Question

when dealing with Crohn's Disease

1) What are the mutated genes that are associated with this disease and explain each one of them?

2) In detail, explain the genetics in this disease

3) Explain how does Crohn's disease work and the mechanism behind it?

Thank You!!!

Answer 1

1, Crohns disease, an inflammatory bowel disease, is caused by mutations in genes located on chromosome 5. These genes include majorly ATG16L1, IL23R, IRGM, and NOD2/CARD15 genes, which are involved in immune system functions. Risk of Crohns disease also increases with mutation in DLG5, IBD5, LRRk2. IRGM is Immunity-related GTPase family M, and regulates autophagy in response to intracellular pathogens. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) or caspase recruitment domain-containing protein 15 (CARD15) codes for an intracellular pattern recognition receptor protein. It is also known as IBD1 (inflammatory bowel disease protein 1). It recognizes special muramyl dipeptides present in bacteria and LPS in gram negative bacteria. Thus it is involved in innate immunity. IL23R or interleukin 23 receptor is a type I cytokine receptor present on plasma membrane. It co-transports sodium ions and ergothioniene antioxidant. ATG16LI is autophagy related protein 16-1 involved in autophagy. DLG5 is disks large homolog 5, a scaffolding protein for cell-cell contact. Leucine-rich repeat kinase 2 (LRRk2) is involved in chaperone mediated autophagy. IBD5, or inflammatory bowel disease protein 5 is a locus and its variants has been linked to Crohn’s disease in Europeans and Malaysians. It is locus that has several genes involved in inflammatory bowel disease. It is present on chromosome 5q31 and has genes such as OCTN1 and OCTN2 (carnitine/organic cation transporters). There are nearly 11 single nucleotide polymorphism known in this region that increases susceptibility to Crohn’s disease. Most genes code for solute carrier proteins.

2. Crohn’s disease is caused by mutations in genes that are involved in autophagy and immune system dysfunctions. The proteins help the immune system in responding to bacteria that infect the digestive tract. These bacteria are then destroyed by autophagy via specific proteins. Mutations affect the ability of these proteins to immune functions and autophagy. The disease affects walls of intestine, especially of ileum and the colon. It is more common in Western Europe and North America. It is known to run in families and thus has a genetic origin as well. Around 20% of people with Crohns disease have family members with some kind of bowel inflammation. Adults in ages between 20-30 yrs are usually diagnosed with this disease. Families of Caucasians and Ashkenazi Jews of European descent are known to inherit this disease, while Asians and African Americans have lower risk. There is a 7-9% risk of developing Crohns disease in children whose one parent has the disease. This risk increases to 35% if both parents are affected. In case of identical twin, if one twin has the disease then there is 55% risk of the other twin also being affected by the disease. Hence, this disease has a partial genetic origin. The rest is via environmental factors such as alcohol, high fat/fiber diet, milk proteins etc. Over 30 genes in chromosome 5 and 10 have been observed to have a genetic link to Crohns disease. Genes on these chromosomes when mutated cause an increased risk of Crohns disease.

CARD15 gene shows three mutations- Arg702Trp, Gly908Arg and the frameshift mutation in rich repeat region required for bacterial recognition as it binds to muramyl dipeptide. Mutations cause defective binding to muramyl dipeptide, thereby affecting proinflammatory responses. Mutations are observed in the promoter regions of OCTN1 and OCTN2 causing decreased carnitine transport in intestinal epithelium, macrophages and T cells. There are two haplotypes seen in DLG5, a scaffolding protein required for epithelial integrity.

3. Crohn’s disease is an inflammatory bowel disease type and is an idiopathic, chronic, relapsing, inflammatory condition in humans. It is a complex interplay of genetic, epigenetic, immunological, and microbiological mechanisms. Mutations in innate immune response genes and autophagy genes lead to overly aggressive T cell responses against some commensal bacteria. Mutations in the genes such as NOD2, OCTN1, DLG5 and others will affect intestinal cell integrity, autophagy and innate immune responses. Innate immune responses and acquired immune responses are activated causing less tolerance to enteric bacteria which are commensals of the intestine. TNF alpha and IL-12 p40 have been implicated in this disease. There is increase in numbers of macrophages and dendritic cells in lamina propria along with increased production of proinflammatory cytokines. The T helper cell responses are usually TH1 and TH17. ICAM1 helps the mononuclear cells and polymorphonuclear cells to move to the affected region. Pro-inflammatory cytokines are produced by these mononuclear cells and polymorphonuclear cells. The epithelial cells start expressing Toll like receptors which attract immune cells. NFkB activation leads to expression of IL-1β, TNF, IL-6, IL-8 etc. IL-17 mediates the TH17 responses while IFN gamma mediated IL-12 activates TH1 response. T cells will bind to the epithelium via integrin alpha 4 beta 7. Endothelial cells express CCL25 which attracts T cells. The enteric microflora can stimulate the innate immune response by acting as adjuvants or antigens. Anti-inflammatory drugs such as NSAIDs are known to trigger Crohn’s disease. They initiate non-specific inflammation, which breaks the intestinal barrier thereby activating innate immune responses. Food additives such as aluminum and iron are adjuvants that can stimulate bacterial virulence.