Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment. METHODS: Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used RESULTS: Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p < 0.02), and in mannan binding lectin (MBL)-concentration and MBL-C4-activation capacity (AC) values compared to UC patients (p < 0.02). Before treatment, plasma from UC patients showed significant elevations only in the classical pathway-mediated C3-AC compared to values obtained from healthy controls (p < 0.01). After treatment was initiated, significant reductions, which persisted during follow-up, were observed in the classical pathway-mediated C3-AC and MBL-C4-AC in plasma from CD patients (p < 0.05). CONCLUSION: Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation

Rapid Accumulation of CD14+CD11c+ Dendritic Cells in Gut Mucosa of Celiac Disease after in vivo Gluten Challenge

Of antigen-presenting cells (APCs) expressing HLA-DQ molecules in the celiac disease (CD) lesion, CD11c(+) dendritic cells (DCs) co-expressing the monocyte marker CD14 are increased, whereas other DC subsets (CD1c(+) or CD103(+)) and CD163(+)CD11c(-) macrophages are all decreased. It is unclear whether these changes result from chronic inflammation or whether they represent early events in the gluten response. We have addressed this in a model of in vivo gluten challenge.Treated HLA-DQ2(+) CD patients (n = 12) and HLA-DQ2(+) gluten-sensitive control subjects (n = 12) on a gluten-free diet (GFD) were orally challenged with gluten for three days. Duodenal biopsies obtained before and after gluten challenge were subjected to immunohistochemistry. Single cell digests of duodenal biopsies from healthy controls (n = 4), treated CD (n = 3) and untreated CD (n = 3) patients were analyzed by flow cytometry.In treated CD patients, the gluten challenge increased the density of CD14(+)CD11c(+) DCs, whereas the density of CD103(+)CD11c(+) DCs and CD163(+)CD11c(-) macrophages decreased, and the density of CD1c(+)CD11c(+) DCs remained unchanged. Most CD14(+)CD11c(+) DCs co-expressed CCR2. The density of neutrophils also increased in the challenged mucosa, but in most patients no architectural changes or increase of CD3(+) intraepithelial lymphocytes (IELs) were found. In control tissue no significant changes were observed.Rapid accumulation of CD14(+)CD11c(+) DCs is specific to CD and precedes changes in mucosal architecture, indicating that this DC subset may be directly involved in the immunopathology of the disease. The expression of CCR2 and CD14 on the accumulating CD11c(+) DCs indicates that these cells are newly recruited monocytes

The asthma epidemic and our artificial habitats

BACKGROUND: The recent increase in childhood asthma has been a puzzling one. Recent views focus on the role of infection in the education of the immune system of young children. However, this so called hygiene hypothesis fails to answer some important questions about the current trends in asthma or to account for environmental influences that bear little relation to infection. DISCUSSION: The multi-factorial nature of asthma, reflecting the different ways we tend to interact with our environment, mandates that we look at the asthma epidemic from a broader perspective. Seemingly modern affluent lifestyles are placing us increasingly in static, artificial, microenvironments very different from the conditions prevailed for most part of our evolution and shaped our organisms. Changes that occurred during the second half of the 20th century in industrialized nations with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance). Asthma according to this view is a manifestation of our respiratory maladaptation to modern lifestyles, or in other words to our increasingly artificial habitats. The basis of the artificial habitat notion may lie in reduced exposure of innate immunity to a variety of environmental stimuli, infectious and non-infectious, leading to reduced formulation of regulatory cells/cytokines as well as inscribed regulatory pathways. This could contribute to a faulty checking mechanism of non-functional Th2 (and likely Th1) responses, resulting in asthma and other immuno-dysregulation disorders. SUMMARY: In this piece I discuss the artificial habitat concept, its correspondence with epidemiological data of asthma and allergy, and provide possible immunological underpinning for it from an evolutionary perspective of health and disease

Accumulation of immunoglobulin-containing cells in the gut mucosa and presence of faecal immunoglobulin in severe combined immunodeficient (scid) mice with T cell-induced inflammatory bowel disease (IBD)

Scid mice transplanted either with a gut wall graft or with low numbers of purified CD4+ T cells from immunocompetent syngeneic donor mice show clinical signs of IBD 3–4 months post-transplantation. The disease is mediated by mucosa-infiltrating CD4+ TCRαβ+ T cells. The pathology of 52 individual colon segments obtained from 20 gut wall- or CD4+ T cell-transplanted diseased scid mice was evaluated by histology and the numbers of infiltrating immunoglobulin-containing cells were determined. In particular, cells positive for IgM, IgA and non-inflammatory immunoglobulin isotypes such as IgG1 and IgG2b were found to accumulate in colon segments displaying the most severe histopathology, including inflammatory cellular infiltration, epithelial hyperplasia and ulcerative lesions. Compared with colon segments of normal C.B-17 mice, the lesional scid colon shows increased levels of cells positive for the IgG classes. Faecal extracts of the CD4+ T cell-transplanted scid mice revealed the presence of all six murine immunoglobulin isotypes. Disease progression was accompanied by an increased level of excreted IgM and IgG3 and decreased levels of IgA. It is concluded that locally secreted immunoglobulins may play an immunomodulating role in the pathological changes observed in the present model of T cell-induced inflammatory bowel disease

Detection of complement C3 and factor B gene expression in normal colorectal mucosa, adenomas and carcinomas

Local secretion of complement components in the human intestine has been previously reported. However, the cellular source has not been identified. In this study, we demonstrate complement C3 and factor B mRNA expression in the normal colonic mucosa by in situ hybridization analysis. C3 and factor B genes were found to be expressed at high levels in the epithelial cells of the lower parts of the crypts in colonic mucosa, and this expression decreased gradually from the crypt base to the luminal surface. At the upper crypt and the luminal surface, these genes almost disappeared. C3 and factor B genes were expressed in all crypts at the same level. Furthermore, C3 and factor B gene expression was also identified in adenomas and carcinomas. In these neoplastic tissues, C3 and factor B genes were expressed uniformly, and the polarized distribution observed in the normal crypts was not detected. It is likely that complement components are locally synthesized in the intestine, and that these complement components may actively participate in normal immune and inflammatory responses over the enormous surface area of the intestinal mucosa

Immunohistochemical analysis of coeliac mucosa following ingestion of oats

There is now considerable clinical evidence that oats do not activate coeliac disease. Nonetheless, a reluctance to include oats in the gluten-free diet remains. Because gluten-induced damage is accompanied by activation of the gastrointestinal immune system, the purpose of this study was to investigate if similar changes were induced by oats ingestion. Small intestinal histological sections from 10 patients who ingested 50 g of oats daily for 3 months were investigated for possible evidence of immune activation. Tissue obtained before and after oats challenge was stained with a series of antibodies directed against the following molecules: human leucocyte antigen D-related (HLA-DR), Ki-67, CD25, CD54 [intercellular adhesion molecule 1 (ICAM-1)] and mast cell tryptase. None of the patients developed clinical or laboratory evidence of adverse effects. The distribution of intestinal HLA-DR expression was not affected by oats ingestion and the crypt epithelium remained unstained. In the pre-oats biopsies, the percentage of Ki-67 positive enterocytes, 29·5 ± 6·9 [95% confidence interval (CI) 13·9–45·0] did not differ significantly from that found in postoats biopsies, 41·2 ± 3·7 (95% CI, 32·8–49·6), P = 0·19, not significant. Furthermore, oats ingestion did not alter the number of CD25 positive and tryptase positive cells. Finally, the distribution and intensity of ICAM-1 staining was unchanged by dietary oats. In summary, detailed immunohistological studies of biopsies from patients ingesting oats for 3 months did not reveal evidence of immune activation. Together with other reported findings, this study strengthens the view that oats can be included safely in the diet of gluten sensitive patients