The exact cause of Crohn's disease is still unknown, although more and more details are emerging and has become clear that the interplay of environmental factors and in a genetically predisposed host ignites disease . The genetic risk factors have now more or less been comprehensively elucidated, making Crohn's disease the first genetically complex disease of which the genetic background has been resolved.. The relative risks of contracting the disease when one has a mutation in one of the risk genes, however, are actually very low (approximately 1:200). Broadly speaking, the genetic data indicate that innate immune systems in patients with Crohn's disease malfunction, and direct assessment of patient immunity confirms this notion.. This had led to the notion that Crohn's disease should be viewed as innate immune deficiency, chronic inflammation being caused by adaptive immunity trying to compensate for the reduced function of the innate immune system.
Genetics
Some research has indicated that Crohn's disease may have a genetic link. The disease runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population. Ethnic background is also a risk factor.
Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease and with susceptibility to certain phenotypes of disease location and activity. In earlier studies, only two genes were linked to Crohn's, but scientists now believe there are over thirty genes that show genetics play a role in the disease, either directly through causation or indirectly as with a mediator variable. Anomalies in the XBP1 gene have recently been identified as a factor, pointing towards a role for the unfolded protein response pathway of the endoplasmatic reticulum in inflammatory bowel diseases.
Environmental factors
Diet is believed to be linked to its higher prevalence in industrialized parts of the world. Smoking has been shown to increase the risk of the return of active disease, or "flares".
The introduction of hormonal contraception in the United States in the 1960s is linked with a dramatic increase in the incidence rate of Crohn's disease. Although a causal linkage has not been effectively shown, there remain fears that these drugs work on the digestive system in ways similar to smoking.
Immune system
Abnormalities in the immune system have often been invoked as being causes of Crohn's disease. Crohn's disease is thought to be an autoimmune disease, with inflammation stimulated by an over-active Th1 cytokine response. However, more recent evidence has shown that Th17 is of greater importance in the disease. The most recent gene to be implicated in Crohn's disease is ATG16L1, which may induce autophagy and hinder the body's ability to attack invasive bacteria.
Contrary to the prevailing view that Crohn's disease is a primary T cell autoimmune disorder, there is an increasing body of evidence in favour of the hypothesis that Crohn's disease results from an impaired innate immunity. The immunodeficiency, which has been shown to be due to (at least in part) impaired cytokine secretion by macrophages, is thought to lead to a sustained microbial-induced inflammatory response, particularly in the colon where the bacterial load is especially high.
Microbes
A variety of pathogenic bacteria were initially suspected of being causative agents of Crohn's disease. However, most health care professionals now believe that a variety of microorganisms are taking advantage of their host's weakened mucosal layer and inability to clear bacteria from the intestinal walls, both symptoms of the disease. Some studies have suggested that ''Mycobacterium avium'' subsp. ''paratuberculosis'' plays a role in Crohn's disease, in part because it causes a very similar disease, Johne's disease, in cattle. The mannose bearing antigens (mannins) from yeast may also elicit an antibody response. Other studies have linked specific strains of enteroadherent ''E. coli'' to the disease. Still, this relationship between specific types of bacteria and Crohn's disease remains unclear.
Some studies have suggested that some symptoms of Crohn's disease, ulcerative colitis and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease. Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome as well as colitis, which is associated with all three diseases. The authors of that study were unable to identify the source of the protease, but a separate review noted that regional and temporal variations in those illnesses follow those associated with infection with a poorly understood protozoan, Blastocystis.
A study in 2003 put forth the "cold-chain" hypothesis, that psychrotrophic bacteria such as Yersinia spp and Listeria spp contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease. Later studies have provided support for this hypothesis.
Studies done at the University of Liverpool have offered ideas that would explain the apparent connection between Crohn's disease, Mycobacterium, other pathogenic bacteria, and genetic markers. In many individuals genetic factors predispose individuals to Mycobacterium avium subsp. paratuberculosis infection. This bacteria then produce mannins which protect both itself and various bacteria from phagocytosis, which causes a variety of secondary infections. Other mycobacterial diseases, such as leprosy and Tuberculosis could be considered similar in that they have strong genetic components, but are not genetic per se.
Further Reading
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