Ulcerative Colitis and Crohn’s Disease: a role of autophagy and innate immunity in IBD pathogenesis.

February 4, 2013, Featured in Autoimmune Disorders, 0 Comments

The cause of chronic inflammatory bowel disease (ulcerative colitis and Crohn’s disease) is unknown. However, exposure of the bowel immune system to infections is believed to play a role in the development of these chronic diseases that are very common among young people.

Some people with inflammatory bowel disease (IBD) may experience various extra-intestinal symptoms along with their gastrointestinal (GI) symptoms. These can include skin irritation (erythema nodosum), eye problems (episcleritis), and joint pains (arthritis). Some people with IBD also develop mouth sores (oral aphthous ulcers).

Behçet’s syndrome, an inflammatory disease affecting many organs, including the eyes, genitals, skin, joints, blood vessels, brain, and gastrointestinal, can cause recurring, painful mouth sores. Although the gastrointestinal and systemic features of Behcet’s syndrome and IBD overlap to a considerable extent, they are generally viewed as two distinct diseases.

Diagnosis and therapeutic management of extra-intestinal manifestations of inflammatory bowel disease.

A case of intestinal Behcet’s disease similar to Crohn’s colitis.

Potential Infectious Etiology of Behçet’s Disease.

Some studies have suggested that acute gastrointestinal infections with e.g. Salmonella and Campylobacter may initiate the disease process. But these studies have not taken into consideration the fact that patients generally have a lot faecal samples taken during the process of being diagnosed with IBD. Salmonella and Campylobacter infections do not cause chronic IBD. But, the presence of unfriendly bacteria such as Klebsiella pneumoniae and Proteus mirabilis in the digestive tract can be a risk factor for IBD

Much attention has also been focused on the role of measles virus infection and/or vaccination in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD). However, a published report on MMR (measles, mumps, and rubella) vaccination and IBD and pervasive developmental disorders (such as autism) has never been replicated by other studies and has subsequently been retracted by the journal.

There has also been a resurgent interest in potential viral etiologies of IBD, including norovirus (norwalk-like virus) and rotavirus (small bowel) as well as cytomegalovirus (CMV) and herpes simplex virus (HSV) in immune compromised people. CMV colitis is common in patients with IBD (UC and CD) who are on long-term immunosuppressive therapy.

Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobacter gastroenteritis.

Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease.

Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis.

Measles vaccination and inflammatory bowel disease: controversy laid to rest?

Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine.

Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander?

Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease.

Intestinal epithelial cells play a critical role in mediating the protective responses and there is increasing appreciation of the likely importance of antimicrobial peptides (AMPs) of the defensin family that they express. Defensins are produced at a variety of epithelial surfaces. They are divided into three major groups, α, β and θ-defensins, of which only α and β-defensins have been identified in the intestinal tract.

In the intestinal tract, they contribute to host immunity and assist in maintaining the balance between protection from pathogens and tolerance to normal flora (defensins modulate immune responses). Although it is clear that defensin expression is altered in IBD. However, defensin deficiency is due to mucosal surface destruction as a result of inflammatory changes, indicating that reduced defensin expression is a symptom of the disease and not the cause.

Intestinal antimicrobial peptides during homeostasis, infection, and disease.

Defensins in innate antiviral immunity.

Defensins and inflammation: the role of defensins in inflammatory bowel disease.

Dissecting genetic predisposition to inflammatory bowel disease: current progress and prospective application.

Autophagy (macroautophagy; “self-eating”) has long been recognized as a stress response to nutrient deprivation.  In fact, autophagy is a process by which cells degrade long-lived or insoluble proteins and microorganisms, and it may also regulate inflammation. Thus, autophagy plays critical roles in regulating a wide variety of pathophysiological processes, including tumorigenesis, embryo development, tissue remodeling, and most recently, immunity. The latter shows that a self-eating (autophagy) process could regulate a self-defense (immune) system.

The intestinal mucosa is a site of careful immune regulation where the epithelium and immune cells encounter pathogens as well as a robust and diverse population of indigenous microbes that are predominately bacteria. Autophagy has been shown to modulate the production of pro-inflammatory cytokine production and to contribute to antigen processing and presentation through the major histocompatibility complex.

Recent research suggests several genetic variants linked to IBD, especially CD, are associated with autophagy, a process that is critical for proper responses to viral and bacterial infections. Autophagy plays a critical role in defense against intracellular infection. In turn, evasion or inhibition of autophagy has emerged as an important virulence factor for intracellular pathogens. One of the key proteins involved in the execution of the autophagic process is the modulator, ATG16L1, which is responsible for the membrane localisation of the autophagic machinery and formation of the autophagosome.

The intracellular bacterial sensors, NOD (nucleotide-binding oligomerization domain) 1 and 2, are also important for the autophagic response to invasive bacteria. Colocalisation of NOD1 or NOD2 with ATG16L1 at the cell membrane is a crucial step in the initiation of the autophagic process probably independent of the activation NF-κB (a prototypical proinflammatory signaling pathway).

Defects in this pathway, particularly in individuals that are bearing IBD risk alleles for either NOD2 or ATG16L1, may lead to failed bacterial killing due to impaired lysosomal degradation, inefficient immune-mediated bacterial clearance and consequently to mucosal inflammation. Therefore, it is possible that certain aspects of the autophagy pathway are evolutionarily plastic and critical for a balanced immune response in the face of infectious threats that change over time.

Inflammatory bowel disease: dysfunction of autophagy?.

Autophagy and Intestinal Homeostasis.

Viruses, autophagy genes, and Crohn’s disease.

Role of autophagy and autophagy genes in inflammatory bowel disease.

Autophagy: from basic science to clinical application.

Self-eating and self-defense: autophagy controls innate immunity and adaptive immunity.

Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2.

Innate immune defence: NOD2 and autophagy in the pathogenesis of Crohn’s disease.

Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis.

Regulation of innate immune responses by autophagy-related proteins.

Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections.

Etiology of Crohn’s disease: many roads lead to autophagy. 

Autophagy-related proteins are involved in the innate immune response and may contribute to the development of inflammatory disorders. Proper regulation of innate immune responses by autophagy-related proteins is important for the regulation of innate immunity.  Indeed, the mutations that disrupt autophagy may be the possible trigger for IBD under some infectious conditions.

Intestinal epithelial cells with impaired autophagy lose their adhesive capacity in the presence of TNF-α.

Therefoer, it would be unwise either by adding prednisone (corticosteroid) or increasing the azathioprine (an immunosuppressive drug) in the setting of possible infection. Prednisone can also weaken your immune system. Optimal therapy is orally administered GinolZym and should be initiated promptly for severely ill patients. GinolZym can modulate the autophagic response in the intestinal tract.

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