July 25, 2006

Where'd my gene go?

The German Cancer Research Center, DKFZ have an article which describes a possible genetic cause of Crohn's disease.

Patients with Crohn’s disease of the colon have one copy less than healthy persons of the beta-defensin 2 gene, a gene coding for an important defense molecule of the body.

[...]

Defensins are part of the arsenal of defense weapons used by the human immune system. [...] Patients with Crohn’s disease of the colon (colonic CD) have a lower level of beta-defensins in the mucous membranes.

Defensin genes are arranged in nests, called clusters, on chromosome 8. The number of clusters varies considerably across the population; this is technically called a polymorphism. The research team has now shown that patients with colonic CD have on average only three copies of the gene encoding beta-defensin 2, whereas healthy control persons as well as patients with small bowel CD or ulcerative colitis, another inflammatory bowel disease, have an average of four copies of this gene per cell.

The researchers showed that a lower number of gene copies is indeed associated with reduced production of the endogenous antibiotic, which explains the known low defensin level. They presume that this causes the defense of the intestinal mucous membrane to become porous so that bacteria can attach to and invade the mucous membrane, which leads to the typical inflammatory hot spots of Crohn’s disease.


The purpose of the defensin is described by MedicineNet as:
A family of potent antibiotics made within the body by neutrophils (a type of white blood cell) and macrophages (cells that can engulf foreign particles). The defensins play important roles against invading microbes. They act against bacteria, fungi and viruses by binding to their membranes and increasing membrane permeability.


The DKFZ work is an extension of earlier research published in PNAS which examined the connection between Crohn's disease and reduced defensin levels.

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human {alpha}-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC {alpha}-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC {alpha}-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of {alpha}-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of {alpha}-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.