Crohn’s Disease

1. Crohn’s Disease Brian Sims Andrew Parikh

2. Overview • What is Crohn’s Disease • Symptoms-populations commonly affected • Causes • Tests/Diagnostics • Treatment

3. Crohn’s • Chronic disorder that primarily affects the digestive system (GI tract) and is classified as inflammatory bowel disease (IBD) • Involves abnormal inflammation of the intestinal walls; particularly the ileum and colon (small and large intestine)

4. Crohn’s • Inflammation can occur in any part of the digestive system leading to thick and swollen surfaces called ulcers. Healthy ileum Ileum affected by Crohn’s

5. Symptoms • Abdominal pain, rectal bleeding, diarrhea, weight loss, fever, anemia, nutritional deficiencies, are most common. Fistulas can appear in certain cases. Fistula between the bladder and large intestine Photo courteous of Merck

6. Who does it affect? • Jewish Populations • Not sure why, researchers of MAP say that it’s a direct correlation between Johne’s and MAP • Teens and young adults • Reasons unknown • Between 450-800 thousand people in the U.S.

7. Projected Causes • There are several theories of what causes Crohn’s but non have been accepted entirely. However, researchers commonly agree bacteria is the culprit. • Theory 1- Autoimmune/Hyperactive • Theory 2-IL-23 • Theory 3- MAP bacteria

8. Theory 1- Autoimmune/Hyperactive • Some autoimmune diseases are mediated by direct cellular damage • This occurs when lymphocytes or antibodies bind to cell membrane antigens causing cellular lysis and/or an inflammatory response in the affected organ(s). • Without treatment the damaged cellular structure is replaced by connective tissue (fibrosis) which in turn leads to declining organ functionaility. • Why does this occur?

9. Theory 1- Autoimmune/Hyperactive • Naturally occurring bacteria promote an immune response that becomes hyperactive • Treatment involves Interleukin-10 to regulate hyperactive T-cells • IL-10 is known as a cytokine synthesis inhibitory factor (CSIF) …… meaning it is an anti-inflammatory cytokine. • An immunoregulator in the intestinal tract • With overactive T-cells inducing collateral damage to intestinal tissue, IL-10 can inhibit the hyperactive T-cells and prevent damage to the surrounding tissue. • Depends of the severity of disease, this treatment is particularly for early stage patients. Crohn’s Video IL-10

10. Theory 1- Autoimmune/Hyperactive • More severe cases • High-Endothelial Venules (HEVs) are found in chronic inflammatory disease's like Crohn’s • HEVs can be described as cuboidal or “high” in shape • Regions of plump endothelial cells resembling HEVs appear along the vasculature in tertiary extralymphoid sites of chronic infection. • These HEV-like regions appear to be sites of lymphocyte extravasation into the inflamed tissue • Therefore, development of this HEV-like vasculature is likely to facilitate a large-scale influx of leukocytes which contributes to chronic inflammation.

11. Theory 1- Autoimmune/Hyperactive HEV Overview

12. Theory 1- Autoimmune/Hyperactive • This suggests that an effective approach for treating Crohn’s would come from controlling the development of HEV-like regions • Antibody therapies reduce leukocyte extravasation • However, this has been conducted in patients with Crohn’s using anti-α4 antibodies and led to virally linked leukoencephalopathy due to decreased migration of immune cells into sites of the immune system.

13. Theory 2- IL-23 • Structure • Heterodimeric subunits • IL12p40 (shared w/ IL12) • IL23p19 • Function • induces proliferation and IFNG production by T cells • preferentially stimulates memory T cells • plays a key role in development of IBD

14. IL-23 • Similarity to IL12 • Secreted by macrophages and dendritic cells • Shares the IL12p40 subunit • The receptors for IL12 and IL23 can be distinguished by their response to the secondary subunit of IL12 or IL23 • Blocking the shared subunit will inhibit both cytokines • Both influence adaptive immunity • IL12 and IL23 interaction is not completely known • IL12 without IL23 leads to severe acute inflammation

15. IL-23 • IBD • Immune system of intestine must balance tolerance to some antigens and ability to fight pathogens • balance is achieved by reciprocal regulation of proinflammatoryeffector CD4+ T cells • deregulation of IL23 pathway leads to organ inflammation • IL-23 and IBD • produced by macrophages following bacterial stimulation or CD40 sign • cytokine cascade leading to increased levels of TNFA, IL6, INFG and IL17 • IL17 is increased in in IBD patients • causes increased neutrophil recruitment into tissues • induces inflammatory cytokine production by macrophages • Possible Treatments • IL12p40 monoclonal antibody that neutralizes IL12 and IL23 may be effective as a treatment for Crohn’s Disease. • Anti-TNFa antibodies to treat the inflammation

16. IL-23

17. IL-23 • Conclusion • It is not known specifically what triggers Crohn’s Disease • It is known that IL23 plays a key part in regulation of cytokines • We do not know how a mutation of IL23 can lead to Crohn’s • Theoretically the most effective treatment would be to block IL12 and IL23 due to their parallel pathways to inflammatory response • To block IL12 and IL23 would compromise the host ability to react to pathogens

18. Theory 3- Mycobacterium avium subspecies paratuberculosis (MAP) • Derivative of Mycobacterium Paratuberculosis=TB • Johne’s Disease found in cows • MAP is proven to be the cause of Johne’s • Crohn’s and Johne’s-the same? • -almost similar in symptoms • How does MAP work? • MAP disseminates from infected to non-infected macrophages allowing the bacterium to avoid humoral and cellular mechanisms of immunity. • Lesions spread and grow by accumulation, reinfection, and expansion of macrophage populations in the intestinal wall. • Although infection is often restricted to the intestine, bacteria can spread via monocytes from the primary site of infection in the intestine to the liver, spleen, kidney, uterus, and/or mammaries through lymphatic routes.

19. MAP • How do people become infected? • Macrophage • w Ith • Lurking • Killer

20. MAP • Transmission of MAP • Consuming milk and other dairy products infected with MAP • Pasteurization is not enough, look for milk that has been ultra-pasteurized • Wide scale • U.S. and Great Britain retail store milk contaminated • Samples showed MAP in quantities of 50CFU/50ml milk • Cultures also proved positive for MAP from milk

21. MAP • Recent Studies • Approximately 83% of Crohn’s patients showed evidence of serum antibodies to MAP. • Mothers • Lactating mothers with Crohn’s shed MAP in their breast milk • Is it enough? • Unlike Johne’s disease, reports are mixed as to the presence of MAP at the site of the intestinal lesions. • Purely coincidence… or something else? Milk and Crohn’s

22. Tests/Diagnosis • Timescale • 1-3 years is usual in determining Crohn’s due to its similarities with other GI problems/ disease like ulcerative colitis • CT Scans (computed tomography) • Determine whether an infection has spread or to locate it before a surgery • Colonoscopy • Determine whether ulcers, lesions, infection, etc. present

23. Treatment • Variability • Since Crohn’s patients symptoms vary from person to person, flare ups and remission can occur at random so finding a treatment can be frustrating. • Medication • No cure…yet…but prescribed drugs to reduce inflammation, lower fever, and reduce diarrhea. Examples • Prednisone suppresses the immune system • Pentasa (mesalamine) acts as an anti-inflammatory • Surgery • Last resort- typical for Crohn’s patients to have surgery 6-8 years throughout their lifetime…but each persons situation is different depending on the severity of the disease

24. Complicated Disease • Kacey • 22F with anemia as only correlation, 2.5 years to diagnose between 11 doctors, 1 being a Crohn’s specialist • Progression of severity • Within one year, stomach pain became unbearable and led to uncontrollable shaking • 4 CT scans within a period of 2 days at hospital • Could not determine why radiopaque was not showing up in scan • Surgery • The “idea” came up of a blockage

25. Complicated Disease • Good idea • Fistula kinked part of large intestine, food and barium sulfate concentrated, fecies introduced into surrounding area causing infection leading to severe pain • Six inches of the ileum removed along with an infected appendix which is rare

26. The Stomach-Battle Wound