Crohn's disease: Encyclopedia II - Crohn's disease - Causes

Crohn's disease - Causes

Crohn's disease - Barrier problem and autoimmunity to the luminal flora

The efficacy of immunosuppression, as well as scanty reports of complete disease resolution after bone marrow transplant, is highly suggestive of an autoimmune pathogenesis. A definite epitope to which the autoimmunity is directed is unknown, which also hampers the search for a virus or other pathogen that could induce molecular mimicry.

Present evidence suggests that there is not a single causative antigen but that the response of the mucosal immune system is polyclonal. It is mostly directed against a multitude of bacterial, not dietary, antigens. This overreaction to the normal bacteria of the intestinal flora may be due (1) to a barrier problem of the epithelial lining of the gut or (2) to a disturbed regulation of the mucosal immune system. Multiple lines of recent evidence suggest that the deficient epithelial barrier may be due to relative lack of defensins, i.e. endogenous peptide antibiotics secreted by the small and large intestinal epithelium. This lack would then allow a slow bacterial invasion with the consequence of a secondary immune response. This hypothesis also allows us to explain the frequent finding of M. paratuberculosis in the Crohn´s mucosa discussed below. A molecular mechanism for a potential dysregulation has not yet been identified.

Since Crohn's disease is often found in families, it is likely that it has a genetic component. Studies have identified a gene named CARD15 (or NOD2) which is suspected to participate in the inflammatory process at the heart of Crohn's disease. While mutations or polymorphisms (common variations) in this gene do not directly cause the disease, they may help determine who is affected or how serious one's symptoms are. One study reported that 50% of patients with Crohn's disease carried one or more mutations in CARD15. Some mutations were associated with more severe cases or earlier age or onset. While a number of independent studies have reported the association of CARD15 with Crohn's disease, some populations like the Japanese do not have these mutations. Mutations in NOD2 have been linked to low levels of alpha defensins in Paneth cells of the small intestine. Further studies are in progress to delineate the contribution of this gene.

Both Crohn's disease and ulcerative colitis are chronic, they affect men and women approximately equally, and they are most common in northern Europe and North America. Approximately 20 percent of individuals with Crohn's disease have a blood relative with some form of IBD. The onset of Crohn disease is usually between the ages of 15 and 30 with a second smaller peak of incidence between the ages of 50 and 70. Over the past decade, several reports have noted an increase in the prevalence of Crohn disease in various geographic regions. Although there are many theories concerning the cause of Crohn's disease and ulcerative colitis, none have been proven. Since many of the symptoms of Crohn's disease and ulcerative colitis are similar, diagnosis is often difficult, time consuming, and invasive. Approximately 10-12 percent of cases are not initially classifiable and are referred to as "indeterminate colitis." Over time, about half of these patients are eventually diagnosed with CD or UC.

Crohn's disease - Anti-Saccharomyces cerevisiae Antibodies ASCA IgG and IgA

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been found to be significantly more prevalent in patients with Crohn disease compared to patients with ulcerative colitis or healthy controls. These antibodies, which can include antibodies in both the IgG and IgA classes, appear to be directed against mannose sequences in the cell wall mannan of Saccharomyces cerevisiae. The presence of IgG or IgA ASCA has been shown to have a high specificity for Crohn disease. However, the majority of Crohn´s patients do not exhibit this antibody, although when positive it may be helpful in differentiating Crohn disease from ulcerative colitis in some patients. A pathogenetic role of these anitbodies is unproven.

Crohn's disease - Anti-Neutrophil Cytoplasmic Antibodies ANCA IgG

Anti-neutrophil cytoplasmic antibodies (ANCA) that demonstrate atypical perinuclear staining (atypical pANCA; classic perinuclear pattern on ethanol-fixed human neutrophils, but absent on formalin-fixed neutrophils) are found in 70 percent of patients with UC, but only 20 percent of patients with CD.

Crohn's disease - OmpC IgA

The OmpC IgA assay is promoted by one laboratory as a way to detect patients with Crohn disease who are ASCA negative but none of these serum assays is part of the routine diagnostic workup in these patients.

Crohn's disease - Mycobacterial infection

The disease has long been suspected of being due to a Mycobacterium because of the similarity of many features to human tuberculosis and veterinary Johne's Disease. Mycobacterium avium subspecies paratuberculosis (MAP), which causes Johne's disease in cattle, is a primary area of research for many scientists and doctors involved in Crohn's disease. MAP has been proven to affect both cattle and human hosts and is passed on through the mammary glands. Current pasteurization methods have proved ineffective in ridding dairy products of Mycobacterium Paratuberculosis. This remains a controversial area of research, although recent studies have lent more credence to the theory, and government agencies in some countries have begun investigations into the possibility.

Nearly all practicing physicians and many researchers are unwilling to accept that MAP is a primary cause of Crohn's. Dozens of studies have been done in which evidence of MAP infection could not be found in tissue and blood samples of Crohn's patients. However, other studies ([1]) have been performed which (with more stringent methodology) show that MAP was found in up to 90% of the Crohn's patients in the study. Mycobacteria are known to be fastidious, which means they are extremely difficult to grow in culture. Therefore, unless very stringent precautions are taken, cultures for mycobacteria can underestimate the presence of the bacterium.

For this reason, PCR is a more promising technique than culture. Researchers have identified an insertion sequence called IS900 that is unique to the MAP organism, and many studies have been performed using PCR to test for the presence of MAP. However, the problem with PCR is that it will detect dead or near-dead ("non viable") MAP organisms, so often times a combination of PCR and careful culture is needed to prove that MAP is present.

Researchers using PCR and careful culture have found that live MAP bacteria are present in significant numbers of Crohn's patients, and other studies using PCR and culture have shown that live MAP bacteria are present in significant percentages of pasteurized milk in the United States, the United Kingdom, and the Czech Republic.

Many experts in the field now suggest, however, that there is no single microbial species that causes Crohn's disease. More likely, Crohn's represents the loss of immunological tolerance to one's own gut bacteria or commensal microflora. For this reason, Crohn's is often considered a defect in the barrier function of the intestinal epithelium, combined with immune dysfunction arising in genetically susceptible individuals.

Adapted from the Wikipedia article "Causes", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki