Disease Basis Genetic and Environmental Triggers

The crucial role that activated T cells, macrophages, and monocytes play in the initiation and maintenance of the inflammatory process and tissue damage in IBD has been widely reported.2 However, the pathogenesis of CD and UC is still incompletely understood. A consistent emerging theme is that IBD results from an abnormal innate mucosal immune response to gut microflora in a genetically susceptible host.

The intestinal tract is unique in the body in regard to its constant exposure to insults from potentially pathogenic microbes and an abundant commensal bacterial microbiota. As sentinel, it performs a delicate balancing act between immune surveillance and waging war on opportunistic infections. In IBD, this balance is disrupted in favor of uncontrolled and excessive recruitment of activated lymphocytes, macrophages, monocytes, and neutrophils to the intestinal lamina propria. Once resident, these cells overproduce among others the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) and the interleukins IL1b, IL6, IL8, and IL18 and a proteolytic soup of matrix metalloproteinases (MMP-1 and MMP-3 especially) which together culminate in the prothrombotic destruction of the gut mucosa.

Genetic linkage analyses have generated some of the most compelling evidence relating a host microfloral trigger and an imbalance in innate and adaptive immunity with a causal link to IBD. In 2001, mutations in the NOD2/CARD12 gene were mapped to one of the five genetic susceptibility loci linked to CD, IBD1 (OMIM 605956) on chromosome 16q12.4'5 NOD2 is an intracellular receptor for the bacteria-derived peptidoglycan, muramyl dipeptide (MDP), expressed on macrophages and dendritic cells, and is especially enriched in intestinal Paneth cells. CD patients harboring NOD mutations are especially predisposed to ileal lesions, the major location of Paneth cells. Upon binding to MDP, NOD2 oligomerizes and binds the scaffolding kinase RIP2/RICK. RIP2 then oligomerizes to transmit NOD2's signal directly to the IKK complex and the activation of nuclear factor kappa B (NFkB) (Figure 1). Individuals with one of the three major NOD2 alleles have a two- to fourfold increased risk of developing CD; homozygous and compound heterozygous carriers have an up to 40-fold increased risk. Mutated NOD2 mutations can be found in 20-30% of CD patients, but despite this strong disease association, mutated NOD2 alleles are neither necessary nor sufficient for the development of CD, as they also occur in healthy individuals. While mutant NOD2 is a predisposing factor, it is still not clear whether the effects of these mutations are 'gain-of-function' or 'loss-of-function' on NFkB activation. However, mice harboring the common CD susceptibility allele, 3020insC, are more sensitive to dextran sodium sulfate (DSS)-induced colitis, and produce elevated amounts of IL1b, IL6, and other products of the NFkB pathway.

TLR/IL-1-R

TNF-aR

TNF-aR

TLR/IL-1-R

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment