Scandinavian Journal of Immunology最新文献

Celiac disease (CD) is a common immune-mediated, gluten-sensitive enteropathy that develops in human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 allele carriers due to the dysregulation of gluten-specific T helper cells. Although ingested gluten from cereals was identified as the disease driver in the 1950s, the ultimate cause (or disease trigger) remains unknown. CD is further characterized by the production by intestinal B cells of autoantibodies against tissue transglutaminase 2, an enzyme that can modify gluten peptides by deamidation, thus rendering gluten more recognizable for celiac patient T cells. The celiac intestinal lesion is hallmarked by crypt hyperplasia and villus atrophy, but also by intraepithelial T cells and lamina propria plasma cell infiltration.^{1, 2}

So far, an accurate CD model in rodents that would unite the features listed above does not exist.³ HLA-DQ2 or HLA-DQ8 transgenic, mouse class II knockout models provide appropriate restriction of T helper cells, valuable for the experimental study of cellular and humoral immune responses directed at gluten. But HLA-transgenic mice do not develop disease on gluten-containing diet, or following various additional challenges, while any histological changes in the intestine remain mild and rudimentary.^4-7 In contrast, Rag1^−/− mice adoptively transferred with gliadin memory T cells have been described as a CD model with an intestinal phenotype that includes villus atrophy, crypt hyperplasia and mucosal mononuclear cell infiltration.⁸ However, the gluten-sensitive enteropathy in this model depends on the quantitative depletion of regulatory T cells. Consequently, negative control mice on gluten-free diet also show mild-to-moderate (autoimmune) enteropathy.

In-depth histological analyses are vital for the development of animal models of human diseases. Since CD primarily affects the proximal small intestine, and is characterized by well-documented histological changes,² thorough histological investigation of at least the entire small intestine, that is, duodenum, jejunum and ileum, is key for the validation of any animal model of human CD.³ Non-validated surrogate biomarkers such as immune mediators or anti-gliadin antibodies cannot replace histological parameters. The assessment of architectural changes in the small intestine forms an important part of the histological analysis in CD and its animal models. However, it is well known that villus/crypt (V/C) ratios are notoriously unreliable as sole parameters of intestinal damage for various reasons; they are affected by diets, the age of the animal, and location in the intestinal compartment, as well as technical issues, for example, sampling consistency,⁹ tissue orientation¹⁰ or compression by luminal content. Intraepithel

Background: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations.

Objectives: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes.

Methods: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions.

Results: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use.

Conclusions: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.