Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’)

Elastomeric biomaterials for tissue engineering

Mast cells appear to promote fibroblast proliferation, presumably through secretion of growth factors, although the molecular mechanisms underlying this mitogenic potential have not been explained fully by known mast cell-derived mediators. We report here that tryptase, a trypsin-like serine proteinase of mast cell secretory granules, is a potent mitogen for fibroblasts in vitro. Nanomolar concentrations of dog tryptase strongly stimulate thymidine incorporation in Chinese hamster lung and Rat-1 fibroblasts and increase cell density in both subconfluent and confluent cultures of these cell lines. Tryptase-induced cell proliferation appears proteinase-specific, as this response is not mimicked by pancreatic trypsin or mast cell chymase. In addition, low levels of tryptase markedly potentiate DNA synthesis stimulated by epidermal growth factor, basic fibroblast growth factor, or insulin. Inhibitors of catalytic activity decrease the mitogenic capacity of tryptase, suggesting, though not proving, the participation of the catalytic site in cell activation by tryptase. Differences in Ca++ mobilization and sensitivity to pertussis toxin suggest that tryptase and thrombin activate distinct signal transduction pathways in fibroblasts. These data implicate mast cell tryptase as a potent, previously unrecognized fibroblast growth factor, and may provide a molecular link between mast cell activation and fibrosis.

/pdf/mast-cell-tryptase-is-a-mitogen-for-cultured-fibroblasts-4a7vznajqb.pdf

Mast cell tryptase is a mitogen for cultured fibroblasts.

Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.

/pdf/gluten-sensitivity-from-gut-to-brain-mz3xmwlhvj.pdf

Gluten sensitivity: from gut to brain

Angiogenesis is tightly regulated by pro- and anti-angiogenic factors. Secreting mast cells are able to induce and enhance angiogenesis via multiple in part interacting pathways. They include mast cell-derived (i) potent pro-angiogenic factors such as VEGF, bFGF, TGF-beta, TNF-alpha and IL-8, (ii) proteinases and heparin, that release heparin-binding pro-angiogenic factors lodged on cell surfaces and in the extracellular matrix (ECM), (iii) histamine, VEGF, and certain lipid-derived mediators that induce microvascular hyperpermeability having pro-angiogenic effects, (iv) chemotactic recruitment of monocytes/macrophages and lymphocytes that are able to contribute with angiogenesis-modulating molecules, (v) activation of platelets that release pro-angiogenic factors, (vi) activation of neighboring stationary non-mast cells, which secrete pro-angiogenic factors, ECM-degrading proteinases and stem cell factor which attracts, mitogenically stimulates and activates mast cells, (vii) auto- and paracrine stimulation of mast cells by stem cell factor, (viii) recruitment of mast cells by pro-angiogenic factors such as VEGF, bFGF and TGF-beta. As a result of ECM-degradation and changes in the microenvironment following initial mast cell secretion, the mast cell populations may change significantly in number, phenotype and function. In tumor models, mast cells have been shown to play a decisive role in inducing the angiogenic switch which precedes malignant transformation. There is, moreover, strong evidence that mast cells significantly influence angiogenesis and thus growth and progression in human cancers.

Mast cells and angiogenesis.

The effect of mast cell activation and degranulation on the proliferation in the intact mesentery was studied in Sprague-Dawley rats. Mast cell activation was achieved by a single intraperitoneal injection of Compound 48/80. The proliferation was studied using three independent methods for estimation of cell production and DNA synthesis: 1. the mitotic index, 2. the relative number of cells having a DNA content in the S and G2 regions, by Feulgen photometric measurement in individual cells, and 3. the specific DNA activity, employing a method which combines a liquid scintillation technique after an intravenous injection of 3H-thymidine and Feulgen photometric determination of the DNA content per membrane preparation. It was found that the proliferation of the normal mesenchymal cells adjacent to the activated and degranulated mast cells in the mesentery was significantly increased within 24 and 32 h, the maximum increase being more than 20-fold compared to untreated controls. The results suggest that the common type of mast cell may have a pathophysiological function related to stimulation of local cell proliferation.

Mast cell activation and tissue cell proliferation.

Gastrointestinal investigation of 14 adult patients with polymyositis disclosed coeliac disease in five. The inflammatory myopathy in our patients is not the same as the myopathy often seen in coeliac disease with osteomalacia. One patient has been free from both gastrointestinal and muscular symptoms for 5 years on a gluten-free diet alone. The findings strongly suggest an association between polymyositis and adult coeliac disease.

Polymyositis and adult coeliac disease

The occurrence of coeliac disease has been less recognized among adults than in children. We have examined the prevalence of adult coeliac disease in a defined population in Sweden, on the basis of results obtained during 7 years' gastroenterological routine practice. On 1 July 1979, the overall prevalence rate was found to be 58/100, 000 (1:1700). The age-adjusted rates were unevenly distributed. The peak rate, 130/100, 000 (1:750), appearing in the age interval of 45–54 years, indicates that unrecognized middle-aged coeliacs are not symptom-free and that they can be found in routine practice. Our peak rate of coeliac disease unaccompanied by dermatitis herpetiformis is in the same range as the rate found in Swedish children.

On the Prevalence of Adult Coeliac Disease in Sweden

An intact tissue model which can be used for detailed microscopic studies, quantitative cytochemical analysis and biochemical analysis has been explored, using a number of cell proliferation parameters. The preparations consist of mesenterial “windows” from rats dispersed on object slides. A technique for determining, in one and the same preparation, DNA content and mitotic activity of individual, selected cell types, and DNA synthesis in terms of incorporation of tritiated thymidine into DNA is described.

A tissue model for the study of cell proliferation parameters in vivo.

The influence of thyroid remnant size, antithyroid antibody titre, thyroid morphology, and lymphocyte infiltration on postoperative thyroid function was studied in 179 patients undergoing subtotal thyroidectomy because of hyperthyroidism. The surgical procedure was strictly standardized and included determination of the thyroid remnant size. The preoperative medication used was beta-adrenoceptor blocking agents in 101 patients and antithyroid drugs and thyroxine in 78. With remnant size adjusted to 6–10 g (or, in goiters less than 20 g, to 25–30% of initial gland weight), the overall recurrence rate after 2–8 years (mean 5.3±2.0) of follow-up was 1.7% and the incidence of thyroid hypofunction was 29.6%. 
In toxic nodular goiter (TNG; n=63), a significant negative correlation was found between TSH and remnant size after 12 months as well as a significantly lower remnant weight in patients developing postoperative hypothyroidism. In toxic diffuse goiter (TDG; n=116), there was no difference in remnant size between euthyroid and hypothyroid patients. For patients with TDG treated preoperatively with beta-blockers, the incidence of autoantibodies against thyroid cytoplasm was increased in patients who postoperatively developed thyroid dysfunction. Within the group of TDG developing hypofunction, we found increased titre of autoantibodies and “presence of lymphoid tissue” more often in patients treated preoperatively with beta-blockers compared to thyrostatics. In toxic nodular goiter, the remnant size was considered the parameter most helpful to the surgeon in predicting postoperative thyroid function.

The influence of remnant size, antithyroid antibodies, thyroid morphology, and lymphocyte infiltration on thyroid function after subtotal resection for hyperthyroidism.

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