Genetic and functional profiling of Crohn's disease: autophagy mechanism and susceptibility to infectious diseases

Abstract

Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an increased risk of developing the disease and most of these are also implicated in other autoimmune disorders. The gut has many tiers of defense against incursion by luminal microbes, including the epithelial barrier and the innate and adaptive immune responses. Moreover, recent evidence shows that bacterial and viral infections, as well as inflammasome genes and genes involved in the autophagy process, are implicated in Crohn's disease pathogenesis. The aim of this review is to establish how much the diagnostic system can improve, thus increasing the success of Crohn's disease diagnosis. The major expectation for the near future is to be able to anticipate the possible consequences of the disease already in childhood, thus preventing associated complications, and to choose the best treatment for each patient.

Figure 1

Crohn's disease is a heterogeneous disorder of multifactorial etiology in which genetic, environmental, and microbial factors, together with the immunological response, interact to produce the disease.

Figure 2

More than 90 distinct genomic susceptibility loci have been found to be associated with an increased risk of developing CD. The genes variants relate largely to the innate immunity genes, in particular to the disruption of the innate and adaptative arms of the immune systems, to the process of autophagy, to the epithelial barrier function, and to the activation of the endoplasmic reticulum stress response.

Figure 3

The role of microbiota in Crohn's disease pathogenesis. The interplay between the host microbiota and the environmental factors in a genetic susceptible host results in a progressive inflammatory damage to the host intestinal mucosa.

Figure 4

Up- and Downregulation of the proinflammatory cytokines evidenced in the immune system dysregulation of CD patients.

Figure 5

CD pathogenesis and autophagy: susceptible CD genes ATG16L1, NOD2, and IRGM are proteins critical for the autophagy process. (a) The process of mammalian autophagy is divided into the following principal steps: initiation, elongation, closure, maturation, and degradation. (b) At the bacterial entry site NOD2 activated by MDP recruit ATG16L1 to the plasma membrane. Follow the assembling of the ATG5-ATG12 complex, stabilized by ATG16L1, that facilitates the formation of an autophagosome around the invading bacterium. (c) IRGM, another autophagy-related gene, could be involved in the final steps of the degradation step.