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There is a recognised association between pernicious anaemia and the development of gastric carcinoma, endocrine cell hyperplasia, and carcinoid tumour. Multiple endoscopic biopsies from the body mucosa of seven patients with pernicious anaemia showed small intestinal metaplasia with varying degrees of inflammation, fibrosis, and expansion of the lamina propria. Using conventional silver and lead stains, endocrine cells were inconspicuous. Staining for the general neural and neuroendocrine markers NSE and PGP 9.5 revealed a proliferation of endocrine cells in the epithelium and isolated clumps of endocrine cells in the lamina propria. The clumps were composed of two cell types, either small or large. Some of these endocrine cells showed gastrin, 5HT, VIP and substance P immunoreactivity of varying intensity. Ultrastructurally nine morphologically distinct types of granules were found some of which correlated with the immunohistochemistry. Some separate islands were composed solely of endocrine cells while others had a definite neural component, suggesting that the former arise from 'budding off' of enteroendocrine cells and the latter originate from the neuroendocrine cells of the lamina propria plexus. Thus there may be a dual origin of carcinoid tumours. Carcinoid tumours associated with pernicious anaemia tend to be multifocal and are infrequent. Less than 50 such cases have hitherto been reported. Our findings of endocrine cells proliferations in seven cases of pernicious anaemia indicate that this may be an adaptive change that occurs frequently and provides the basis on which carcinoids, less frequently, develop. [ABSTRACT FROM PUBLISHER]

B cells, distinct from those seen in myasthenia gravis, are present in normal human thymic medulla, concentrated around the Hassall's corpuscles. We have shown that they constitute 33 ± 4.8% of the total cells in the thymic medulla. In tissue sections they were often seen to have rosettes of thymocytes around them, a relationship which was maintained when the cells were isolated from the thymus. Thymic B cells expressed cytoplasmic immunoglobulins IgD, IgM and IgG but only rarely IgA. Unlike murine thymic B cells, human thymic B cells were CD5-. Freshly isolated thymic B cells were activated cells, but they rapidly became quiescent and died in culture over a 10-day period unless stimulated with mitogens. Thymic B cells responded to polyclonal B-cell activators SAC and TPA and when stimulated, maintained their relationship with thymocytes. Electron microscopic studies showed that two morphologically different thymocyte populations associated with the B cells. The plasma membranes of larger thymocytes were juxtaposed to the B-cell membrane, but smaller thymocytes with darker cytoplasm were associated with the B cells via cytoplasmic strands. Studies in mice have suggested that B cells are involved in thymic negative selection. The close association between activated B cells and thymocytes observed in this study supports this hypothesis. [ABSTRACT FROM AUTHOR]

Thyroid tissue from 18 consecutive cases of Hashimoto's thyroiditis treated surgically were stained immunohistochemically for neurone specific enolase (NSE), somatostatin, calcitonin and thyroglobulin. Cells staining for NSE and somatostatin were present in 14 cases. In four cases large numbers of cells including oxyphil cells stained for NSE. Consecutive sections showed an identical staining pattern of these cells for somatostatin. Sections stained for calcitonin showed few or no positively staining cells. There were moderate numbers of NSE and somatostatin-containing cells in five of the cases, occasional cells in five and none in four cases. Electron microscopy confirmed neurosecretory-like granules within positively staining cells. Somatostatin is known to inhibit T3 and T4 production or release from thyroid cells by a direct action. We suggest, in Hashimoto's disease, somatostatin in paracrine cells serves as a local inhibitory neuroendocrine effector and could be causally related to the hypothyroid state. [ABSTRACT FROM PUBLISHER]

For many years, Sjögren's syndrome was a purely descriptive diagnosis of symptoms such as xerostomia and dry eye (sicca syndrome). The different classification criteria proposed for Sjögren's syndrome comprise a rather variable spectrum of diagnostic possibilities, at one extreme of which we find an array of exclusively objective parameters while, at the other extreme, the objective parameters and patients' symptoms balance out. Improved accuracy in the diagnosis of Sjögren's syndrome can be attained only through the combination of a symptoms questionnaire, histopathology, scintigraphy or sialography or evaluation of the unstimulated salivary flow and specific autoantibodies. In these last few years, further methods have been proposed to increase diagnostic accuracy: the analysis of various salivary constituents, saliva and tear ferning tests, the search for new autoantigens and, above all the use of ultrasonography and magnetic resonance imaging. Color-power Doppler and magnetic resonance sialography have recently been proposed as promising techniques to improve sensitivity and diagnostic specificity. This study discusses the data present in the literature and personal experience regarding diagnostic methods in a group of 350 patients affected by primary Sjögren's syndrome.

Antibodies binding to double-stranded (ds) DNA are strongly associated with renal involvement in patients with systemic lupus erythematosus (SLE). We have generated two new IgG DNA-binding monoclonal antibodies (mAb), RH-14 and DIL-6, from the peripheral blood lymphocytes of two SLE patients with glomerulonephritis using the heteromyeloma cell line CB-F7. RH-14 is an IgG1 lambda antibody which also bound to single-stranded DNA, histones and nucleosomes. DIL-6 is an IgG3 lambda antibody with restricted antigen binding specificity. cDNA encoding the variable regions of the heavy (V(H)) and light (V(L)) chains of RH-14 was sequenced and the antigen binding site of this mAb was computer modelled. Sequence analysis of V(H) and V(L) regions of RH-14 showed that V(H) is derived from germ-line gene V3-7, a member of the V(H)3 family, and V(L) is derived from DPL 11, a member of the V(lambda)2 family. Somatic mutations and basic amino acid residues are identified in the complementarity-determining regions of both V(H) and V(L) regions. The nephritogenic properties of these mAb were analyzed by implanting and growing the hybridoma cells secreting the mAb in the peritoneum of SCID mice. The animals that received the RH-14 hybridoma produced higher levels of proteinuria (3 to > or = 4) (p < 0.001) compared to the groups that received DIL-6 (trace to > or = 1) or CB-F7 (trace). Electron microscopy of kidney sections from all the RH-14-implanted animals showed granular immunoglobulin deposition in the renal glomerular capillaries and mesangium. In this study we have shown for the first time using electron microscopy that a human IgG anti-dsDNA mAb, RH-14, is nephritogenic and that deposition of such an antibody alone is sufficient to induce renal damage.

We investigated the capacity of five human monoclonal IgG anti-DNA antibodies derived from lupus patients to produce glomerular immune deposits. The hybridomas secreting these antibodies were administered intraperitoneally to severe combined immunodeficiency (SCID) mice. Three of the five antibodies (B3, 35.21, 33.C9) were detected in the kidneys, but only one (33.C9) deposited exclusively in the glomeruli in the mesangium and capillary wall, whereas the other two antibodies bound to nuclei both in the kidney and in other organs. The antibodies were tested against a variety of autoantigens by ELISA, the only unique feature of 33.C9 was that it also bound strongly to histones. There were no particular amino acid motif that was related to immunoglobulin deposition in the kidney. All the mice that had immunoglobulin deposited in the kidney, either extracellularly or intranuclearly developed 2 to 3+ proteinuria, whereas the other mice had only trace amounts of proteinuria. This study demonstrates that some human monoclonal IgG anti-dsDNA antibodies are capable of binding to the glomerulus while others can penetrate cells and bind to nuclei in vivo. Although no abnormal pathology was observed, proteinuria was detected, perhaps representing an early phase of disease. These results indicate that the affinity for dsDNA is not the sole determining factor governing the biological properties of human anti-DNA antibodies in vivo.

Three monoclonal antibodies (mAbs) have been applied to 14 adenocarcinomas, eight mesotheliomas, and nine reactive mesothelial proliferations. One of these, AUA1, is a novel antibody in this context. It was found in 13/14 of the adenocarcinomas but not in benign or malignant mesothelial tissue, making it a potential substitute for carcinoembyronic antigen (CEA) in the differential diagnosis of mesotheliomas from adenocarcinomas. In addition, the lesions were stained using an argyrophil technique to identify nucleolar organizer regions. The results of counting these showed a small but significant overlap in their numbers between malignant and benign mesothelial proliferations. Although there was a difference overall in the numbers of nucleolar organizer regions in adenocarcinomas and mesotheliomas, on the one hand, and benign hyperplasias, on the other, this overlap considerably reduces their value in assessing individual difficult cases.

The stratified inner layer of the embryonic fetal brain, the ventricular zone (VZ), contains glial fibrillary acidic protein (GFAP)-positive cell bodies of radial glia. The adult cerebral ventricle is lined by a single layer of cuboidal, ciliated common ependymal cells which are, immunohistologically, GFAP negative. In late gestation, the ventricular lining is formed by tanycytes, ependymal cells with short, intensely GFAP-positive basal fibres. The development of ependyma was examined, morphologically and immunohistologically, in human fetal brain from between 11 weeks gestation to 6 months post-term to determine the relationship between the radial glia cell, tanycyte and common ependymal cell. This study was not able to show whether tanycytes were formed from radial glia or were formed from a previously uncommitted population of VZ cells. The study did show, however, that tanycytes probably mature into common ependymal cells following acquisition of cilia and loss of basal fibres. Electron microscopic data indicate that tanycytes have features suggestive of a secretory and/or transport function.

The effects of the administration of oestrogens on the activity of hepatic tryptophan oxygenase have been assessed both directly (by measurement of enzyme activity in vitro) and indirectly (by measurement of urinary excretion of tryptophan metabolites) in rats, and indirectly in menopausal women receiving hormone replacement therapy. Intraperitoneal administration of 500 micrograms of oestradiol or ethinyl oestradiol/kg body wt had no effect on the activity of tryptophan oxygenase in homogenates of liver from mature (13-week-old) female rats. Both adrenalectomy and ovariectomy led to a reduction in the activity of tryptophan oxygenase in homogenates of liver from mature rats; again there was no effect of giving 500 micrograms of oestradiol/kg body wt by intraperitoneal injection. Intraperitoneal administration of 210 micrograms of oestrone sulphate/kg body wt for 1 or 2 days before killing, or its incorporation in the diet for up to 8 weeks at an equivalent dose rate, had no effect on the activity of tryptophan oxygenase in homogenates of liver from ovariectomized 6-14-week-old female rats. Intraperitoneal administration of 500 micrograms oestradiol/kg body wt to intact mature female rats together with 500 mg tryptophan/kg body wt caused a reduction in the urinary excretion of xanthurenic and kynurenic acids, kynurenine and N1-methyl nicotinamide. When peri- and post-menopausal women were treated with ethinyl oestradiol (20 micrograms/day) or piperazine oestrone sulphate (3 mg/day) for 3 months, there was an increase in the concn of tryptophan in plasma, with no change in the urinary excretion of xanthurenic and kynurenic acids and kynurenine. This study provides no evidence for the induction of tryptophan oxygenase by oestrogens in rats or human beings.

A review of 35 cystadenofibromas of the ovary has revealed certain morphological features which implicate the role of estrogenic hormones in the pathogenesis of these neoplasms. The epithelium was tubal in type and at the ultrastructural level was found to be comparable with that of the normal Fallopian tube during estrogenic stimulation. The appearance of the stromal fibroblasts in the connective tissue component of the tumor was also consistent with an estrogenic influence. It is suggested that the source of estrogen responsible for both the epithelial differentiation and the fibrous proliferation may be found in functional steroidogenic cells present in the stroma of the neoplasm.

An unusual variant of a poorly differentiated leiomyosarcoma of the uterus, containing osteoclast-like giant cells, is described. Areas of the resected tumor bore a close resemblance to giant cell tumor of bone. It is postulated that these giant cells, as well as the osteoclast-like giant cells reported in a number of tumors of other tissues, originate from the monocyte/histiocyte group of cells. The diagnosis of leiomyosarcoma was possible only after the tumor had been examined in the electron microscope. The ultrastructural features are consistent with a smooth muscle origin of the neoplasm; the final assessment is based on the relative proportions and frequency of such structures as: bundles of myofilaments with focal densities, marginal densities, pinocytotic vesicles, and an external lamina.

The lamina propria of the human appendix possesses a recently defined ganglionated neural plexus with neurosecretory-type component cells. In order to elucidate the functional role of this plexus, immunohistochemical light and electron microscopic studies were performed on 21 appendixes. By light microscopy, 18 specimens showed within the lamina propria neuron-like and neurosecretory-type cells that stained positively with lead hematoxylin and were positive for serotonin. The number of these cells varied from specimen to specimen. No correlation between the number of serotonin-immunoreactive intraepithelial enterochromaffin cells and the number of plexus cells could be established. Electron microscopic examination revealed identical pleomorphic neurosecretory granules within enterochromaffin cells and plexus cells. The site of serotonin storage in these granules was revealed by electron immunocytochemical methods. It is suggested that, under physiologic conditions, the lamina propria plexus has a modulatory role between the epithelium and the deeper mural enteric nervous system mediated by serotonin neurotransmission. Uncontrolled release of serotonin by the plexus may initiate inflammation and elicit pain related to the appendix.

Eight cases of benign granular cell tumour of tongue and skin all showed immunohistochemical staining for neurone specific enolase (NSE). Four Schwannomas, two neurofibromas and Schwann cells of nerves related to these tumours and the granular cell tumours showed no staining for NSE. NSE is a marker for neuronal type cells of the nervous system and cells of the neuroendocrine system. The results support a neural derivation of granular cell tumours. The histogenetic precursor may be an undifferentiated spindle-shaped 'reserve' cell of peripheral nerve, perhaps necessary for replacement of shed sensory organs.

Dermal elastic fibres in biopsies taken from sun-exposed involved digital skin and sun-protected uninvolved skin on the medial aspect of the upper arms from 13 patients with systemic sclerosis were examined by light and transmission electron microscopy. For controls, biopsies were taken from similar sites from 4 age- and sex-matched healthy volunteers and 4 patients with primary Raynaud's phenomenon. On light microscopy only the control digital biopsies showed mild actinic changes of the elastic fibres whereas in all the biopsies from patients with systemic sclerosis identical changes of thickening, clumping and fragmentation of the elastic fibres were observed. Quantitative assessment of the dermal elastic fibres using microdensitometry and video image analysis showed no significant difference between the patients and controls. On electron microscopy more advanced abnormalities similar to those seen in actinic damage and chronological aging were found in the biopsies from all the patients with systemic sclerosis compared to the controls.

The human ovary may contain binovular or polyovular follicles at birth, but they are unusual later in life. Binbovular follicles were found in bilateral ovarian biopsies from a patient with primary amenorrhea who had been treated with exogenous gonadotropins. The fine structural morphology of these follicles has shown that both oocytes were in the resting meiotic prophase, that their respective vitelline bodies faced each other across the intervening plasma membranes, and that the adjacent oocytes made mutual contacts similar to those found between granulosa cells and oocytes. From the appearance of the multivesicular bodies in nearby stromal fibroblasts it is suggested that these follicles had formed by fusion of two adjacent primordial follicles by a mechanism similar to the depolymerization of the ground substance in the apex of the Graafian follicle that leads to ovulation.

Female CBA mice, aged 11 months, were treated cyclically with oral ethynyl oestradiol or oestrone sulphate for 3 months. The ovaries of all animals appeared to be atrophied. Target tissues throughout the genital tract showed a response to both oestrogens. Electron microscopy of both the endometrium and the urothelium demonstrated morphological changes characteristic of increased cellular metabolic activity in the treated mice. Endometrial hyperplasia developed in both treatment groups but more pronounced epithelial changes occurred with oestrone sulphate. This hyperplasia was accompanied by a doubling in the number of uterine cytoplasmic oestrogen receptors. A 50% fall in serum levels of luteinizing hormone in the treated mice revealed that the hypothalamic-pituitary system was still intact. Both oestrogens improved skeletal balance by changes in cortical-endosteal bone remodelling. The results suggest that the CBA strain of mouse is a suitable model for the study of the human climacteric and its response to hormone replacement therapy.

Carcinoid tumours of the appendix are generally thought to be derived from enterochromaffin cells; in-situ abnormalities of these cells are, however, rarely observed in the mucosal epithelium. One hundred appendices, removed consecutively at surgery, were stained with an alcian blue-PAS diastase-lead haematoxylin sequence and, in 69, cells were found in the lamina propria with a cellular and architectural morphology identical to those of an archetypal appendiceal carcinoid tumour. These cells appeared to contain neurosecretory granules, were diazo-positive and showed argentaffinity. They were further characterized by the localization of cytoplasmic neurone specific enolase and the presence of neurosecretory granules was confirmed by electron microscopy. These cells are designated subepithelial neurosecretory cells (SNC). It is suggested they are an integral component of the subepithelial nervous plexus and are in progenitors of appendiceal carcinoid tumours. A neuroectodermal origin of the SNC-and hence appendiceal carcinoid tumours-is proposed.

The fine structure of a neuroendocrine complex within the lamina propria of the human appendix is described. This complex contains four types of neurosecretory cells, occasional neurons, Schwann cells, and numerous nerve processes, including axons with varicose swellings. Few of the axons form true synapses, but many make some junctional contact with the neurosecretory cells and with other nerve processes. From the morphology of their vesicles, most of the nerve fibers appear to belong to the peptidergic component of the enteric nervous system. The mucosal neuroendocrine complex appears to be an integral part of the mucosal nervous plexus.

Monoamine oxidase (MAO) in lung and liver is important in the degradation of circulating 5-hydroxytryptamine. These sites of MAO activity have been investigated histochemically in the human fetus of 12 to 18 weeks gestation. Enzyme activity could be demonstrated in the liver by both tryptamine and adrenaline oxidation. In the lung, MAO activity was present only when adrenaline was used to substrate. It may be, therefore, that in the premature baby the capacity of MAO to metabolize 5-hydroxytryptamine is not fully developed, which could lead to deleterious effects on pulmonary function.