GI Tract – Chron’s Disease (CD)
According to Podolsky, K, D, CD can be defined as “discontinuous lesions in the GI tract with common localisations of impaired alpha defensin response or expression via paneth cell metaplasia in the ilium and colon” (Podolsky, K, D. 2002).
Figuire 1 provides a basic illustration of IBD:
Genetically speaking the mutated NOD2 gene which causes a leucine rich repeats (which aids in bacterial receptor recognition), this binds to muramyl dipeptide (MDP). Which in turn activates nuclear factor NFkB. Causing stimulation of several genes which when mutated contribute to chronic inflammation which are as follows:
OCTN1 will promote the dysfunction of organic cation transpoters. DLG5 gene co-works with NOD2, but in CD conditions deverts from its normal function which is to maintain epithelial integrity. Other genes worth mentioning are HLA-DR1 and its sub allele DQ5, TLR 4&9. Which are associated with the regulation on innate immune system and the mucousal barrier function.
Intestinal macrophage have to respond to bacterial adjuvants via their recognition receptors (TLR9) and LPS pathway receptors (TLR4). Epithelial paneth cell do the same via NFkB. The MYD88 pathway can converge the differeing routes to specific bacterial adjuvants. Which will always result in the activation of NFkB and a pro-inflammatory cytokine environment and protective molecules which inhibit inflammation. This is summarised in figure 2:
CD activates innate and acquired immune responses. Evidence suggests that macrophages and adhesion molecules are abundant in CD, which mediate the migration of extravasated immune cells and chemokine production. This is a highly selective mechanism known as cell trafficking and is shown as an illustration in figure 3:
Figuire 3 shows the interplay of circulating effector and regulatory cells in CD. In summary the inflamed colon will contain CD4+ T-Cells which will secrete chemokines creating a chemotactic gradient sustaining inflammation further. Intracellular adhesion molecule 1 (ICAM1) is in abundance allowing further aid in the circulating cells to stick to the activated endothelium. CD is also prolonged by a decrease in cellular apoptosis and molecules which can regulate pro and anti apoptosis. Evidence suggests that CD is a TH1 cell mediated response which is regulated by IFN-Y, which is stimulated by IL-12 produced by antigen presenting cells (feedback loop). It is this feature which creates delayed type hypersensitivity. This is illustrated in figure 4 below:
The memory of TH1 cells will activate macrophages when the antigens are present again in the future. Also in the damaged tissue vascular leakiness and cellular infiltration is present.
T cell activation and differentiation is triggered by interaction between APC and the T-Cell subset in question as shown in figure 5:
In summary the differentiation is based on the products secreted from the APC so IL12 will stimulate TH1 and IL10 will stimulate TH3. And vice versa the products secreted from T-Cells will promote their purpose so TH1 will secretes IFN-Y which will further MHC expression and TH3 will secrete TGF-beta which will inhibit APC activity.The ligation of APC and T-Cells will be maintained by the CD80/86/28 and CLTLA4 molecules.
Its worth noting that histological evidence has exposed granulomatous inflammation which might indicate the pathogen Myobacterium Avum Paratuberculosis as a causative agent. But patients respond positivley to a combination of antibiotic treatment.
An assessment of each individual should be made and then a decision met in how to treat that person. The first port of call should be a corticosteroid to reduce symptoms, then if that does not suffice then an immunsupressive drug should be introduced. For cases of colonic manifestation a NSAID (non steroidal anti-inflammatory drug) should be the desired option. The avoided treatment is surgery to remove the inflamed part of the intestine. But of course the treatment might simply be atering ones diet or intstalling a touch of rest and relaxation into ones life.
In conclusion CD is the inefficient response to dealing with chronic intestinal inflammation caused by genetic, immunological, microbial and environmental triggers. Genetically predisposed hosts fail to clear pathogenic threats by stimulating the appropriate innate immune response, but instead activate the pathogenic T-Cell response to bacteria therefore sustaining an inflamed mucousal barrier. Because of this continuous resistance to dealing with the riggers successfully CD can arise at any time in susceptile hosts.
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