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Biomedical subjects

M N Marsh

Publications and source records attributed to M N Marsh.

At least 19 recordsLinked to original sources
PubMed2002

Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease.

Susceptibility to coeliac disease involves HLA and non-HLA-linked genes. The CTLA4/CD28 gene region encodes immune regulatory T-cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta-analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non-parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0.004 and 0.039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0.0001 and 0.0014 at D2S2214, respectively, and 0.0008 and 0.0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.

Abatacept↗
PubMed2001

Diagnosing coeliac disease by rectal gluten challenge: a prospective study based on immunopathology, computerized image analysis and logistic regression analysis.

The purpose of this study was to evaluate the use of rectal gluten challenge in the diagnosis of coeliac disease. A total of 103 patients with features suggestive of this diagnosis were prospectively enrolled into the study; a diagnosis of coeliac disease was based on strictly defined criteria used in judging the proximal jejunal biopsy. On that basis, 45 out of the 103 patients were deemed to have coeliac disease. A slurry of gluten powder in physiological saline was introduced into the rectum, and biopsies taken before and at 2 h or 4 h after the challenge were examined immunohistochemically by computerized image analysis. Cell counts were analysed by logistic regression, and the best equations were obtained for each challenge group. The 2 h challenge yielded diagnostic sensitivity and specificity of 69.6% and 78.6% respectively. The 4 h challenge provided sensitivity and specificity of 100% and 100% respectively. These results were compared with other clinical diagnostic predictors,including anti-endomysial antibodies, which yielded diagnostic sensitivity and specificity of 70% and 98% respectively. It is concluded that a 4 h rectal challenge is a highly sensitive means of identifying gluten-sensitized individuals, and would be of particular value in cases showing negative antibody screening or equivocal biopsy appearances.

Adult↗
PubMed1998

Studies in vivo of omega-gliadins in gluten sensitivity (coeliac sprue disease).

1. Highly purified omega-gliadins from wheat were used to challenge gluten-sensitized individuals. Characteristic responses by mucosal CD3(+) and gamma delta+ lymphocytes were demonstrated. Each lymphocyte subset showed an increase within 8-12 h post-challenge, indicating a specific response by the rectal mucosa to this gliadin species.2. Available sequence data for the omega-gliadins and homologous proteins from barley and rye indicate a common repeating octapeptide motif (consensus PQQPFPQQ). The results indicate, therefore, that the octapeptide repeat, or a contained sequence such as PQQP, plays an important role in the mucosal immunopathology of gluten sensitivity.

CD3 Complex↗
PubMed1997

Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge.

Activation of T cells in the intestinal mucosa in response to gluten exposure is thought to play a key role in the pathogenesis of coeliac disease. Moreover, the response of the rectal mucosa to gluten challenge has been considered a useful predictor of gluten sensitivity in coeliac disease. In the present study, we assessed early changes in the expression of proinflammatory cytokine genes and the T cell receptor (TCR) Vbeta repertoire in the rectal mucosa of coeliac disease patients following experimental gluten challenge. Cytokine gene expression was assessed in rectal mucosal biopsies from coeliac disease subjects and controls before and after rectal gluten challenge using quantitative reverse transcription polymerase chain reaction analysis, and the TCR Vbeta repertoire was characterized using a multiprobe RNase protection assay. Marked up-regulation of expression of the C-X-C chemokine IL-8, the proinflammatory cytokine IL-1beta, and the C-C chemokine monocyte chemotactic protein-1 occurred within 24 h of rectal gluten challenge in coeliac disease subjects, but not in controls. Furthermore, these changes occurred in the absence of parallel changes in the expressed repertoire of TCR Vbeta genes in the rectal mucosa. Thus, an increased expression of proinflammatory cytokine genes precedes the expansion of antigen-specific T cell populations in the early period following experimental exposure of the rectal mucosa of coeliac disease patients to gluten. These findings provide new insights into pathways that may be involved in the activation or reactivation of coeliac disease.

Administration, Rectal↗
PubMed1997

Linkage analysis of candidate regions for coeliac disease genes.

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.

Celiac Disease↗
PubMed1995

Morphology of the mucosal lesion in gluten sensitivity.

Gluten sensitivity is associated with a spectrum of mucosal lesions, arbitrarily termed pre-infiltrative, infiltrative-hyperplastic, flat-destructive and atrophic-hypoplastic. Histologically and immunohistologically these lesions are all compatible with T-cell-driven events operative at a local mucosal level. They are classifiable either in terms of antibody titres (pre-infiltrative) (see Chapter 10) or by the characteristic disposition of IELs throughout the surface and crypt epithelium. From in-vivo challenges, it has been demonstrated: (i) that all these lesions comprise a dynamically interrelated series of events, culminating in the severe flat-destructive lesion; and (ii) that gluten evokes a dose-responsive infiltration of IELs (CD3+ CD8+ and TCR alpha beta + or gamma delta +) into the epithelium. Apart from that, little is known of the functions of IELs; it is possible they may have little to do with the evolving mucosal pathology of gluten sensitivity. Increasing work seems to support a view, proposed from this laboratory over 10 years ago, that the immune-mediated responses in jejunal tissue in gluten sensitivity arise in the lamina propria, in association with DR+ macrophages and an abundance of CD4(+)-activated lymphocytes. Many other inflammatory consequences flow from these interactions, involving activation of mast cells, eosinophils and neutrophils, elaboration of cytokines and other products of inflammation, and increased hyperpermeability of the microvasculature with upregulation of adhesion molecules. The result is a doubling of lamina propria volumes in the severe flat lesion. Evidence is also given to show that measurable changes in lamina propria inflammation occur with the infiltrative-hyperplastic lesion. Symptomatology is not related to the degree of proximal mucosal pathology, but to the extent of the mucosal lesion. Data, although scanty, suggests that lesional pathology involves only 30-50% of the entire small bowel mucosa. Thus, most patients, irrespective of proximal mucosal damage, have latent (or asymptomatic) gluten sensitivity. Symptom development requires additional environmental triggers, of which infection is a major contributor. It should also be noted that, while these various environmental triggers may precipitate symptomatology, they do not advance the severity of the mucosal lesion.

Celiac Disease↗
PubMed1994

Morphometric analysis of intestinal mucosa. VI--Principles in enumerating intra-epithelial lymphocytes.

The mucosal response by intra-epithelial lymphocytes (IEL) to antigenic challenge is a useful monitor of local immune activity. Conventional counts of IEL (determined as profile ratios of IEL to enterocyte nuclei) are inaccurate, and over-estimate values by a factor of two, both for disease-control mucosae and untreated 'flat' gluten-sensitized mucosae. Two further proofs are advanced in this paper which expose the inaccuracy of conventional profile-density IEL counts. New ranges (log-transformed data) indicate a disease-control mean of 11 IEL per 100 enterocytes (95% confidence limits 5-27) and 29 IEL per 100 enterocytes (95% confidence limits 14-61) for untreated flat gluten-sensitive mucosae. For simplicity, if conventional IEL "counts" are halved, correct values (based on precise morphometric analyses) are easily obtained for comparative and other purposes.

Cell Count↗
PubMed1994

Screening and monitoring coeliac disease: multicentre trial of a new serum antibody test kit.

A multicentre trial was conducted to evaluate a new test for anti-gliadin antibodies (AGA) in serum (Coeliac Screening Kit, CSK, Medical Innovations Limited, Artarmon, NSW, Australia). The test showed excellent reproducibility for both anti-gliadin IgA and IgG detection. The average intraassay coefficient of variation (CV) was 3.0% for IgA and 2.4% for IgG (n = 6), while the average interassay CV was 6.4% for IgA and 4.3% for IgG (n = 3). By defining a positive test as both IgA and IgG elevated, a sensitivity of 93% in untreated coeliacs (n = 75) was observed. The corresponding specificities in healthy adults (n = 130) and healthy children (n = 77) were > 99% and 100% respectively, while in patients with other gastrointestinal disorders (disease controls) the specificity was 94% (n = 129). The test was also useful in monitoring patients, with anti-gliadin IgA and IgG falling for up to a year after commencing a gluten-free diet (GFD) (12 adults). In some patients however, antibody levels did not reach the normal cutpoint after many months on a GFD, which may reflect the patients' poor adherence to their gluten free diet. The test was superior to the Pharmacia anti-gliadin ELISA, and should be useful as an aid to the diagnosis of coeliac disease, as well as in the follow-up of treated patients.

Adult↗
PubMed1993

Morphometric analysis of small intestinal mucosa. IV. Determining cell volumes.

This study was concerned with the measurement of volumes of surface epithelial cells in human small intestine, both in disease-control subjects and, for comparison, in patients with gluten sensitivity. Four procedures were employed, of which two were geometrical, based on cylindrical or truncated conoid models. The third method evolved from the proportionality of area to volume, and required determination of cellular and nuclear profile areas, and an estimation of nuclear volume based on models conforming to (1) a prolate spheroid, or (2) a cylinder with hemispherical caps. This procedure appeared to underestimate enterocyte volumes and failed to reveal volume differences between controls and gluten-sensitive individuals. Finally, a fourth method was devised, based on traditional intraepithelial profile counts per hundred enterocyte nuclei, calculation of surface epithelial volume and of the absolute number of lymphocytes contained therein. Enterocyte volumes appeared to be overestimated twofold by this procedure compared with the first two geometric methods. The results of this study indicate that the cuboidal-type enterocyte profiles typical of the untreated mucosa in gluten sensitivity are a reflection of cells with a reduced volume. From the number of enterocytes and the absolute lymphocyte population present within a morphometrically defined volume of surface epithelium, the ratios of intraepithelial lymphocytes to enterocytes were found to be 50% less than conventional density-profile counts.

Adult↗
PubMed1993

Observations of the time-course of the inflammatory response of rectal mucosa to gliadin challenge in gluten-sensitive subjects.

Expression of endothelial adhesion molecules is a key factor in localizing inflammatory processes. We have evaluated the time-course expression of E-selectin, ICAM-1, and VCAM-1 in rectal mucosae from coeliac patients (CD) with T-lymphocyte sensitization to wheat (gliadin) protein. Ten treated, eight untreated CD patients and five disease controls underwent a dynamic 4 h rectal gluten challenge. Seven treated CD patients had a 24 h challenge to evaluate the time-course changes. Coeliac tissue significantly increased VCAM-1 expression [p < 0.001 (untreated and treated CD)] and E-selectin [p = 0.01 (untreated CD only)]-expression compared to controls but not ICAM-1. VCAM-1 continued to increase up to 24 h, while E-selectin decreased after 4 h. These findings relate to a 8 h rise in CD3 (+) lymphocytes [p < 0.05 (treated)] and a 4 h rise in neutrophils (p < 0.005). This approach permits a novel study of the inflammatory response to a known immunogen in human patients.

Celiac Disease↗