Current knowledge in inflammatorty bowel diseases immunopathogenesis

Ulcerative colitis (UC) is a chronic disease characterized by inflammation of the colonic mucosa. The etiology of this disease is not completely understood, but a multifactorial origin has been proposed, involving genetic, environmental and immunological factors. The genetic factor seems to be essential, based on both epidemiological and family studies. Environmental factors such as tobacco, NSAIDs, oral contraceptives, diet and exposure to pathogens have also been shown to play a role. Genome-wide association studies (GWAS) have highlighted the association of several genetic polymorphisms with UC. The loci involved (IBD genes) encode molecules that directly interfere with both innate and acquired immunity. A recent meta-analysis showed an association of 47 loci with UC, 40% of which are specific for UC and the rest shared with Crohn's disease (CD). Some of these loci involve a greater risk of epithelial dysfunction, such as EMC1 (a mutated member of a transmembrane complex required for efficient folding of proteins in the ER), HNF4A (hepatocyte nuclear factor 4 alpha), CDH1 (encodes epithelial cadherin or E-cadherin), and LAMB1 (encodes laminin subunit beta-1). The DAP locus (Death-associated protein 1, which encodes a protein that acts as a positive mediator of programmed cell death), involves impaired autophagy and apoptosis. PRDM1 (encodes PR domain zinc finger protein 1, also known as BLIMP-1), interferon regulatory factor 5 (a protein that in humans is encoded by the IRF5 gene), and NKX2-3 (homeobox protein Nkx-2.3) are associated with defects in the transcription process. Loci overlapping with CD include several genes from the interleukin 23 (IL-23) signaling pathway, and HLA genes that associated with autoimmunity. The IL-33/ST2 axis is a new discovery in the pathogenesis of UC. This axis's role had been previously demonstrated in other chronic inflammatory diseases, and in 2010, IL-33 and its cognate receptor ST2 were shown to be upregulated in gut of UC patients. This proinflammatory axis has the ability to enhance Th2 pathogenic responses in gut-associated lymphoid tissues and seems to have an important role in the pathogenesis of UC. This review describes the current evidence on the pathogenesis of UC, including alterations in the intestinal barrier leading to dysfunction of the mucosa and acquired immune response. The data support the multifactorial hypothesis, where, in a genetically predisposed individual, pathogenic bacteria initiate intestinal inflammation, and the inflammatory process is sustained by loss of tolerance to the commensal microbiota. © 2013 Nova Science Publishers, Inc. All rights reserved.