Az NKX2-3 transzkripciós faktor szerepe a bél-asszociált nyirokszövetek veleszületett limfoid sejt-megoszlásának és a gyulladásos bélbetegségek lefolyásának szabályozásában

Abstract

Inflammatory bowel disease (IBD) is one of the most common chronic inflammatory diseases of the gut. We can distinguish two main types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). Several people are affected worldwide and IBD develops mostly in young adults. (Loftus et al, 2002) There are several genetic and environmental factors that contribute to the development of these diseases. (Fisher et al, 2008; Cho et al, 2007) In recent years several IBD associated loci were identified with the help of GWAS, meta-analysis and fine-mapping procedures. (Verstockt et al, 2018; Liu et al, 2015; Zhang et al, 2018) Despite hundreds of identified genetic alterations –mostly single nucleotide polymorphisms (SNP)– only a few of them proved to have real biological role in the development of IBD. One of those alterations is the SNP of the coding region of the homeodomain containing transcription factor Nkx2-3, that can be associated with the incidence of CD and UC. (Parkes et al, 2007; Fisher et al, 2008) The combination of genetic and environmental factors can alter the composition of the microbiome, decrease epithelial barrier function and induce inflammation due to the pathological activation of the immune system. (Loftus et al, 2002) The individual-specific intestinal microbiome has an important role in ensuring proper nutrient uptake in the intestinal tract and in the development and regulation of the local immune system. (Bäckhed et al, 2005) Perturbation of the delicate balance between the host and the microbiome can lead to the development of severe inflammatory processes. (Elson et al, 2005) Epithelial cells ensure limited access of the mucosal immune system to bacterial and other antigens of the digestive tract. In IBD this barrier function is damaged due to the increased permeability of the intestinal wall that can lead to the development of inflammation. (Wang et al, 2006) Immune cells of the GALT can contribute to the maintenance of immunological homeostasis in normal conditions; however, in IBD they can induce inflammation due to the higher influx of bacterial and other antigens through the epithelial barrier with increased permeability. Mucosal accumulation and abnormal activation of these cells can lead to an enhanced production of inflammatory factors. The regulated migration of immune cells through the vascular-endothelial network is controlled by the α4β7-MAdCAM-1 interaction. In chronic inflammation the increased expression of adhesion molecules, inflammatory chemokines and other soluble factors enhance the migration of lymphoid cells into the intestinal tract. (Hatoum et al, 2006) Transcription factor Nkx2-3 regulates the expression of MAdCAM-1 addressin that ensures gut homing of lymphoid cells through the interaction with leukocyte receptor α4β7. (Iwata et al, 2004) In the absence of these endothelial factors the perturbed gut homing of lymphocytes influences the local immune response and the course of inflammatory processes. (Pabst et al, 2000) Since Nkx2-3 can regulate the addressin-pattern of the intestinal mucosal vasculature, this transcription factor can be associated with the development of IBD.