Abstract
Celiac disease (CD) is a systemic disorder characterized by an immune-mediated reaction to gluten and a wide spectrum of clinical manifestations. Currently, the main treatment of CD is represented by adherence to a gluten-free diet (GFD) which determines the resolution of symptoms, and the normalization of the serology and of the duodenal villous atrophy. In the present study, we aimed to identify changes in gene expression in peripheral blood mononuclear cells (PBMCs) of celiac patients on GFD for at least 2 years, in order to identify novel disease biomarkers and candidate targets for putative therapeutic approaches. Microarray analysis was performed on PBMCs from 17 celiac patients on long-term GFD and 20 healthy controls. We identified 517 annotated genes that were significantly modulated between celiac patients and controls. Significant biological pathways were functionally clustered using the Core Function of Ingenuity System Pathway Analysis (IPA). Intriguingly, despite being on a GFD, celiac patients exhibited a peculiar PBMC profile characterized by an aberrant expression of genes involved in the regulation of immunity, inflammatory response, metabolism, and cell proliferation. Random forest algorithm was then used to validate the prediction ability of core genes as classifiers of the “celiac status”. In conclusion, our study identified a characteristic PBMCs signature profile in clinically asymptomatic celiac patient.
Highlights
Alkaline phosphatase (ALP), alanine aminotransferase (ALT), potassium, magnesium, lactate dehydrogenase (LDH) and anti thyroperoxidase antibodies (Ab anti-TPO) levels resulted increased while total cholesterol, thyroglobulin and eosinophils were significantly lower in celiac patients compared to controls
We observed a significant increase in the mRNA levels of mitogen-activated protein kinase 1 (MAPK1), heat shock protein 70 (HSPA1a), toll-like receptor 5 (TLR-5) and tumor necrosis factor superfamily member 10 (TNFSF10) involved in both innate and adaptive immune responses (Fig 3A)
Genetic predisposition (HLA-DQ2 and HLA-DQ8 haplotypes), with positive duodenal biopsy and serological antibodies upon gluten contained diet are required for the diagnosis of Celiac disease (CD) [18;19]
Summary
HLA class II genotype expressed on the cell surface of antigenpresenting cells plays an essential role in CD by presenting gliadin peptides to CD4+ Th1 cells, which trigger an immune response leading to the production of inflammatory cytokines, such as IFN- [4]. During the pathogenesis of celiac disease an inflammatory cascade occurs, involving Th1 activation and an innate immune response in the intestinal mucosa, characterized by cytokines production such as interleukin 15 (IL-15), which promotes the differentiation of intraepithelial lymphocytes into cytotoxic CD8+ T cells [4]. CD patients following GFD recommendation exhibit T lymphocytes specific to deamidated gluten peptides in the peripheral blood, which are able to produce pro-inflammatory cytokines such as IFN-gamma and IL-6 [9].
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