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Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFa) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFa on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFa of three groups of DRB1∗1502-DQB1∗0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1∗1502-DQB1∗0601 was strongly associated with the TNFa13 allele. DRB1∗1502-DQB1∗0601 was strongly associated with the TNFa12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFa12 and non-TNFa13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFa is associated with a predisposition to progression to insulin dependency in GADab/DRB1∗1502-DQB1∗0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients’ TNFa genotype may allow for better prediction of their clinical course.

Recent evidence suggests that a new member of the mono-ADP-ribosyltransferase/NAD glycohydrolase family, RT6, may be important in immune regulation. RT6 is expressed in two allelic forms and is present on post-thymic T cells in the rat. RT6-expressing T cells in the rat may have a regulatory role, a conclusion based on their ability to prevent autoimmune diabetes in the BB rat model of insulin-dependent diabetes mellitus. This observation led to investigation of RT6 at a molecular and biochemical level resulting in the determination that RT6 protein exists as both glycosylated and non-glycosylated glycosylphosphatidylinositol (GPI)-linked cell surface molecules. RT6, like many GPI-linked proteins, can mediate cell signal transduction events associated with T cell activation, and is also present in a soluble form in the circulation. The discovery that RT6 is an NAD glycohydrolase and auto-ADP-ribosyltransferase led to the ongoing investigations into the role that enzymatic activity may have in the immunoregulatory function of rat RT6+ T cells. A homologue of rat RT6, termed Rt6, has been identified in the mouse. Rt6 is predominately an ADP-ribosyltransferase enzyme as determined using simple guanidino compounds (e.g. arginine) as ribose acceptors. Abnormalities in mouse Rt6 mRNA are associated with the expression of autoimmunity. In the present manuscript, we review recent data on RT6/Rt6, and discuss the potential mechanisms by which RT6-expressing cells, and perhaps RT6 protein itself, may mediate immune regulation.

Rat RT6 proteins, and perhaps mouse Rt6, identify a set of immunoregulatory T lymphocytes. Rat RT6.1 (RT6.1) and rat RT6.2 (RT6. 2) are NAD glycohydrolases, which catalyze auto-ADP-ribosylation, but not ADP-ribosylation of exogenous proteins. Mouse Rt6.1 (mRt6.1) also catalyzes auto-ADP-ribosylation. The activity of mouse cytotoxic T lymphocytes is reportedly inhibited by ADP-ribosylation of surface proteins, raising the possibility that mRt6 may participate in this process. The reactions catalyzed by mRt6, would, however, need to be more diverse than those of the rat homologues and include the ADP-ribosylation of acceptors other than itself. To test this hypothesis, mRt6.1 and rat RT6.2 were synthesized in Sf9 insect cells and rat mammary adenocarcinoma (NMU) cells. mRt6.1, but not rat RT6.2, catalyzed the ADP-ribosylation of guanidino-containing compounds (e.g. agmatine). Unlike RT6.2, mRt6.1 was a weak NAD glycohydrolase. In the presence of agmatine, however, the ratio of [adenine-14C]ADP-ribosylagmatine formation from [adenine-14C]NAD to [carbonyl-14C]nicotinamide formation from [carbonyl-14C]NAD was approximately 1.0, demonstrating that mRt6.1 is primarily a transferase. ADP-ribosylarginine hydrolase, which preferentially hydrolyzes the alpha-anomer of ADP-ribosylarginine, released [U-14C]arginine from ADP-ribosyl[U-14C]arginine synthesized by mRT6.1, consistent with the conclusion that mRt6.1 catalyzes a stereospecific Sn2-like reaction. Thus, mRt6.1 is an NAD:arginine ADP-ribosyltransferase capable of catalyzing a multiple turnover, stereospecific Sn2-like reaction.

We present the unusual case of a 49-year-old female carrier of HTLV-I with myasthenia gravis who presented with acute transverse myelitis. Laboratory data suggested a recent infection with varicella zoster virus and demyelination by an autoimmune process in the central nervous system. Adult T-cell leukemia-like cells were observed in the cerebrospinal fluid. T-cell-mediated immune responses modulated by HTLV-I infection may be involved in the pathogenesis of myasthenia gravis and acute transverse myelitis in this case.

The RT6 alloantigenic system of the rat was discovered in the 1970s. It was originally designated Pta, AgF, A.R.T.-2, and RTLy-2 by the laboratories involved in its characterization. Exchange of reagents demonstrated that these laboratories had identified the same system, and the official designation RT6 was assigned in 1982 (1).

We report that rat RT6.2 and recombinant mouse Rt6 locus 1 proteins possess autoADP-ribosyltransferase activity and that Rt6, but not RT6, catalyzes the ADP-ribosylation of exogenous histones. Based on NH2OH sensitivity, it appeared that the ADP-ribose was attached to arginine residues on proteins. We also observed that the NAD+ concentration in culture medium correlates inversely with the proliferation of rat RT6+ T cells. The data suggest that lymphocyte surface ADP-ribosyltransferases could be involved in signaling and immunoregulatory processes.

We investigated the expression of fos oncogene proteins in lymphoproliferative disorders, using a monoclonal antibody (FO-120) that was prepared against a synthetic oligopeptide of fos protein (amino acid sequence from 127 to 152). Although peripheral blood leukocytes were rarely positive for FO-120, they were transiently stained after lectin (PHA) stimulation. After culture with IL-2 for 1 or 2 weeks, less than 40% of the lymphocytes weakly reacted with FO-120, whereas strongly positive cells were detected in more than 70% of cells in half the T-cell lines established from preleukemic state of adult T-cell leukemia (pre-ATL) and all of ATL derived T-cell lines. All in vivo specimens of non-Hodgkin's malignant lymphomas, except for one case of T-cell lymphoma were also strongly positive. In addition, the extent of the antibody reactivity correlated with the histopathological grade of malignancy in B-cell lymphoma. The reactivity to most AILD-IBL lesions overlapped with that to T-lymphomas, and could be distinguished from that to reactive lesions. FO-120 appears to be a useful tool for detecting early neoplastic changes in lymphoproliferative disorders.

Two kinds of monoclonal antibodies recognizing fos proto-oncogene (c-fos) products were prepared using a synthetic oligopeptide corresponding to amino acids 127-152 of the fos oncogene products. These monoclonal antibodies (FO-120 & FO-145) detected fos gene products induced in a human monocyte cell line (U-937) by phorbol acetate (TPA) and induced in both human and mouse fibroblast cell lines (284, BALB/c 3T3) by serum-stimulation. One of the monoclonal antibodies (FO-120) reacted with 50-kDa and 42-kDa proteins and the other antibody (FO-145) reacted with a 30-33-kDa protein. The expression of the fos gene in various human hematopoietic cell lines was investigated using these prepared monoclonal antibodies. While almost all hematopoietic cell lines tested reacted with these monoclonal antibodies to various degrees, the majority of normal peripheral blood lymphocytes cultured with lectin (PHA) and interleukin 2 (IL-2) did not, suggesting that cells of some permanent hematopoietic cell lines, irrespective of their lineage specificity and growth factor dependency, continuously express the fos oncogene. These monoclonal antibodies may be useful for detecting early neoplastic changes in hematopoietic cells.

血管腫を伴ったリンパ管腫,いわゆるhemolymphangiomaは,ほとんど報告をみない.最近,我々は後腹膜原発のhemolymphangiomaを経験し,超音波, CT,血管造影などに加え,磁気共鳴映像法(MRI)を施行し,術前診断を試みた。嚢腫内容は, CTではenhanceされなかったが, MRI計算値においてT1時間の著明な短縮を示したことから陳旧性血液成分と診断でき,内容の性状診断にMRIは有用であった.また,術後の免疫組織学的検索では,血管腫の内皮だけでなく,リンパ管腫の内皮にも,第VIII因子関連抗原が陽性であった.既報告の後腹膜リンパ管腫99例とhemolymphangiomaの病態を比較し,リンパ管腫の発生に関し,若干の考察を加えて報告する.