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Biomedical subjects

M N Marsh

Publications and source records attributed to M N Marsh.

At least 73 records · Page 4Linked to original sources
PubMed1985

Functional and structural aspects of the epithelial lymphocyte, with implications for coeliac disease and tropical sprue.

Epithelial lymphocytes comprise a compartmentalised and specialised population of presumed effector cells which, in general, express the surface phenotypes (Lyt-2+; OX2+; OKT8+) of suppressor/cytolytic (Ts/c) cells. Granular cells within this population (gEL) morphologically resemble the circulating large granular lymphocytes (LGL) which subserve spontaneous (NK) cytolytic activity. Recent in vitro results indicate that gEL can develop this function after prolonged in vitro culture; the relevance of this, in vivo, remains to be decided. EL also appear to be able to mediate ADCC with sIgA against enteric micro-organisms. This is the kind of integrated activity that might be anticipated from local immunocytes within the intestinal mucosa. Other recent work suggests that gEL are not precursors of mucosal mast cells. EL also appear to be capable of inducing Ia-like expression in surface and crypt enterocytes, a property enjoyed both by highly purified Th, but also Ts/c, cells as well. This raises the interesting prospect that enterocytes may display antigen in macrophage-like fashion to other adjacent cells within the inter-epithelial cell spaces. These latter observations might be more consistent with the presence of 'activated' and 'blast-transformed' lymphocytes in such conditions as coeliac disease and tropical sprue. Another emergent view that demands appropriate attention is that the infiltrate of Ts/c cells into surface, and crypt, epithelium of coeliac mucosa does not necessarily cause injury or damage to the jejunal tissues. Nevertheless the role, either primary or secondary, that EL play either in coeliac disease or tropical sprue still remains obscure.

Celiac Disease↗
PubMed1984

Morphometric analysis of small intestinal mucosa. II. Determination of lamina propria volumes; plasma cell and neutrophil populations within control and coeliac disease mucosae.

Morphometric techniques were employed to measure (i) lamina propria volumes and (ii) the absolute numbers of neutrophils and plasma cells, of A, M and G isotype, within the lamina propria of jejunal mucosa. Mucosal specimens were obtained with a Watson capsule (a) from 5 patients with untreated coeliac disease, and again at least 3 months after starting on a gluten-free diet, and (b) from 9 control individuals. Lamina propria volume of untreated coeliac mucosa (2.5 +/- 0.17 X 10(6) micron3 ) was increased 2.3-fold (p less than 0.01) above that of control mucosae (1.35 +/- 0.08 X 10(6) micron3 ). Compared with control mucosae, there was a 20-fold increase of neutrophils in untreated coeliac mucosae (p less than 0.005). The total complement of all plasma cells in untreated coeliac mucosae (309) was twice that (149) of control mucosae. The populations of each isotype were also significantly increased over controls by factors of 1.6 (IgA; p less than 0.05), 3.0 (IgM; p less than 0.01) and 3.5 (IgG; p less than 0.01). Their percentage distributions in untreated coeliac mucosae (A:M:G--52:43:5) differed from those in control mucosae (A:M:G--69:28:3) but were restored after treatment with a gluten-free diet. However, when each isotype was expressed per unit volume of lamina propria, there was an apparent fall (X 1.4) in IgA cells, while the increase in IgM and IgG cells was less marked i.e. X 1.4 and X 1.5 respectively. These precise measurements explain why many previous investigators found a paradoxical fall in IgA cells because the (increased) volume of distribution of these cells was not taken into account. The importance of morphometric techniques in achieving valid cell 'counts' within the intestinal mucosa is thus illustrated by this study.

Celiac Disease↗
PubMed1984

Morphometric analysis of small intestinal mucosa. I. Methodology, epithelial volume compartments and enumeration of inter-epithelial space lymphocytes.

Morphometric techniques for quantitating cytologic and volumetric changes in small intestinal mucosae are described: measurements were controlled with respect to a constant 'test area' of muscularis mucosae, thus following valid comparisons between normal and damaged mucosae. Procedures for enumerating cell populations within mucosal volume compartments are illustrated by analyzing lymphocytes within surface epithelium. These techniques serve to distinguish (i) absolute cell counts from (ii) relative cell counts ("densities") the latter being shown to be considerably affected by changes in epithelial volume. They also permit construction of mathematical models e.g. cubes of equivalent volume, volume-density graphs, proportional volumes, which are illustrated. Use of these morphometric procedures showed that there is no major difference in epithelial lymphocyte populations between untreated coeliac disease, and control, mucosae. The data thus fail to support the widespread view that "infiltration" of coeliac disease epithelium by lymphocytes represents a local cell-mediated immune reaction to gluten.

Celiac Disease↗
PubMed1983

Studies of intestinal lymphoid tissue. VI--Proliferative response of small intestinal epithelial lymphocytes distinguishes gluten- from non-gluten-induced enteropathy.

Several diseases of the small intestine, including gluten-sensitivity, present with malabsorption and a "flat" mucosa. Determination of the mitotic index of epithelial lymphocytes provides a simple, objective method of assessing, and thus of predicting, whether a flat mucosa is due to gluten-sensitivity (index greater than 0.2%), or not (index less than 0.2%). The use of this index in circumstances especially likely to cause diagnostic confusion--for example, intestinal lymphoma; Crohn's jejunitis of immunodeficiency--is illustrated in this paper. Of seven cases, five (two primary lymphoma, three immunodeficiency) had been treated with a gluten-free diet without benefit; a mitotic index performed on the initial biopsy in each of these patients could have predicted from the outset that none was gluten-sensitive. Of the remaining two cases, determination of the mitotic index on the biopsy initially obtained from a man with severe hypogammaglobulinaemia would have indicated that he was also gluten-sensitive. Empirical use of a gluten-free diet was avoided in the other patient (with flat small intestinal mucosa and low mitotic index) in whom the diagnosis was ultimately shown to be due to Crohn's disease of jejunum.

Adolescent↗
PubMed1983

Studies of intestinal lymphoid tissue. VII. The secondary nature of lymphoid cell "activation" in the jejunal lesion of tropical sprue.

Morphometric techniques were used in the evaluation of lymphocyte morphology and activity in tropical sprue. jejunal biopsies from control subjects (8), patients with epidemic disease (7), patients with endemic disease (11), and subjects who had recovered from sprue (4) were analyzed blindly. In patients with sprue, lymphocytes were increased significantly within crypt (but not surface) epithelium. Immunoblasts (greater than 6 mu in diameter) were increased by 5% over control subjects. Group means for lymphocytic mitotic indexes were also significantly raised, while flux ratios only differed significantly between endemic sprue patients and control subjects. The lymphocytic infiltration was distributed focally in the upper crypt and crypt-villus interzones. Analysis of epidemic cases (presenting within 4-28 days) revealed detectable changes in lymphocyte behavior only after 3 weeks' illness, whereas mucosal lesions and malabsorption were already established during the first week. These data indicate that lymphocyte activation, suggestive of a local cell-mediated immune reaction, does occur in tropical sprue but is secondary to damage already inflicted on enterocytes and their function.

Adult↗
PubMed1982

Studies of intestinal lymphoid tissue. IV--The predictive value of raised mitotic indices among jejunal epithelial lymphocytes in the diagnosis of gluten-sensitive enteropathy.

It has been established that considerable blast-transformation and mitotic activity occurs among epithelial lymphocytes of untreated coeliac mucosa. This paper is concerned solely with the proliferative activity of epithelial lymphocytes (expressed as percentage "mitotic index") in the prospective diagnosis of coeliac disease, in comparison with other conditions such as lymphoma. Crohn's disease and immunodeficiency which are often associated with malabsorption and flattening of jejunal mucosa. The results demonstrate that a high mitotic index (greater than 0.2%) clearly distinguishes, and hence predicts, gluten-associated enteropathies (including dermatitis herpetiformis and malignant histiocytosis) from others in which gluten plays no aetiological role and where the mitotic index differs insignificantly from normal control mucosae (much less than 0.2%). Furthermore, it has been demonstrated that the mitotic index is raised in so-called "non-responsive coeliacs," thus suggesting that such patients may also be gluten-sensitive despite their subsequent failure to respond morphologically to dietary gluten restriction.

Adolescent↗
PubMed1981

Studies of intestinal lymphoid tissue: the cytology and electron microscopy of gluten-sensitive enteropathy, with particular reference to its immunopathology.

Knowledge of the cytology, ultrastructure and histochemistry of the small intestinal mucosa has advanced considerably over the last 20 years, particularly in regard to the changes associated with coeliac disease. Many of the known structural and cytological changes in coeliac mucosa are probably non-specific, and not directly related to its pathogenesis. It seems important to move away from purely descriptive images of mucosal abnormality such as "villous atrophy', and static measurements, such as crypt-villous ratios. Rather, the mucosa should be viewed as a dynamic, three-dimensional structure and evaluated in terms of total villous cell counts, crypt cell production rates, and so on. The organisation of the lamina propria is still poorly documented, and requires further exploration at the ultrastructural level. More thought should be given to the meaning of mucosal permeability and to its structural counterparts. The immunocytopathology of the coeliac lesion is far from understood; it is questionable whether local humoral activity is central to the pathogenesis of the condition. More needs to be learned of the role of T cells, not only in local mucosal reactions, but also in terms of possible regulatory effects on crypt cell kinetics, villous shape and hence mucosal structure. Increased mitotic activity of epithelial lymphocytes in coeliac disease appears to correlate exclusively with gluten-sensitivity and the use of this presumed immunological marker in the histological diagnosis, and thus prediction, of gluten-sensitised individuals is proposed in this paper.

Basement Membrane↗
PubMed1980

Studies of intestinal lymphoid tissue. III. Quantitative analyses of epithelial lymphocytes in the small intestine of human control subjects and of patients with celiac sprue.

To investigate the morphology and proliferation of small intestinal lymphocytes, 1-micrometer sections of Epon-embedded jejunum from 14 control subjects and 5 celiac sprue patients were studied by light microscopy. Results showed that: (a) Epithelial lymphocytes were of significantly greater diameter in untreated, compared with treated, celiacs (P < 0.001), and comprised 5% more cells > 9 micrometer diameter compared with control mucosa. (b) Mitotic indices of epithelial lymphocytes were considerably raised in untreated sprue, and a brisk rate in accumulation of metaphase-arrests was observed during a 4-hr period of colchicine administration; after treatment, proliferative activity fell steeply, but not to the zero levels found in controls. (c) "Areal densities" (number of lymphocytes subtended by unit area of muscularis mucosae) were reduced in untreated patients (P < 0.02) and increased to control levels after treatment. "Flux ratios" (number of epithelial lymphocytes penetrating basal lamina/unit area muscularis divided by "areal density") were greater in untreated, than treated, specimens (P < 0.005) suggesting that in untreated sprue, there is increased traffic of lymphocytes across basal lamina. Thus celiac epithelium contains fewer, but significantly larger lymphocytes that exhibit heightened mitotic activity; greater numbers of lymphocytes also appear to be in transit across the basal lamina. With the exception of mitotic activity, all other observed changes were completely reversed by gluten withdrawal.

Adolescent↗
PubMed1978

Computed tomographic scanning in liver disease.

The non-invasive diagnostic technique of computed tomograph (CT) has been assessed in 100 patients with established liver disease. CT can differentiate extra- from intrahepatic cholestasis and may define the obstructing lesion in the former group. It is of value in detecting infiltrations with fat or iron, and provides useful information in patients with cirrhosis and metastatic deposits. At present it appears of less value in the diagnosis of non-fibrotic parenchymal liver disease.

Chronic Disease↗
PubMed1978

Computed tomography, ultrasound, and cholestatic jaundice.

Computed tomography detected the presence of dilated ducts in 15 of 18 cases with extrahepatic obstructive jaundice and demonstrated the obstructing lesion in 18 out of 25. The cause of the obstruction was detected in the absence of duct dilatation, and calculi which were radiolucent on conventional radiographs were demonstrated. Ulstrasound detected dilated ducts in eight of 10 cases, but demonstrated the cause of the obstruction in only one of 13 cases. Both techniques are capable of demonstrating dilated ducts in the majority of cases, but computed tomography is better at detecting the cause of the obstruction.

Bile Duct Neoplasms↗
PubMed1975

Studies of intestinal lymphoid tissue. I. Electron microscopic evidence of 'blast transformation' in epithelial lymphocytes of mouse small intestinal mucosa.

The morphology of epithelial lymphocytes in osmium-fixed, Epon-embedded jejunum of adult mice was studied by light and electron microscopy. Toluidine blue-stained 1 mum 'thick' plastic sections were compared with adjacent thin sections, thereby permitting precise ultrastructural identification and description of selected epithelial lymphocytes. Their size and appearances varied considerably, ranging from typical small lymphocytes through medium-sized lymphocytes to large immunoblasts. A high proportion of medium-sized epithelial lymphocytes (mean diameter 6-9 +/- 1-1 mum) contained several lysosomes, extensive Golgi complexes, prominent centrioles and abundant ribosomes. Their appearances, therefore, corresponded directly to mitogen-stimulated lymphocytes. In contrast, immunoblasts were big cells (mean diameter 11-0 +/- 0-8 mum) with large, euchromatic nuclei and prominent nucleoli. The majority had pale-staining, ribosome-studded cytoplasm and thus resembled type I, or T blasts. Very rarely, densely staining blasts containing ribosomes and well developed rough endoplasmic reticulum were observed; these corresponded to type II or B blasts. These observations indicate that transformation of lymphocytes occurs within the interepithelial cell spaces of the small intestinal mucosa, suggesting that epithelial lymphocytes are immunocompetent cells which may be responsive to local antigenic stimulation.

Animals↗
PubMed1975

Studies of intestinal lymphoid tissue. II. Aspects of proliferation and migration of epithelial lymphocytes in the small intestine of mice.

Mice were given either intraperitoneal tritiated thymidine (3H-Tdr) or colchicine to study proliferation and migration of intestinal epithelial lymphocytes. Both labelled medium and large lymphocytes ('immunoblasts') were observed throughout the epithelium, crossing the basement membrane and within villous lymphatics for at least seven days after 3H-Tdr administration. Epithelial lymphocytes are predominantly young cells, actively dividing at the rate of 1% per hour. They do not migrate along the villi, unlike epithelial cells, but circulate rapidly through the epithelium, returning to the lamina propria at the rate of approximately 3 epithelial lymphocytes/1000 epithelial cell nuclei/hour. The labelling pattern of epithelial lymphocytes and intralymphatic cells with time was very similar suggesting that epithelial lymphocytes therefore may directly enter adjacent lymphatics and hence gain access to thoracic duct lymph.

Animals↗