The gamma chain of the interleukin-2 (IL-2) receptor is an indispensable subunit for IL-2 binding and intracellular signal transduction. A monoclonal antibody to the gamma chain, TUGm2, inhibited IL-2 binding to the functional IL-2 receptors and also inhibited IL-4-induced cell growth and the high-affinity binding of IL-4 to the CTLL-2 mouse T cell line. Another monoclonal antibody, TUGm3, which reacted with the gamma chain cross-linked with IL-2, also immunoprecipitated the gamma chain when cross-linked with IL-4. These results suggest that the IL-2 receptor gamma chain is functionally involved in the IL-4 receptor complex.

https://science.sciencemag.org/content/sci/262/5141/1874.full.pdf

Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4.

Human T-cell leukemia virus type I (HTLV-I) is an etiological agent of adult T-cell leukemia A viral gene pX encodes for p40X and it has been proposed that this protein trans-activates the viral long terminal repeat and possibly some cellular genes; this activation may be associated with T-cell transformation The mechanism of pX gene expression and the primary structure of p40X are now reported Two-step splicing generates the 21-kilobase pX mRNA; the initiator methionine for env becomes part of the pX protein These splicing signals are conserved among all members of the HTLV family except for the acquired immune deficiency syndrome-associated viruses

Expression of the pX gene of HTLV-I: general splicing mechanism in the HTLV family.

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The Bethesda System for Reporting Cervical Cytology

In this study, we examined the methylation status of the CDKN2A gene in patients with different forms of adult T-cell leukemia (ATL) using Southern blot analysis, methylation-specific PCR (MSPCR), and nucleotide sequencing We found that the CDKN2A gene was more frequently methylated in fresh tumor cells isolated from patients with acute ATL (47%) or lymphoma-type ATL (73%) than in those with less malignant chronic (17%) and smoldering (17%) ATL In addition, deletions of the CDKN2A gene were found in 24% of acute ATL patients; thus, abnormalities of the CDKN2A gene totaled 71% in acute ATL patients In contrast, no CDKN2A gene methylation was found in asymptomatic carriers or uninfected individuals Methylation of the p15 gene was not found in any samples from 36 ATL patients Direct sequencing of the CDKN2A gene after sodium bisulfite treatment of genomic DNA revealed that the methylation of CpG sites had occurred in 24 of 32 ATL cases (75%) including chronic and smoldering ATL, even when MSPCR and the Southern blot had failed to detect CDKN2A gene methylation Among fresh ATL samples with methylation, methylation was detected in the promoter region and exon in 17 of 24 cases, and methylation in the exon without promoter region was detected in 7 of 24 cases In one case, the pattern of methylation proved to be different between peripheral blood cells and lymph node cells, suggesting the presence of multiple subclones with regard to methylation patterns, despite the same HTLV-I integration site Quantitative PCR showed a marked decrease in CDKN2A mRNA expression in the cells with a methylated CDKN2A gene, especially if the promoter region was methylated These findings suggest that CpG methylation decreases CDKN2A expression and represents a critical factor in the disease progression of ATL

https://cancerres.aacrjournals.org/content/canres/60/4/1043.full.pdf

Increasing Methylation of the CDKN2A Gene Is Associated with the Progression of Adult T-Cell Leukemia

To discern the T cell subtype associated with T cell differentiation, the expression of CD45RA and CD27 was measured from total CD8(high) cells and from human T cell lymphotropic virus type I (HTLV-I) Tax11-19 peptide-specific CD8(+) cells in peripheral blood lymphocytes of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Phenotypically defined memory and/or effector cells (CD45RA(-)CD27(+), CD45RA(+)CD27(-), and CD45RA(-)CD27(-)) were increased in HAM/TSP CD8(+) cells, compared with those of HTLV-I-seronegative healthy control subjects. The percentage of human leukocyte antigen (HLA)-DR-positive cells was also increased in CD8(+) cells of HAM/TSP, compared with those in HLA-DR(+)CD8(+) cells of healthy control subjects. HTLV-I provirus load correlated with the frequency of Tax11-19-specific CD8(+) cells. The high frequency of memory and/or effector type HTLV-I Tax11-19-specific CD8(+) cells suggests that continuous restimulation driven by HTLV-I antigens in vivo may be associated with the pathogenesis of HAM/TSP.

Increased activated human T cell lymphotropic virus type I (HTLV-I) Tax11-19-specific memory and effector CD8+ cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with HTLV-I provirus load.

Cocultivation of spleen cells, lymph node cells, and thymocytes of female Wistar-King-Aptekman rats with short-term cultured male adult T cell leukemia (ATL) cells in the presence of 5-bromo-2'-deoxyuridine (BrdUrd) resulted in the establishment of rat lymphoid cell lines, TARS-1, TARL-2, and TART-1. Cytogenetic analysis of the three cell lines showed a female rat karyotype with 42 chromosomes. The surface phenotypes of TARS-1 and TART-1 were those of rat T cells. TARL-2 was only positive for rat Ia and leukocyte common antigens. The cell lines continuously produced a type C retrovirus, human T cell leukemia virus (HTLV) and expressed ATL-associated antigens. TARS-1 and TART-1, but not TARL-2 were transplantable into newborn syngeneic rats and nude mice. These results strongly indicate that HTLV not only immortalizes, but also transforms rat T cells in vitro. Adult rats immunized with either TARS-1 or TARL-2 produced antibodies specific for HTLV. The biochemical analysis of the antigens that reacted with rat sera revealed that they are the two HTLV-specific polypeptides, p24 and p28.

https://rupress.org/jem/article-pdf/159/4/1105/1094230/1105.pdf

Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization.

We describe here a rapid, high-throughput genotyping procedure that allows the simultaneous detection of 16 high- and low-risk genital human papillomavirus (HPV) types by multiplex PCR in a single reaction tube. Multiplex PCR is based on the amplification of HPV DNA by sets of HPV genotype-specific primers, and the genotypes of HPV are visually identified by the sizes of amplicons after they are separated by capillary electrophoresis. The procedure does not include a hybridization step with HPV-specific probes and is rapid and labor-saving. We detected all 16 HPV genotypes (types 16, 58, 52, 51, 56, 31, 18, 39, 66, 59, 6, 33, 30, 35, 45, and 11) with a high sensitivity and a high degree of reproducibility. By using this newly developed method, we conducted a pilot study to examine the correlation between the prevalence and genotype distributions of HPV and the cytological group classifications for 547 cervical samples. Compared with the group of samples considered normal (14.7%), there was a significant increase in the prevalence of HPV in women with atypical squamous cells of unknown significance (61.3%), low-grade intraepithelial lesions (75.8%), and high-grade intraepithelial lesions (HSILs) (82.2%). The prevalence and distribution of type 58 were correlated with cytological malignancies, with the highest prevalence in women with HSILs. In conclusion, the novel multiplex PCR method described appears to be highly suitable not only for the screening of cervical cancer precursor lesions but also for the characterization of genotype distributions in large-scale epidemiological studies and HPV vaccination trials.

Genotyping of Human Papillomaviruses by a Novel One-Step Typing Method with Multiplex PCR and Clinical Applications

With the aim of standardizing Ki-67 immunohistochemistry, we assessed interobserver and interlaboratory variability of the Ki-67 labeling index and Ki-67 score among eight general pathologists for 24 gastrointestinal stromal tumors (GISTs) and 12 leiomyosarcomas, which were predominantly of the gastrointestinal (GI) tract, mesentery and retroperitoneum, based on a review of a tissue microarrays subjected to immunohistochemistry with antibodies for Ki-67. For Ki-67 immunostaining of mesenchymal tumors of the GI tract, including GISTs, differences were seen in the scores given by regional hospitals. Conversely, for two categories of the Ki-67 labeling index, namely <10% and ≥10%, concordance of the Ki-67 score between microscopic observation and image analysis, and between the observers, was good, but it was not good for the other four categories of the index for <5%, 5-9%, 10-29%, and ≥30%. The concordance of the Ki-67 scores between the observers in two categories was higher using the Ki-67 pre-stained tissue microarrays (TMAs) within each participating institute than that using the Ki-67 stained TMAs between the participating institutes. The reproducibility of a 10% cut-off value for the Ki-67 labeling index to predict the prognosis of GISTs was relatively high, but there is an urgent need to standardize the staining technique.

Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas

Molecular analysis of a HTLV-I pX defective human adult T-cell leukemia

A rare autopsy case of Goodpasture's syndrome with systemic necrotizing angiitis is reported. The patient, a 56-year-old male, died of respiratory failure with massive pulmonary hemorrhage and renal failure. The autopsy showed widespread hemorrhage in both lungs, diffuse crescentic glomerulonephritis, and systemic necrotizing angiitis in the small arteries. Immunofluorescence studies demonstrated a linear deposition of IgG along the glomerular basement membrane (GBM) as well as the alveolar basement membrane. A granular deposition of C3 was also found along the GBM. Electron microscopy showed that the GBM was irregularly thickened and wrinkled, but electron-dense deposits were indistinct. Anti-GBM antibody activity was detected in the patient's serum and had cross reactivity with normal alveolar basement membrane. The renal eluates contained IgG antibody activity for normal human GBM. These results suggest that glomerulonephritis and pulmonary hemorrhage in the present case were mediated by anti-basement membrane antibodies. We also discussed whether anti-basement membrane antibody is involved in the pathogenesis of systemic necrotizing angiitis.

Nobuo Kondo

Papers

Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization.

Genotyping of Human Papillomaviruses by a Novel One-Step Typing Method with Multiplex PCR and Clinical Applications

Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas

Molecular analysis of a HTLV-I pX defective human adult T-cell leukemia

Immunopathological studies of an autopsy case with Goodpasture's syndrome and systemic necrotizing angiitis.