bluuebunny/crossref_metadata_2025 huggingface dataset:
T‐cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein–Barr viral infection
Authors: AU W.Y. , SHEK W.H. , NICHOLLS J. , TSE K.M. , TODD D. , KWONG Y.L.
Published: November 2003

Aims:

Intravascular lymphomatosis (IVL) is a very rare non‐Hodgkin's lymphoma characterized by proliferation of lymphoma cells in the vascular lumina without involvement of adjacent parenchymal tissue. IVL is predominantly of B‐cell lineage, but occasional cases of T lineage IVL involving almost exclusively the skin have been described. A case of IVL that occurred initially in the epididymis of a patient with an antecedent nasopharyngeal carcinoma was studied to define the clinicopathological features associated with this unique presentation.

Methods and results:

This lymphoma was studied by standard histological and immunophenotyping methods. The results showed lymphoma cells confined within the blood vessels, which expressed leucocyte common antigen, and T‐cell markers CD3 and UCHL‐1. The T‐cell origin of the IVL prompted investigations for an assciation with Epstein–Barr virus infection (EBV). In‐situ hybridization with digoxigenin‐labelled anti‐sense RNA probes to EBV encoded RNA (EBER) showed strong signals in the nuclei of virtually all of the lymphoma cells.

Conclusions:

EBV infection of the malignant cells was demonstrated by in‐situ hybridization. This case suggests that T‐cell IVL may be another EBV related human neoplasm. This observation will need to be validated by further studies.
Mammary epidermoid inclusion cysts after wide‐core needle biopsies
Authors: DAVIES J.D. , NONNI A. , D'COSTA H.F.
Published: November 2003

Aims:

To investigate the prevalence of squamous epidermoid inclusion cysts after wide‐core needle biopsy.

Methods and results:

Epidermoid inclusion cysts were found in five of 17 surgical excisions (29%) after preliminary wide‐core needle biopsies in a 7‐month period. Thereafter they were not seen in 26 subsequent postwide‐core surgical excisions in a period of 6 months.

Conclusions:

The cysts appear to be an iatrogenic complication of wide‐core biopsy, and need morphological recognition in order to avoid confusion with spontaneous squamous metaplasia of benign or malignant breast epithelium. Longer term implications are unknown.
Intravascular lymphomatosis: a case presenting with encephalomyelitis and reactive haemophagocytic syndrome diagnosed by renal biopsy
Authors: CHENG F.Y. , TSUI W.M.S. , YEUNG W.T.C. , IP L.S. , NG C.S.
Published: November 2003

Aims:

To report an unusual instance of intravascular lymphomatosis presented with encephalomyelitis and reactive haemophagocytic syndrome. There was no skin involvement. The diagnosis was made on a renal biopsy. Methods and results: The marrow smear was air dried and stained with Diff‐Quik. The tissue sections were stained with haematoxylin and eosin, Masson trichrome, periodic acid–Schiff's reagent, Elastic van Gieson's stain, modified hexamine‐silver technique and Martius scarlet blue. Immunohistochemistry for CD45, CD20, CD45RO, Factor VIII related antigen, CD31 and CD34 was performed on paraffin‐processed tissue. The marrow smear showed active haemophagocytosis in the histiocytes. The renal biopsy showed intravascular lymphomatosis with tumour cells positive for CD45 and CD20. Conclusion: The possibility of intravascular lymphomatosis should be considered in patients with reactive haemophagocytic syndrome where the underlying cause cannot be found after thorough investigation.
Intravascular lymphomatosis: a clinicopathological study of two cases presenting as an interstitial lung disease
Authors: KO Y.H. , HAN J.H. , GO J.H. , KIM D.S. , KWON O.J. , YANG W.I. , SHIN D.H. , REE H.J.
Published: November 2003

Aims:

Intravascular lymphomatosis is an uncommon type of non‐Hodgkin's lymphoma characterized by intravascular proliferation of neoplastic lymphoid cells. Although the tumour is basically a systemic disease, eventually involving multiple organs, primary presentation in the lung is rare.

Methods and results:

We describe the clinicopathological features of two patients with intravascular lymphomatosis presenting in the lung. One patient complained of fever, headache and chest pain; the other, of dyspnoea on exertion and headache. Both patients showed reticulonodular density on chest radiography and decreased diffusion capacity. Lung biopsy showed features characteristic of intravascular lymphomatosis. Malignant lymphoid cells were CD30 positive T‐cells of anaplastic large cell type in one patient and B‐cells of large cell type in the other. There was a poor response to chemotherapy and both patients died of the disease within 3 months of diagnosis.

Conclusions:

These cases and 10 previous reports illustrate the need to include intravascular lymphomatosis in the differential diagnosis of interstitial lung disease.
Nuclear pleomorphism in typical carcinoid tumours of the lung: problems in frozen section interpretation
Authors: SHEPPARD M.N.
Published: November 2003

Pulmonary typical carcinoid tumours are generally easy to diagnose with their uniform cells, carcinoid growth pattern and lack of mitoses. However, nuclear pleomorphism, which is common in other neuroendocrine tumours, is not emphasized in pulmonary carcinoid tumours. Three cases of typical carcinoid tumours, because of marked nuclear pleomorphism on frozen section, were misdiagnosed as non‐small cell carcinomas.
Static and dynamic bone changes in hospitalized patients suffering from rickets — a histomorphometric study
Authors: RAUBENHEIMER E.J. , VAN HEERDEN W.F.P. , POTGIETER D. , GOLELE R.
Published: November 2003

Aims: The aim of this study was to assess static and dynamic bone changes in patients suffering from rickets. Methods and results: Transcortical iliac crest biopsies of 15 hospitalized children with rickets were taken after labelling new bone formation with two cycles of tetracycline administration 10 days apart. Undecalcified sections were prepared, appropriately stained and histomorphometric analysis performed. Static and dynamic bone changes were measured including the volume of bone and osteoid, trabecular and cortical bone dimensions and resorptive and mineralization activities. The results were compared with normal values. The nature of the mineralization fronts was noted. Trabecular osteoid volumes of all but one patient was above the normal range of 1.9% (± 0.4%). This patient suffered rickets associated with the Kwashiorkor–Marasmus syndrome. Tetracycline labelling was found to be more sensitive than subjective evaluation of the nature of the mineralization fronts. Despite a balanced hospital diet, a bone formation rate of zero was found in three cases, indicating a need for vitamin D and mineral supplementation. Seven cases had decreased mineralization lag times, indicating response to the balanced diet. Conclusions: This study showed that histometric analysis of labelled bone biopsies is a helpful adjunct to the diagnosis but particularly assessment of response to management of deficiency states in children.
Histopathological changes in bone marrow biopsies from patients with chronic myeloid leukaemia after treatment with recombinant alpha‐interferon
Authors: FACCHETTI F. , TIRONI A. , MAROCOLO D. , CAPUCCI A. , RUGGERI G. , BELLOTTI D. , ROSSI G.
Published: November 2003

Aims: Recombinant alpha‐interferon (r‐IFN) is an effective therapy for chronic myeloid leukaemia (CML), inducing haematological and major cytogenetic response in 70% and 30% of patients, respectively. In this study we have evaluated the significance of bone marrow (BM) histology on the subsequent response to r‐IFN therapy, as well as the morphological changes induced by r‐IFN within BM. Methods and results: 73 BM biopsies were studied from 21 patients with Ph1‐positive CML in chronic phase at diagnosis and at different times during r‐IFN treatment. At diagnosis the probability of achieving a major or complete cytogenetic response was significantly higher in patients with a total marrow cellularity lower than 90% (P = 0.02). During therapy with r‐IFN, significant BM changes included disappearance of the CML pattern (P = 0.0002), reduction of M:E ratio (P = 0.0009) and total cellularity (P = 0.0027), and increase in number of terminal megakaryocytes (P = 0.0009) and of fatty tissue regeneration (P = 0.037); only after long‐term therapy (mean 20 months), did reticulin fibrosis increase significantly (P = 0.032). Conclusions: The overall BM morphology in response to treatment displayed different pictures, ranging from persistence of CML (25 biopsies out of 51), to reversion to normal histology (14 out of 51). Persistence of diffuse morphological abnormalities was associated with lack of cytogenetic responsiveness (P = 0.025).
Gastrointestinal hepatoid adenocarcinoma: venous permeation and mimicry of hepatocellular carcinoma, a report of four cases
Authors: ISHIKURA H. , KISHIMOTO T. , ANDACHI H. , KAKUTA Y. , YOSHIKI T.
Published: November 2003

Aims: Four cases of hepatoid adenocarcinoma, three in the stomach, and one in the sigmoid colon, are presented to emphasize venous permeation and mimicry of hepatocellular carcinoma by metastatic liver nodules. Methods and results: Tumour cells in all cases extensively invaded veins, and intravenous tumour thrombi in two cases were grossly observed as anastomosing, worm‐like cords up to 10 mm in diameter in the lesser omentum and mesentery in continuity with the primary mucosal lesions. The cytological features and trabecular architecture of the metastatic liver nodules in these subjects mimicked primary hepatocellular carcinoma. In a third case the tumour contained grossly visible bile in a metastatic lung nodule, but there was no evidence of bile production in the primary gastric or metastatic liver lesions. In the fourth case, detailed histopathological study revealed a gastric origin of the hepatoid adenocarcinoma, rather than primary hepatocellular carcinoma metastatic to the stomach, the initial diagnosis. Conclusions: These cases are reported here to draw attention to this rare variant of gastrointestinal adenocarcinoma, its mimicry of hepatocellular carcinoma when metastatic to the liver and other sites, and its propensity for venous permeation.
Intra‐vascular tumour in pleomorphic adenomas—a report of four cases
Authors: ALTINI M. , COLEMAN H. , KIENLE F.
Published: November 2003

Aims: The aim of this study was to report four cases of pleomorphic adenoma which were characterized by intra‐vascular tumour. Methods and results: The patients ranged in age from 13–43 years, one was male while three were female. The tumours were situated in the parotid gland, submandibular gland and palate (two cases). The intra‐vascular tumour consisted of single, clustered and solid cords of cells within multiple muscular walled blood vessels and capillaries both in the capsule and in the tumour. Immunoperoxidase staining confirmed that the intra‐vascular cells were phenotypically identical to those of the tumour. The possibility that the intra‐vascular tumour represents artefactual ‘spillage’ has been considered, however there is some histological evidence suggesting that this phenomenon represents true vascular invasion. Conclusions: The biological significance of intra‐vascular tumour in pleomorphic adenomas is unknown. Thus far there has been no correlation with either recurrence or metastases.
Human immunodeficiency virus type 1 in an unusual cystic lymphoepithelial lesion of the lung
Authors: MARIE B. , LABOUYRIE E. , SCHEID P. , SIAT J. , MÉNARD O. , COSMIDIS I. , PLÉNAT F. , VIGNAUD J.M.
Published: November 2003

Aims: We present the clinical and histopathological findings of an unusual pulmonary cystic lymphoepithelial lesion in an HIV sero‐positive patient. Methods and results: The 32‐year‐old female patient developed two nodules in the vicinity of the right and left hila. Left upper lobectomy showed a 40‐mm wide cystic lesion. The cyst wall was lined by a squamous epithelium and lymphoid tissue with a marked follicular hyperplasia and a prominent follicular cell dendritic network expressing HIV major core protein p24. Conclusions: The absence of an Epstein–Barr virus infected lymphoid population and monoclonal immunoglobulin gene rearrangement supported the benign nature of the lesion.
Ductal carcinoma in situ of the breast: the clinical significance of histological classification
Authors: QUINN C.M. , OSTROWSKI J.L. , PARKIN G.J.S. , HORGAN K. , BENSON E.A.
Published: November 2003

One hundred and twenty‐one cases of ductal carcinoma in situ, including 26 cases with T1a invasive carcinoma, were reviewed. Seventy‐nine patients (65%) were treated by mastectomy and 42 (35%) had conservative surgery. Ductal carcinoma in situ was classified as well differentiated (11%), intermediately differentiated (22%) or poorly differentiated (67%) according to nuclear morphology and the presence or absence of cell polarization. Poorly differentiated lesions were significantly larger than intermediately and well differentiated lesions (P=0.03 and P=0.01, respectively) and were significantly associated with the presence of extensive necrosis, marked periductal inflammation and periductal fibrosis (P<0.0001). Invasive carcinoma was more common in the poorly differentiated group (25% compared with 18% in the intermediate group and 8% in the well differentiated group) but this was not statistically significant. The spectrum of differentiation was similar in symptomatic and mammographically detected ductal carcinoma in situ. Clinical follow‐up was available in 90 patients (median period 45 months in patients who had undergone mastectomy and 23 months in those who had conservative surgery). Two incidences of recurrent local disease were recorded in the mastectomy group: one patient had well differentiated and the other poorly differentiated ductal carcinoma in situ. No local recurrences were observed in the conservative surgery group, possibly reflecting the shorter follow up period. All histological grades of ductal carcinoma in situ have the potential to progress to invasive carcinoma and mastectomy does not guarantee a cure.
Liver cell atypias: a comparative study in cirrhosis with and without hepatocellular carcinoma
Authors: OJANGUREN I. , CASTELLÀ E. , ARIZA A. , SANTOS J. , PLANAS R. , BRUGUERA M.
Published: November 2003

Various criteria have been proposed for the identification of early neoplastic changes in the setting of both small hepatocellular carcinomas and macroregenerative nodules. In this study we have applied those criteria to cases of liver cirrhosis without tumour (group I) and hepatocellular‐carcinoma‐associated cirrhosis (group II) to assess their discriminatory value in these two situations. Group I included 50 liver biopsies with uncomplicated cirrhosis while group II encompassed 48 liver biopsies of cirrhotic nodules adjacent to hepatocellular carcinomas. The histological changes sought were large cell dysplasia, small cell dysplasia, cytoplasmic basophilia, small microacinar structures, peripheral distribution of nuclei, nuclear irregularities and thickened liver cell plates. These changes were also assessed in macroregenerative nodules (nine in group I and seven in group II). None of these changes was useful to discriminate between group I and group II cirrhotic nodules when assessed separately. On the other hand, cirrhotic nodules showing three or fewer changes were never associated with malignancy, whereas those exhibiting four or more alterations were often located in the vicinity of a tumour. Acinar structures, thickened cell trabeculae, peripheral distribution of nuclei and nuclear irregularities seem to be the most specific indicators of proximity to a hepatocellular carcinoma. Similar results were obtained for macroregenerative nodules. These results may be helpful as guidelines to the probability of having a hepatocellular carcinoma elsewhere in livers containing atypical cirrhotic nodules, and may also prove valuable in the selection of appropriate material for investigating early molecular events in hepatic carcinogenesis.
Absence of EBV genome in lymphoepithelioma‐like carcinomas of the larynx
Authors: TARDÍO J.C. , CRISTÓBAL E. , BURGOS F. , MENÁRGUEZ J.
Published: November 2003

Undifferentiated nasopharyngeal carcinomas are universally associated with Epstein‐Barr virus (EBV). This association has been exclusively established in lymphoepithelioma‐like carcinomas in some locations. The relationship between EBV and lymphoepithelioma‐like carcinomas in the larynx is unknown. In none of the few laryngeal lymphoepithelioma‐like carcinomas reported have EBV investigations been carried out. We present here two supraglottic laryngeal lymphoepithelioma‐like carcinomas in which EBV antigens were not demonstrable using immunohistochemical and molecular methods. Our results suggest that EBV may not be involved in laryngeal lymphoepithelioma‐like carcinoma at least in Western patients.
Odontogenic classification of craniopharyngiomas: a clinicopathological study of 54 cases
Authors: PAULUS W. , STO¨CKEL C. , KRAUSS J. , SO¨RENSEN N. , ROGGENDORF W.
Published: November 2003

Based on the striking histological similarity of craniopharyngiomas and some odontogenic tumours, we reclassified a series of 54 craniopharyngiomas (52 adamantinomatous and two papillary variants) according to the WHO classification of odontogenic tumours. Twenty‐seven tumours (50%) corresponded histologically to calcifying odontogenic cyst, 13 tumours (24%) to ameloblastoma, and eight (15%) tumours showed features of both calcifying odontogenic cyst and ameloblastoma either within the same specimen or in specimens derived from different resections. Rare tumours included three cases resembling calcifying epithelial odontogenic tumour and one case resembling adenomatoid odontogenic tumour. No odontogenic counterpart could be established for papillary craniopharyngiomas. The two major subtypes, i.e. craniopharyngioma corresponding to calcifying odontogenic cyst and craniopharyngioma corresponding to ameloblastoma, did not differ in their basic clinical features. Our data confirm and extend the close histological resemblance between adamantinomatous craniopharyngioma and odontogenic tumours and cysts. Furthermore, although calcifying odontogenic cyst and ameloblastoma arising in the jaw differ in clinical presentation and outcome, our study did not reveal clinical differences for the corresponding subtypes of craniopharyngioma.
Malignant melanoma in stasis dermatitis
Authors: BLESSING K.
Published: November 2003

Two cases of malignant melanoma arising in established stasis dermatitis are described. One case was clinically thought to be melanocytic whereas the other was not. Histologically, both showed similar features with background varicose change of epidermal atrophy, sloughing of the epidermis, intense proliferation of small thick walled blood vessels, lymphocytic infiltrate and dermal fibrosis. In the superficial aspects of the biopsies there was little clue to the diagnosis of melanoma. In the deeper aspects of case 1, groups of melanocytes were present in the reticular dermis which mimicked benign naevus cells. S‐100 protein staining confirmed the melanocytic nature of these lesions, their extent and the epidermal involvement. The latter features supported a malignant diagnosis. These lesions can be overlooked clinically as well as histologically.
Comparison of chromosome 1 aneusomy detected by interphase cytogenetics and DNA ploidy in carcinoma of the breast
Authors: HARRISON M.M. , MAGEE H.M. , O'LOUGHLIN J.F. , GOREY T.F. , COYNE J.D. , DERVAN P.A.
Published: November 2003

Aneuploidy is an important prognostic factor in many cancers. Chromosome 1 abnormalities are present in most breast carcinomas. These may be part of a non‐specific increase in DNA (aneuploid status) or represent a restricted chromosomal abnormality. In 16 breast carcinomas we compared chromosome 1 aneusomy with ploidy status. Patients were selected from a mammographically screened population and interphase tumour nuclei were studied by in situ hybridization using a chromosome 1 pericentromeric probe. Ploidy status was assessed by image cytometry on disaggregated cells from paraffin blocks. Of eight cases showing chromosome 1 aneusomy, six (75%) were aneuploid and two diploid. Six (75%) of the eight eusomic cases were aneuploid. This study demonstrates that chromosome 1 aneusomy does not always reflect a gross aneuploid status but, in some tumours, is part of a more restricted chromosomal abnormality. Interphase cytogenetics, possibly using a small panel of pericentromeric probes, may be more sensitive than DNA cytometry for detecting abnormal nuclear DNA content.
REVIEW The renal pathology of mushroom poisoning
Authors: O'DONNELL M. , FLEMING S.
Published: November 2003

We present the histology and electronmicroscopy of renal failure caused by ingestion of the mushroom species Cortinarius speciosissimus. Light microscopy revealed acute tubular necrosis, multinucleated tubular epithelial cells  and concentric  medial muscular hyperplasia of arteries. Electronmicroscopy showed the displaced and abnormal architecture of actin filaments at the periphery of the cytoplasm in renal tubular epithelial cells.
Metastatic cancer involving pancreatic duct epithelium and its mimicry of primary pancreatic cancer
Authors: MATSUKUMA S. , SUDA K. , ABE H. , OGATA S. , WADA R.
Published: November 2003

We investigated 47 autopsy cases of metastatic cancer involving the pancreas. Metastatic disease in nine cases involved the pancreatic duct epithelium. In two cases, metastatic cancer cells showed Pagetoid features. In three cases, pancreatic metastatic disease showed solitary proliferation with focal in situ carcinoma‐like lesions mimicking primary pancreatic cancers. Each of these three cases had primary lung adenocarcinomas. Serial sections revealed abrupt borders between the in situ carcinoma‐like lesions and the non‐cancerous epithelium. Primary pancreatic cancers did not show Pagetoid features or abrupt borders between the cancerous and non‐cancerous epithelium. We conclude that the possible diagnosis of pancreatic metastasis should be carefully ruled out in the histological detection of latent primary pancreatic cancer.
Epstein–Barr virus‐associated primary gastrointestinal lymphoma in non‐immunocompromised patients in Korea
Authors: LEE S.S. , JANG J.J. , CHO K.J. , KHANG S.K. , KIM C.W.
Published: November 2003

We examined 81 cases of primary gastrointestinal lymphomas in Korea, including 64 gastric lymphomas and 17 intestinal lymphomas, for EBV expression by EBER‐1 in situ hybridization (ISH) and EBNA‐1 PCR. In EBER‐1 positive cases, we performed immunohistochemistry for latent membrane protein‐1 (LMP‐1) and EBV diffuse early antigen (EA(D)) to compare EBV latent gene expression and lytic process.  EBER‐1 was detected in 15 of 81 cases of lymphomas. EBER‐1 expression showed three different patterns on tumour cells; diffuse 4/81 (5%), localized 4/81 (5%), and a few scattered pattern 7/81 (9%). We regarded diffuse pattern and localized pattern as EBER‐1 positive group (8/81: 10%). Diffuse pattern of EBER‐1 was shown in all three T‐cell lymphomas and one B‐cell lymphoma. A localized pattern was seen all in B‐cell lymphomas. The EBER‐1 expression was 11% in the stomach (7/64) and 6% in the intestine (1/17). Five of the eight EBER‐1 positive gastric lymphomas were histologically diffuse large B‐cell lymphomas, and the other three were peripheral T‐cell lymphoma, unspecified, one angiocentric lymphoma, and one intestinal T‐cell lymphoma by REAL classification. Eight MALT type gastric B‐cell lymphomas showed no EBV association. EBV nuclear antigen (EBNA‐1) was detected in 15 of 45 resected cases (33%) by PCR. EBER‐1 positive cases were all EBNA‐1 positive. Twelve EBNA‐positive/EBER‐negative cases consisted of seven cases showing a few scattered EBER‐1 positive lymphocytes. LMP‐1 and diffuse early antigen (EA(D)) was detected in five and three cases, respectively. Although follow‐up information in our series was incomplete, it seemed that there was no significant difference in their staging or prognosis between EBER‐positive cases and EBER‐negative group. It is concluded that EBV is associated with some lymphomas among Koreans without overt pre‐existing immunodeficiency, especially in T‐cell lymphomas.
Lesions produced by the extravasation of urine from the upper urinary tract
Authors: CARR R.A. , NEWMAN J. , ANTONAKOPULOS G.N. , PARKINSON M.C.
Published: November 2003

We present six cases which illustrate the spectrum of clinical features, macroscopic findings and light microscopic findings of urine extravasation from the upper urinary tract. The early lesions are characterized macroscopically by an oedematous, glistening or gelatinous appearance to the renal perihilar and peripelvic fat. Light microscopically there is lipolysis with associated foamy macrophages, multinucleate giant cells and lymphocytes. Immunohistochemical staining for Tamm–Horsfall protein is strongly positive in the extracellular space and in the foamy macrophages confirming urine extravazation. Later lesions are characterized by cicatrization of fibrous tissue around the renal pelvis and hydronephrosis. Microscopically there is relatively bland fibrosis with occasional lymphocytes and histiocytic cells. The late lesions are also characterized by extracellular deposits of weakly eosinophilic, granular or hyaline material, the so called ‘urinary precipitates’. These deposits stain strongly with diastase PAS and weakly positive for Tamm–Horsfall protein. The staining of these urinary precipitates is analogous to renal tubular hyaline casts, thus supporting the theory that they are derived from uroproteins. We consider that these deposits are pathognomic of past urine extravasation.
Mucosal prolapse changes in Hirschsprung’s disease
Authors: Chetty R. , Govender D.
Published: November 2003

The aim of this study was to ascertain the incidence of mucosal prolapse changes in Hirschsprung's disease. Twenty‐three random, consecutive resection specimens for this condition were analysed for the histological features of prolapse. Eight cases showed histological evidence suggesting mucosal prolapse at the junction between ganglionic and aganglionic bowel. Thickening and splaying of the muscularis mucosae with extension into the lamina propria, and the presence of metaplastic or hyperplastic tubules with goblet cell and cryptal hypertrophy were the dominant histological features found in the eight cases. In addition, an increase in elastic fibres in the lamina propria and diamond‐ shaped glands were seen to varying degrees in all eight cases.  Mucosal prolapse was more prominent in the older patients and is, therefore, related to duration of symptoms. Differential pressures in ganglionic and aganglionic segments of bowel, together with faecal stream and straining are likely to be of pathogenetic significance.
Expression of L‐selectin (CD62L) discriminates Th1‐ and Th2‐like cytokine‐producing memory CD4+ T cells
Authors: KANEGANE H. , KASAHARA Y. , NIIDA Y. , YACHIE A. , SUGII S. , TAKATSU K. , TANIGUCHI N. , MIYAWAKI T.
Published: November 2003

Human memory (CD45RO+) CD4+ T cells can be distinguished into two subpopulations on the basis of expression of the lymph node homing receptor, L‐selectin (CD62L). In a prior study we showed that human L‐selectin‐positive memory T‐helper (Th) cells promote the maturation of IgG‐ and IgA‐producing cells by naive B cells. To further elucidate the contribution of memory CD4+ T cells to B‐cell differentiation, human memory CD4+ T cells with or without L‐selectin expression were evaluated for production of cytokines that participate in regulation of immunoglobulin production. It was found that L‐selectin‐positive human memory CD4+ T cells produce mainly interleukin (IL)‐4 and IL‐5, whereas L‐selectin‐negative CD4+ T cells produce mainly interferon‐γ (IFN‐γ). This profile of cytokine expression coincides with the profile that distinguishes Th1 and Th2 subsets. In contrast to the murine system, IL‐10 production was similarly contributed by human L‐selectin‐positive and ‐negative memory CD4+ T‐cell subpopulations. These results suggest that the human L‐selectin‐negative and ‐positive subpopulations of human memory CD4+ T cells contain Th1‐like and Th2‐like cytokine‐producing cells, respectively.
Immunosuppression and cytokine production in mice infested with Ixodes ricinus ticks: a possible role of laminin and interleukin‐10 on the in vitro responsiveness of lymphocytes to mitogens
Authors: GANAPAMO F. , RUTTI B. , BROSSARD M.
Published: November 2003

T cells from BALB/c mice infested 9 days before with Ixodes ricinus nymphs had a suppressed response to in vitro concanavalin A (Con A) stimulation compared to cells from uninfested mice. When laminin (the main component of the extracellular matrix) was used as a coating agent, the Con A response of naive mice was characterized by a decrease in cell proliferation, whereas there was no significant effect on the mitogen response of cells from infested mice. In contrast, an increased response to lipopolysaccharide (LPS) was observed when assaying lymph node cells of infested mice, probably reflecting an increase in B‐lymphocyte number or activity. LPS cell stimulation was not modified by laminin. Supernatants of lymph node cells, taken 9 days after the first infestation of mice, stimulated with Con A in vitro, contained interleukin‐10 (IL‐10) but no significant levels of IL‐5 as tested by enzyme‐linked immunosorbent assay. At this stage of the infestation all T cells reactive with tick antigens generated in lymph nodes that drain the tick fixation site, were CD4+ cells, as determined by CD4+ depletion. With cells taken 9 days after the third infestation an increase of IL‐5 and IL‐10 was observed. The IL‐10 levels were higher than the IL‐5. According to these observations, we conclude that the reduction of T‐cell proliferation in response to Con A observed in lymph node cells from infested mice, may be due to the combined effect of laminin interaction with T lymphocytes during migration and IL‐10 production by these lymphocytes.
Differential localization of allograft nitric oxide synthesis: comparison of liver and heart transplantation in the rat model
Authors: KUO P. C. , ALFREY E. J. , KRIEGER N. R. , ABE K. Y. , HUIE P. , SIBLEY R. K. , DAFOE D. C.
Published: November 2003

Nitric oxide (NO) is a free radical with a diversity of cellular origins and potential functions. Within the realm of solid organ transplantation, NO has been the focus of much attention. Discordant reports have documented both suppression and potentiation of the alloimmune response. In addition to questions regarding its functional role, little is known of the cellular origins of NO in acute rejection of vascularized allografts. To address this question, acute rejection models of rat heterotopic heart and orthotopic liver transplantation were chosen. When compared with naive controls and isografted animals, acute rejection in both heart and liver transplantation was associated with elevated systemic levels of the NO metabolite, nitrite. This was accompanied by increased graft content of iNOS protein as determined by immunoblot analysis of protein extracts. Expression of iNOS mRNA was localized with in situ hybridization. In both heart and liver transplantation, iNOS mRNA was found in the inflammatory infiltrate accompanying acute rejection. In addition, hepatocytes also expressed iNOS mRNA in the rejecting liver allograft. In contrast, cardiac myocytes in the rejecting heart allograft did not stain for iNOS mRNA. These results indicate that organ‐specific, differential cellular expression of iNOS occurs in the acutely rejecting allograft. Transcriptional regulation of iNOS may vary among various organs according to the local cellular milieu. In addition, there may be a variable allograft specific response to acute rejection which may modify the associated immunologic biology.
Derivation of T‐cell receptor α‐chain double expresser lines from normal murine mature T cells
Authors: ESHIMA K. , SUZUKI H. , YAMAZAKI S. , SHINOHARA N.
Published: November 2003

Because the T‐cell receptor (TCR) α‐chain locus is known to lack allelic exclusion of rearrangements, and as a recent report revealed the existence of α‐chain double expressers among normal human peripheral blood lymphocytes (PBL), the possible existence of TCR α‐chain double expressers among mature murine T cells was examined. Although two‐colour staining analysis of normal T‐cell populations did not immediately reveal recognizable clusters of Vα double expressers, alternative in vitro stimulations of normal murine T cells with antibodies to two different TCR Vα chains reproducibly induced TCR α‐chain double‐expresser lines. TCR complexes with different α‐chains on such T cells were both shown to be functional. The cell lines were heterogeneous with respect to Vβ usage and the ratio of the expressed amounts of the two α‐chains on the surface. The ratio of the two expressed α‐chains was found to be very stable over a long period of time. These results are consistent with the earlier report on α‐chain double expressers among human T cells and also show normal occurrence of TCR α‐chain double expressers in murine T‐cell populations.
Oral aspirin and ibuprofen increase cytokine‐induced synthesis of IL‐1β and of tumour necrosis factor‐αex vivo
Authors: ENDRES S. , WHITAKER R. E. D. , GHORBANI R. , MEYDANI S. N. , DINARELLO C. A.
Published: November 2003

We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin‐1α (IL‐1α), IL‐1β, IL‐2, IL‐6, tumour necrosis factor‐α (TNF) and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL‐1β and TNF synthesis induced by exogenous IL‐1α was elevated threefold compared to the pre‐aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE‐2 production returned to pre‐aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS‐ or Staphylococcus epidermidis‐induced cytokine synthesis. However, IL‐1α‐induced synthesis of IL‐1β was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre‐ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo‐oxygenase blunt PGE2‐mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a ‘rebound’ increase in cytokine‐induced cytokine synthesis that is not observed in LPS‐induced cytokines.
Protein kinase C isotype expression and regulation of lymphoid cell motility
Authors: THORP K. M. , VERSCHUEREN H. , DE BAETSELIER P. , SOUTHERN C. , MATTHEWS N.
Published: November 2003

Lymphocyte migration into inflammatory sites involves a change from a spherical, non‐motile phenotype to an irregular, constantly shape‐changing, motile phenotype. We have previously shown that lymphocytes are maintained in the non‐motile state by the constitutive activity of protein kinase C (PKC). In this paper we have attempted to identify the PKC isotype which regulates these morphological changes by three different approaches. (a) Motile and non‐motile T‐cell lines were compared for expression of the α, βI, βII, γ, δ, ε, η, ζ and θ isotypes by Western blotting. There was no obvious correlation of isotype expression with motility. (b) Two different PKC inhibitors, one specific for classical isotypes, Go6976 and the other GF109203X, which inhibits both classical and non‐classical isotypes were compared for induction of motility in non‐motile lymphocytes. Only GF109203X induced motility implying that a non‐classical isotype is involved. (c) Non‐motile lymphocytes were chronically treated with the PKC activator bryostatin and the time courses of induction of motility and downregulation of PKC isotypes were compared. Induction of motility correlated better with downregulation of ε, η and θ than with α or β. It is concluded that the data fit best with the involvement of a non‐classical PKC isotype in regulating lymphocyte motility although no association with a particular isotype was found.
Specific immunotherapy with tumour‐draining lymph node cells cultured with both anti‐CD3 and anti‐CD28 monoclonal antibodies
Authors: HARADA M. , OKAMOTO T. , OMOTO K. , TAMADA K. , TAKENOYAMA M. , HIRASHIMA C. , ITO O. , KIMURA G. , NOMOTO K.
Published: November 2003

For providing costimulatory signals, we utilized anti‐CD28 monoclonal antibody (mAb) for the in vitro culture of tumour‐draining lymph node (LN) cells. The proliferation of B16 melanoma‐draining LN cells in the culture with anti‐CD3 mAb was remarkably enhanced by the addition of anti‐CD28 mAb. In culture with both anti‐CD3 and anti‐CD28 mAb, the B16‐draining LN cells produced a higher level of interferon‐γ, but not interleukin‐4, than with anti‐CD3 mAb alone. The B16‐draining LN cells efficiently expanded in the culture with both anti‐CD3 and anti‐CD28 mAb and subsequently with a low dose of IL‐2 (anti‐CD3 plus anti‐CD28/IL‐2). The expanded cells consisted predominantly of CD8+ T cells and showed a specific cytolytic activity, in a major histocompatibility complex (MHC) class I‐restricted manner, even without in vitro restimulation. In addition, the adoptive transfer of the B16‐draining LN cells, expanded in the culture protocol of anti‐CD3 plus anti‐CD28/IL‐2, showed a significant anti‐tumour effect against metastatic B16 melanoma in combination with IL‐2. The cured mice thus acquired a specific protective immunity. Moreover, this protocol was also moderately effective against poorly immunogenic 3LL carcinoma. Overall, our results suggest the potential for another immunotherapeutic strategy based on ‘the costimulatory theory’ other than vaccination with B7‐transfected tumour cells.
Differential regulation of tissue‐specific lymph node high endothelial venule cell adhesion molecules by tumour necrosis factor and transforming growth factor‐β1
Authors: CHIN Y.‐H. , YE M.‐W. , CAI J.‐P. , XU X.‐M.
Published: November 2003

Lymphocytes migrate from blood into lymph nodes (LN) of rats specifically at segments of venules lined by high endothelium (HEV). We have previously shown that pretreatment of LN HEV cells with pro‐inflammatory cytokines such as tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ), augments their adhesiveness for thoracic duct lymphocytes (TDL). Here we report that a mouse monoclonal antibody, 3C10, recognized tissue‐specific endothelial determinants on rat LN HEV cells and blocked their adhesiveness for TDL and EL‐4J cells transfected with rat L‐selectin. In contrast, 3C10 antibody did not inhibit lymphocyte attachment to Peyer's patch (PP) frozen sections or cultured PP HEV cells. The antibody immunoprecipitated from LN HEV cells two proteins with apparent molecular weights of 90 000 and 50 000. The expression of 3C10 antigen on LN HEV cells was increased by incubation with TNF‐α or IFN‐γ. Furthermore, pretreatment of cytokine‐stimulated LN HEV cells with 3C10 antibody blocked TDL binding in a dose‐dependent manner. In contrast, 3C10 antigen expression on LN HEV cells was significantly decreased following incubation of cells with transforming growth factor‐β1 (TGF‐β1). In addition, TGF‐β1 also abrogated the adhesiveness of LN HEV cells stimulated with TNF‐α, IFN‐γ or both cytokines. Together, these data suggest that endothelial determinants recognized by the 3C10 antibody are tissue‐specific ligands for lymphocyte adhesion and cytokines such as TNF‐α and TGF‐β differentially regulate their expression and function.
The bacterial superantigen Staphylococcal enterotoxin B stimulates lymphocyte locomotor capacity during culture in vitro
Authors: NEWMAN I. , WILKINSON P. C.
Published: November 2003

The bacterial superantigen Staphylococcal enterotoxin B (SEB) was investigated for its effects on lymphocyte locomotion in vitro. Culture of peripheral blood mononuclear cells (PBMC) for 24–72 hr in SEB (1–100 μg/ml) increased the proportion of lymphocytes in locomotor (polarized) morphology and capable of invading collagen gels, to the same extent as the established locomotor activator, anti‐CD3 (α‐CD3), though the conventional antigen, tetanus toxoid was ineffective. The cells responding to SEB were predominantly T cells. SEB had no effect on lymphocyte locomotion in short‐term (45 min) assays, thus its effect is to stimulate growth‐related locomotor capacity and it does not act as a chemoattractant. During culture of PBMC in SEB, the chemokines interleukin‐8 (IL‐8) and macrophage chemotactic protein‐1 (MCP‐1) were released into the culture medium. The presence of anti‐IL‐8, but not of anti‐MCP‐1, either during culture or added to SEB culture supernatants and tested in short‐term assays, inhibited the development of polarization suggesting that IL‐8, which is a lymphocyte chemoattractant, also plays a key role in SEB‐induced locomotor activation. Among SEB‐activated lymphocytes, CD45RO+CD45RA− lymphocytes showed enhanced locomotor responses, but a relation was not found between locomotor activity and the presence of cell surface CD69.
Distribution of porcine CD4/CD8 double‐positive T lymphocytes in mucosa‐associated lymphoid tissues
Authors: ZUCKERMANN F. A. , GASKINS H. R.
Published: November 2003

The present study describes the distribution of CD4/CD8 double‐positive (DP) T cells in lymph nodes and mucosa‐associated lymphoid tissues of pigs at 6–7 months of age. Proportions of lymphocytes isolated from peripheral, bronchial and mesenteric lymph nodes expressing CD4 and/or CD8 molecules were similar and ranged from 10–13% CD4/CD8 DP cells, 25–27% CD4 single‐positive (SP) cells, and 27–32% CD8 SP cells. Mucosa‐associated lymphoid tissues had significantly smaller proportions of CD4+ and/or CD8+ T cells than lymph nodes and CD4/CD8 DP cells accounted for a larger proportion of the total CD4+ lymphocytes than in lymph nodes. Compared to the lymph nodes, the predominant CD4+ and/or CD8+ T‐cell subset in tonsils was the CD4/CD8 DP population (18%), because of both a higher proportion of these cells and a lower proportion of CD4 SP (12%) and CD8 SP (14%) lymphocyte subsets. Jejunal Peyer’s patches were comprised of 12% CD4 SP, 28% CD8 SP and 10% CD4/CD8 DP lymphocytes. In contrast, the mid‐section of the continuous Peyer’s patch in the ileum contained 7% CD4 SP, 8% CD8 SP and 4% CD4/CD8 DP lymphocytes. The distribution of T lymphocytes in porcine mucosal lymphoid aggregates agrees with the reported correlation between high and low rates of lymphocyte entry into these tissues and the abundance or scarcity of T cells, respectively. Defining the role of CD4/CD8 DP lymphocytes and their unique distribution in mucosa‐associated lymphoid tissues in the pig may reveal novel T‐cell‐mediated regulatory pathways.
The collagen‐like component of the complement system, C1q, is recognized by 7 S autoantibodies and is functionally impaired in synovial fluids of patients with rheumatoid arthritis
Authors: TRINDER P. K. E. , MAEURER M. J. , BRACKERTZ D. , LOOS M.
Published: November 2003

Cross‐reactivity between type II collagen (CII) and C1q, the collagen‐like subunit of the first component of complement, has been demonstrated in synovial fluid (SF) from rheumatoid arthritis (RA) patients. Many authors have studied autoimmunity to CII in RA, but little work has been done on autoimmunity to C1q in RA. In the data presented here, we have been able to show that in addition to native C1q, an altered form of C1q is present in SF from RA patients. Furthermore, a low molecular weight form of C1q is present in RA SF, although its role, if any, in the pathogenesis of RA is unclear. The presence in these RA SF of C1q‐specific antibodies (IgG and IgM) has been studied and we have partially characterized the antibody moieties involved. As well as binding to C1q and fragments representing the collagen‐tails from C1q, 7 S IgG autoantibodies against C1q also bind to a C1q molecule altered in vitro by incubation with reactive oxygen species and to the non‐apeptide KGEQGEPGA (representing residues 26–34 from the C1q A‐chain), which has previously been shown to suppress the onset of CII‐induced arthritis in an animal model.
Evidence against T‐cell development in the adult human intestinal mucosa based upon lack of terminal deoxynucleotidyltransferase expression
Authors: TAPLIN M.‐E. , FRANTZ M. E. , CANNING C. , RITZ J. , BLUMBERG R. S. , BALK S. P.
Published: November 2003

Several lines of evidence indicate that a subset of murine intestinal intraepithelial lymphocytes (iIEL), particularly those which express the CD8αα homodimer, mature extrathymically. This study confirms that a small fraction of adult human iIEL also express the CD8αα homodimer and demonstrates that most of these cells in the small intestine are T cells using the αβ T‐cell receptor (TCR). Whether these cells or other subsets of adult human iIEL mature extrathymically in the intestine was assessed by measuring the expression of terminal deoxynucleotidyltransferase (TdT), an enzyme expressed exclusively by immature lymphocytes. Very low levels of TdT message could be detected by polymerase chain reaction (PCR) amplification in some iIEL samples. The level of TdT expression was assayed by competitive PCR amplification and compared with thymocytes and peripheral blood lymphocytes. These measurements indicated that the number of immature T cells expressing TdT in the intestinal epithelium was less than one cell per 107 lymphocytes. This demonstrates that there are few if any TdT expressing immature T cells in the adult human intestinal mucosa and indicates, therefore, that T‐cell development in the intestinal mucosa does not contribute significantly to the T‐cell repertoire of the adult human intestine.
Thymic B cells of pig fetuses and germ‐free pigs spontaneously produce IgM, IgG and IgA: detection by ELISPOT method
Authors: CUKROWSKA B. , ŠINKORA J. , MANDEL L. , ŠPLÍCHAL I. , BIANCHI A. T. J. , KOVÁŘŮ F. , TLASKALOVÁ‐HOGENOVÁ H.
Published: November 2003

The aim of this study was to investigate spontaneous immunoglobulin production and a pattern of isotype switching by thymic B lymphocytes (TBL) as compared with cells isolated from spleen during early ontogeny using a pig model in which B‐cell development is not influenced by maternal regulatory factors. A sensitive ELISPOT assay was therefore employed to detect immunoglobulins in pig fetuses, colostrum‐deprived germ‐free (GF) piglets as well as conventionally (CONV) reared pigs. The first spontaneously immunoglobulin‐secreting cells in the thymus were detected in 67‐day‐old fetuses (the length of gestation period in pigs is 114 days), their number increasing during fetal ontogeny. In contrast to fetal splenic cells, which secrete exclusively IgM, fetal thymic immunoglobulin‐secreting cells were determined to undergo spontaneous isotype switching to IgG and IgA. In 28‐day‐old GF piglets and 3‐month‐old CONV pigs the number of thymic immunoglobulin‐secreting cells of all isotypes was comparable to the number of thymic immunoglobulin‐secreting cells detected in the newborn thymus. Considerable augmentation of IgG and IgA production by splenic immunoglobulin‐secreting cells in CONV pigs was observed as compared to GF newborns and GF piglets, in which IgG‐ and IgA‐secreting cells were detected occasionally. Our results indicate that TBL represent the first B‐cell population in early fetal ontogeny spontaneously undergoing isotype switching to IgG and IgA; in the postnatal period the TBL population does not appear to be influenced by external antigenic stimuli of conventional microflora.