1. Etiology of Crohn’s Disease
Theresa Ho -
Joo-Young Lee –
Isaac Wade –
Kirby Yee –
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson

2. What is Crohn’s Disease ?
Belongs to a group of conditions known as inflammatory bowel disease (IBD) : causes inflammation and irritation of the GI tract, mainly the small intestine
Generally affects younger people with the age of onset years with an incidence of 3.1 to 14.6 cases per people in North America
Symptoms include abdominal pain, cramping, diarrhea, nausea, vomiting and weight loss

3. The Real Deal
While there has been and is a lot of research done on Crohn’s disease, there seems to be no certain cause.
However the following factors seem to play a role:
Pathogenic
Genetic
Environmental

4. Pathogenic Factors:
The disease is caused by an abnormal, overactive autoimmune response to bacteria in the digestive tract → results in the patchy inflammation
The intestinal barrier is disrupted, permitting bacterial antigens to enter the submucosal and laminal layer (below the epithelium)
Causes increased cellular recruitment, overexpression of pro- inflammatory cytokines and decreased levels of immunosuppressive cytokines

5. Environmental Factors:
Higher prevalence of Crohn’s disease in more developed countries than rural populations and within ethnic minorities suggesting that low exposure to pathogenic infections could disturb the mucosal immune balance and increase the risk for the disease
Lifestyle choices, like smoking, are associated with a higher risk of CD and an increased number flare ups (sudden intensification of symptoms)
The effect of diet is an increasing area of interest as there are more studies that reflect the role of nutrition in intestinal permeability and antigen clearance

6. Genetic Factors
Genome wide association studies (GWAS) have identified over genetic risk loci for IBD, 70 which seem to be closely associated with Crohn’s
Parent and sibling studies reflect that an individual is at a higher risk of developing the disease if a parent or sibling has it
Among the numerous genes (such as TLR4, CARD9, STAT3…), the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is of major importance

7. Normal Gene Expression of NOD2
NOD2 gene is located on the long arm(q) of Chromosome 16  at position
A member  of the  NOD-Like Receptor (NLR) family
All NLR proteins recognize pathogen and damage-associate molecular patterns (PAMP and DAMP) of a pathogen, and initiates an innate immune response
NLR proteins’ structure consist of an amino-terminal effector domain, a central NBD, and a carboxy-terminal-leucine-rich repeat (LRR)
NOD2 is highly expressed in ileal Paneth cells , but less in epithelial cells of intestine, oral cavity and lungs.
NOD2 is highly expressed in myeloid cells such as dendritic cells and macrophages, but less in T cells

8. Normal Gene Expression of NOD2
Recognizes muramyl dipeptide (MDP)
MDP is derived from peptidoglycan found mainly in Gram- positive bacteria and to a lesser extent in Gram-negative bacteria.
LRRs at C-terminus directly recognizes MDP
Activation of NOD2 protein ultimately leads to the formation of protein complex  nuclear factor-kappa-B (NF-κB) .
Two NF-κB binding sites  is located at upstream of the transcription start site of NOD2.
This binding site regulates the activity of multiple genes that include inflammatory reactions, and immune responses
The protein complex binds to NF-κB binding site which induces the production of a various  cytokines, chemokines, and antimicrobial.
Cytokines, chemokines, and antimicrobial play a role in regulating the immune system and maintain the gut’s microbiota.

9. Nod2 Mutations in Crohn’s Disease
3 mutations within leucine-rich region of the Nod2 protein
Arg702Trp, Gly908Arg, 1007 frameshift variant (SNP13)
2-fold risk for Nod2 heterozygotes or 20-fold risk for Nod2 homozygotes
Disturbance of gut homeostasis due to:
Reduced MDP sensing
Impaired antimicrobial responses in Paneth cells (in the ileum)
Results in defective bacterial clearance

10. Altered Nod2 Immune Response in CD
Decreased stimulation of NF-κB activity in response to common bacteria
Escape of intestinal bacteria from first-line of defense
Accumulation of bacteria in the intestinal tract causes dysbiosis
Altered interaction between mucosal immunity and gut microbiota causes abnormalities of Peyer’s patches and mesenteric lymph nodes
Stimulation of mucosal immune system inducing Th1 (T helper type 1) immune response

11. Inflammatory Immune Response in CD
T helper type 1 (Th1)
Lineage of CD4+ T cells involved in host defense against intracellular viruses and bacteria
Initiation of pro-inflammatory responses through secretion of IFN-ɣ, IL-2, IL-10, TNF-α/β
Results in chronic inflammation and perpetuation of autoimmune responses leading to uncontrolled tissue damage
Signature cytokines
Immune Reaction
Role in Disease
Host Defense

12. Drugs Approved for CD TNF Inhibitors Adhesion Molecule Blockers
Infliximab
Adalimumab
Certolizumab
Adhesion Molecule Blockers
Natalizumab
Vedolezumab

13. Infliximab Anti TNF-𝝰 monoclonal antibody
Chimeric (25% murine antigen-binding,  75% human IgG1)
Administered intravenously
Binds to pro-inflammatory cytokine mTNF-𝝰 to exert therapeutic effect

14. Infliximab Mechanism of Action
Infliximab binds to cytokine mTNF-𝝰 on the mucosal cell causing
Downregulation of proinflammatory cytokines (TNF-α, Il-1β, Il-6, Il-8)
Mucosal cell arrest in G0/G1 phase and apoptosis via reverse signaling
Indirect apoptosis in TNFR2+CD4+ T-cells
Antibody-dependant cell-mediated cytotoxicity: NK cell targets antibody-covered mucosal cell
Complement-dependant cytotoxicity

15. Summary
Crohn’s disease is an inflammatory bowel disease that causes irritation and inflammation in the GI tract
Exact causes remain undetermined but research shows that it is a mixture of pathogenic, environmental and genetic factors
Nod2 recognizes MDP and turns on protein complex NF-κB which regulates the genes controlling immune response and inflammatory reactions
Loss of immune response from Nod2 mutations allows for uncontrolled entry of bacteria into GI tract
Initiation of cell-mediated immune response leading to chronic inflammation and tissue damage
Therapeutics approved for CD include TNF-𝝰 inhibitors and drugs that block adhesion molecules
Infliximab is a monoclonal antibody that binds to TNF-𝝰 on mucosal cells resulting in apoptosis and inflammatory cytokine suppression

16. References
Berger, A. (2000). Th1 and Th2 responses: what are they? BMJ (Clinical Research Ed.), 321(7258), Retrieved from
Differentiation of CD4 T Cells into TH1 TH2 and Th17 Effector Cells - Molecular Immunology. (n.d.). Retrieved October 23, 2017, from immunology/differentiation-of-cd4-t-cells-into-th1-th2-and-th17-effector-cells.html
Naser, S. A., Arce, M., Khaja, A., Fernandez, M., Naser, N., Elwasila, S., & Thanigachalam, S. (2012). Role of ATG16L, NOD2 and IL23R in Crohn’s disease pathogenesis. World Journal of Gastroenterology, 18(5), 412–24.
Sidiq, T., Yoshihama, S., Downs, I., & Kobayashi, K. S. (2016). Nod2: A Critical Regulator of Ileal Microbiota and Crohn’s Disease. Frontiers in Immunology, 7,
Van Limbergen, J., Radford-Smith, G., & Satsangi, J. (2014). Advances in IBD genetics. Nature Reviews Gastroenterology & Hepatology, 11(6), 372–385.
T.-E.M., Manuc and Manuc M.M “Recent Insights into the Molecular Pathogenesis of Crohn’s Disease: A Review of Emerging Therapeutic Targets.” Clinical and Experimental Gastroenterology 9:59–70. Retrieved ( AGE=reference&D=emed13&NEWS=N&AN= ).
Nahar, I. K., K. Shojania, C. A. Marra, A. H. Alamgir, and A. H. Anis “Infliximab Treatment of Rheumatoid Arthritis and Crohn’s Disease.” Annals of Pharmacotherapy 37(9):1256–65. Retrieved ( %5Cnhttp://sfx.med.nyu.edu/sfxlcl3?sid=OVID:embase&id=pmid:&id=doi: %2Faph.1C039 &issn= &isbn=&volume=37&issue=9&spage=1256&pages= &date=2003&title=A).

17. References
Rogler, G., Herfarth, H., Hibi, T., & Nielsen, O. H. (2015). Anti-tumor necrosis factor therapy in inflammatory bowel disease. Basel: Karger.
Diculescu, M., Manuc, T., & Manuc, M. (2016). Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets. Clinical and Experimental Gastroenterology, 9, doi: /ceg.s53381
What are Crohn's and Colitis? Retrieved October 20, 2017, from disease?gclid=EAIaIQobChMIqsKvwrmH1wIVybXACh10uQNFEAAYASAAEgLFTPD_BwE
Crohn's Disease. Retrieved October 20, 2017, from information/digestive-diseases/crohns-disease
Lawrence, T. (2009, December). The Nuclear Factor NF-κB Pathway in Inflammation. Retrieved October 22, 2017, from
NOD2 gene - Genetics Home Reference. (n.d.). Retrieved October 22, 2017, from
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