Atsuo Nakayama

Necrotizing tubulointerstitial nephritis associated with adenovirus infection

We report 10 autopsy cases of necrotizing tubulointerstitial nephritis induced by adenovirus (ADV). Hemorrhagic, necrotizing tubulitis with intranuclear inclusion bodies was observed in the kidneys of five bone marrow transplant recipients and five patients treated with intensive chemotherapy for malignancies (four cases of leukemia and one case of lung cancer). It was histopathologically demonstrated that necrobiotic tubular cells had inclusion-bearing cells of three types: smudge cells, Cowdry A intranuclear inclusion cells, and full-type intranuclear-containing cells. Immunofluorescent examination with anti-ADV antibody demonstrated specific fluorescence on the affected tubular cells of all 10 kidneys. Specific antigens for ADV type 11 were also revealed in all but one case by an immunofluorescent test using type-specific antiserum and convalescent serum containing high titer antibody to this serotype. Electron microscopy revealed intranuclear crystalline arrays of viral particles, 75 to 80 nm in diameter, in each of the seven cases examined. Extrarenal involvement, indicated by ADV-induced cytopathologic change, was confined to bladder or prostate. Hemorrhagic cystitis was recorded in all the bone marrow transplant cases as well as in one leukemia case. Adenovirus type 11 was isolated from urine in all five cases tested during these episodes. Renal failure was ascribed to ADV infection in two of five patients who died from renal dysfunction. The presence of hemorrhagic cystitis and localization of invasive infection in urogenital organs suggested that renal infection might occur by ascending route from the bladder. We propose that ADV should be added as a viral agent to the pathogenetic list of tubulointerstitial nephritis.

Lymphomatous features of aggressive NK cell leukaemia/lymphoma with massive necrosis, haemophagocytosis and EB virus infection

Aims

Interdigitating cell sarcoma. A morphologic, immunohistologic, and enzyme-histochemical study.

A 58‐year‐old man presented with an unusual sarcoma of the cervical lymph node. The tumor also involved the mesenteric lymph node and jejunum. Tumor cells possessed intracytoplasmic S100 protein, Leu‐3a (T4), and HLA‐DR antigens. The neoplastic cells also showed membranous ATPase activity. LeuM1, T6, Leu1, Leu2a, B1, lysozyme, and immunoglobulin were not recognized. Their fine structure was similar to that of interdigitating cells. These data are consistent with derivation from lymph node interdigitating reticulum cell.

A case of natural killer/T cell lymphoma of the subcutis resembling subcutaneous panniculitis‐like T cell lymphoma

A case of nasal type natural killer (NK)/T cell lymphoma of the subcutis showing clinical and morphological features that resemble subcutaneous panniculitis‐like T cell lymphoma (SPTCL) is presented. A 73‐year‐old man presented with swelling of the left arm and was diagnosed with panniculitis by a dermatologist. It was concluded from a skin biopsy specimen that the patient had non‐Hodgkin’s lymphoma of the large cell, NK/T cell type because the neoplastic cells showed polyclonal CD3 immunoreactivity. Treatment with interferon‐γ was initiated, but the patient died of disseminated intravascular coagulation and multiple organ failure 2 months after the initial symptoms appeared. However, involvement of additional organs by the lymphoma was not apparent clinically. An autopsy was not performed. A routinely stained section of the biopsy skin specimen revealed massive necrosis of the subcutaneous fat, karyorrhexis admixed with reactive histiocytes, and large atypical lymphoid cells. Immunoreactivity for polyclonal CD3 was present in the perinuclear region, but absent in the neoplastic cell membranes. CD56, CD45RO (UCHL‐1), CD43 (MT1), CD45 (leukocyte common antigen), and the cytotoxic molecules perforin, granzyme B and TIA‐1 were positive, but CD20 (L26), CD4, CD8, and βF1 were negative. Epstein‐Barr virus (EBV) mRNA was detected in the nuclei of neoplastic cells by in situ hybridization. Subcutaneous panniculitis‐like T cell lymphoma is reported to be an EBV‐negative, clonal T cell neoplasm. Although this case showed clinical and morphological features that resembled SPTCL, perinuclear polyclonal CD3 staining and membranous CD56 reactivity seen in neoplastic cells were suggestive of NK cells. Furthermore, the neoplastic cells were positive for EBV. This case is considered to be a NK/T cell lymphoma of the subcutis resembling SPTCL. It is believed that it is important to recognize such a tumor because patients may undergo a fulminant clinical course, despite the tumor being localized in the subcutaneous adipose tissue.

Long-term follow-up in patients with Pendred syndrome: vestibular, auditory and other phenotypes

Fourteen patients with a Pendred syndrome gene ( Pds) mutation and three patients without the mutation were studied to evaluate long-term vestibular and auditory manifestations among patients with bilateral enlarged vestibular aqueducts (EVA). Charts were reviewed retrospectively for age, gender, otological history, presence or absence of vertigo, results of magnetic resonance imaging, relevant gene mutations and perchlorate discharge test. A missense mutation, His 723 Arg (H723R), was identified in the homozygous state in six patients and in the heterozygous state in seven patients. Another missense mutation, Tyr 410 Met (T410xa0M), was identified in the heterozygous state in one patient. Patients with vertigo tended to have hearing fluctuation, compared with the patients without vertigo. Patients homozygous for H723R tended to have more episodes of vertigo than the heterozygous individuals. Only one patient who was homozygous for H723R had goiter. The long-term outcome of hearing level in patients with the H723R mutation was significantly better compared with published results for patients with a Pds mutation, but not for those with the H723R mutation. Whether environmental factors or a subtype of the Pds mutation H723R are related to the long-term outcome for these patients must be clarified.

The immunohistochemical analysis of pendrin in the mouse inner ear

Pendreds syndrome (PS) is an autosomal recessive disorder characterized by deafness and goiter, which are caused by mutations in the Pendreds syndrome gene (PDS). PDS encodes a membrane protein named pendrin that is considered to act as an anion transporter. An expression pattern of the PDS ortholog (Pds) mRNA in the auditory and vestibular systems has been reported in mice, and the localization of pendrin has been reported recently. We generated antipeptide antibodies against human pendrin, and performed immunohistochemical analysis of mouse inner ears. We detected pendrin in the endolymphatic duct and sac, and the utricle, saccule, and external sulcus. In the endolymphatic duct and sac, the expression of pendrin was apparent at the apical membrane. In addition, we detected pendrin in the spiral ligament, Claudius cells, Deiters cells, and the spiral ganglion of the cochlea. Our results are key to defining the role of pendrin in inner ear development and elucidating the pathogenic mechanisms underlying deafness in PS.

Underexpression of neural cell adhesion molecule and neurotrophic factors in rat brain following thromboxane A2-induced intrauterine growth retardation

Intrauterine growth retardation (IUGR) often results in clinical neurodevelopmental disorders. To clarify the influence of uteroplacental insufficiency on central nervous system development, we have created a model of IUGR in rats using maternal administration of synthetic thromboxane A(2). We investigated expression patterns of neural cell adhesion molecule (NCAM) and reelin in this model by semiquantitative competitive polymerase chain reactions. On postnatal day 2, NCAM expression was decreased in rat cerebral cortex, and reelin expression was decreased in hippocampus from levels in controls without maternal thromboxane exposure. No significant differences in NCAM expression were seen in hippocampus, nor did reelin expression differ in cerebral cortex between control and IUGR groups. We also examined expression of two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). In cerebral cortex the IUGR group showed less BDNF and NT-3 expression than controls. Delay of neuronal migration and histological changes observed in our IUGR rats may be related to altered expression of these molecules.

Increment of α B-crystallin mRNA in the brain of patient with infantile type Alexander's disease

Abstract To estimate the expression level of α B-crystallin in the brain of infantile type Alexanders disease, the amounts of protein and mRNA of α B-crystallin were measured by enzyme immunoassay (EIA) and Northern blot analysis, respectively, in the brain of patient and controls, and in the tissues from glioblastoma and astrocytoma. The α B-crystallin protein in the brain of patient was remarkably increased as compared with those of controls. The amount of α B-crystallin mRNA of patient was increased about 7-fold compared to the mean value of the control group and higher than that of glioblastoma tissue. These data suggest that increment of α B-crystallin mRNA in astrocytes leads to the overexpression of this protein and may be one of the main causes of infantile type Alexanders disease.

Interdigitating cell sarcoma (ICS): evidence of interdigitating cell origin, immunocytochemical studies with monoclonal anti-ICS antibodies

Three independent mouse monoclonal antibodies (mAbs) ID1 (IgG3), ID2 and ID3 (IgM) were raised against whole cells of a surgically resected human interdigitating cell sarcoma (ICS). In immunoperoxidase staining, these mAbs strongly stained the cytoplasm of ICS neoplastic cells as well as interdigitating cells in normal lymphoid tissues. These mAbs also detected monocyte/ macrophages and dendritic cells, although their staining was highly variable depending on tissue distribution of the cells. Additional immuno-histological and enzyme histochemical study revealed that the neoplastic cells of ICS had cytoplasmic acid phosphatase and membranous alkaline phosphatase activity, and also possessed S100fβ protein, Ki-1 antigen, DAKO-macrophage antigen, and weak vimentin activity. Neither rearrangement of immunoglobulin heavy chain gene nor of T-cell receptor genes was detected in the DNA of ICS by Southern hybridization. These observations provide further confirmation of our previous finding (Nakamura et al. 1988, 1989) that the origin of ICS is interdigitating rather than lymphoid cell, and indicate that our mAbs could be useful as a cellular differentiation marker of interdigitating cells and for diagnosis of ICS.

Immunohistochemical characteristics of chicken spleen ellipsoids using newly established monoclonal antibodies

Ellipsoids, the extra-vasculature sites surrounding penicilliary capillaries of the chicken spleen, play critical roles in the immune response and also in the clearance of pathogens or other particles. The meshwork of ellipsoids is formed by fibroblastic reticular cells. To characterize ellipsoidal reticular cells, a series of monoclonal antibodies against the chicken spleen have been developed. Of these antibodies, CSA-1 antibody reacts with fibroblastic reticular cells in ellipsoids and with endothelial cells. The reticular nature of positive cells in ellipsoids is indicated by immuno-electron microscopy, and by double-staining with anti-heat-shock protein 47 kDa (hsp47) antibody. The reaction of CSA-1 with reticular cells is limited in ellipsoids; CSA-1 does not react with reticular cells in other lymphoid organs. These findings indicate that ellipsoidal reticular cells share the antigen with endothelial cells. Ontogenic studies reveal that, on embryonic day 18, the development of ellipsoids is completed, penicilliary capillaries become fenestrated, and CSA-1 expression in ellipsoids begins. These findings suggest that CSA-1 is expressed on the cell surface of ellipsoidal reticular cells once they are exposed to blood flow.