mAb reactive with p55 (alpha chain) or p75 (beta chain) glycoproteins of IL-2 receptors had no effects on PSK-enhanced NK activity even when used simultaneously. These results indicate that the PSK could activate human NK cells independently of IFN and IL-2/IL-2R systems.

Differential roles of Annexin A1 (ANXA1/lipocortin-1/lipomodulin) and thioredoxin binding protein-2 (TBP-2/VDUP1/TXNIP) in glucocorticoid signaling of HTLV-I-transformed T cells.

Glucocorticoid (GC) is widely used for therapeutic purposes in immunological and hematological disorders. Annexin A1 (ANXA1/lipocortin-1/lipomodulin), a GC-inducible molecule, was regarded as a vital anti-inflammatory mediator of GC. Thioredoxin binding protein-2 (TBP-2/VDUP1/TXNIP), a regulator of redox reactions, cell growth and lipid metabolism, was also reportedly induced by GC. HTLV-I infected T cells undergo the transition from the IL-2 dependent to IL-2 independent growth during the long-term culture in vitro. We found that these T cells responded to GC with growth arrest and apoptosis in the IL-2 dependent growth stage, whereas they failed to respond to GC after their growth had shifted into the IL-2 independent stage. Here we employed these T cell lines and studied the roles of ANXA1 and TBP-2 in mediating GC-induced apoptosis. In GC-sensitive T cells, ANXA1 expression was negligible and unaffected by GC treatment, whereas TBP-2 was expressed and induced by GC treatment. In GC-resistant T cells, however, ANXA1 was highly expressed regardless of GC treatment and promoted cellular proliferation. In contrast, TBP-2 expression was lost and could not mediate the GC-induced apoptosis. In conclusion, these results suggest that TBP-2, but not ANXA1, is directly involved in the switching of GC sensitivity and GC resistance in HTLV-I infected T cell lines, whereas ANXA1 may be a biomarker indicative of the advanced stage of the transformation.

Induction and Function of FcεRII on YT Cells; Possible Role of ADF/Thioredoxin in FcεRII Expression

Abstract The regulation of low-affinity Fc receptor for lgE (FcγRII) and the characteristics of both membrane and soluble forms of FcγRII were studied using YT cell line. We found that YT cells, a human NK like cell line, expressed FcγRII after IL-1 stimulation. Cross-linking of FceRII on IL-1-stimulated YT cells as well as the transfectant of FceRII-cDNA (YTSER) resulted in the up-regulation of IL-2Rα (p55/Tac). A 59 kDa protein phosphorylated at tyrosine residues was co-immunoprecipitated with FceRII from YTSER lysate using H107 anti-FceRII mAb. YTSER not only expressed FceRII on their surface but also secreted soluble form of FceRII (sFceRII/sCD23; IgE binding factor). Affinity purification revealed that sFceRII released from YTSER is heterogeneous and consisted of several proteins differing in molecular weight. Both EBV + B cells and HTLV-1+ T cells are high producers of ATL derived factor (ADF)/ thioredoxin (TRX) and express FceRII and IL-2Rα respectively. To clarify the mechanism of FceRII and IL-2Ra induction by ADF/TRX, we examined the effect of ADF/TRX on the bindability of nuclear factor κB (NF-κB), which is known to regulate IL-2Rα gene expression. In the gel shift assay, ADF/TRX was shown to enhance the bindability of NF-κB to its responsive element.

Detection of metastatic medullary thyroid cancer with 131I-MIBG scans in Sipple's syndrome.

While 131I-meta-iodobenzyl guanidine (131I-MIBG) scanning has made possible the scintigraphic visualization of pheochromocytoma and neuroblastoma, an accumulation of this agent has recently been reported in medullary thyroid cancer. We present the case of a patient with Sipples syndrome (multiple endocrine neoplasia type IIa), in whom we were able to identify distant metastases and local invasion of medullary thyroid cancer as well as primary thyroid tumour and right adrenal pheochromocytoma, using 131I-MIBG scans. This case highlights the usefulness of 131I-MIBG in the detection of metastatic medullary thyroid cancer and suggests that this agent may also be of therapeutic use in the treatment of tumours.

Signal transduction via Fc receptors; involvement of tyrosine kinase and redox regulation by ADF.

Low affinity Fc receptors for IgE (FcɛRII) were initially described on the surface of peripheral blood B lymphocytes1,2 and turned out to be identical to CD23, one of the B cell activation antigens. Cloning of FcɛRII cDNA revealed a unique primary structure compared to other Fc receptors such as FcγRI-III or FcɛRI, consisting of a cytoplasmic N-terminal domain of 23 amino acids, a transmembrane domain of 21 amino acids, extracellular C- terminal domain of 321 amino acids and no signal sequence.1 FcɛRII belongs to the c-type animal lectin superfamily, whereas FcɛRI and FcγRI-III belong to the immunoglobulin superfamily.