Crohn's Disease Flashcards
Materials that can be used to study Crohn’s disease:
1) Study patients
You can check the diets that IBD people need to use, to give them a better quality of life. They collected stories of patients “Voeding Helpt” with several foundations. They used a new method studying this: to collect the stories and make new hypothesis around
those insights. = PNI method
You get the stories from patients and use them to create research around it.
You ask them open questions.
They found foods to enhance quality of life: Reducing diary, sugars, gluten, meat, alcohol. Enhance vegetables, home-made food. Really obvious actually, but now it can be researched since it has a whole consensus in patients.
Materials that can be used to study Crohn’s disease:
2)Study human tissue
In vitro matured DCs express both CD83 and
DC-SIGN = but this clearly doesn’t happen on CD patients IRL. In vitro and in vivo is different. = see differences in human/in vitro
Materials that can be used to study Crohn’s disease:
3) Study human isolated cells - ILC study - Epigenetics/TNF therapy
ILC study in Crohn’s disease = There’s a specific ILC1 population that’s involved in pathogenesis of disease.
You can stain ILCs with c-Kit and NKp44 = Double negative population in Crohn’s is ILC-1.
ILC-1 is highly expressed in Crohn’s disease patients; they produce IFN-gamma which really drives Crohn’s.
• Check epigenetics from blood = Isolate DNA from blood of patients, then they made an epigenetic profile = DNA methylation is detected. Methylation levels are evaluated before and after biologicals: anti-TNF. DNA methylation is different in people who responded to TNF therapy! Which genes are those = are analysed. In other therapies = other backgrounds are also seen.
there’s much more markers changing, and an algorithm can classify specific patterns for patients that will respond and patients that won’t respond to therapy. = Really expensive therapy to not do it in trial and error. Also max %50 people responds, so it’s great to look at.
Materials that can be used to study Crohn’s disease:
4) Study cell lines - THP1
In Crohn’s disease, there’s too many M1 macrophages, and they want to make it M2 “wound healing” type to reduce the inflammation, and have better intestines. THP1 is good for modeling macrophage differentiation.
Materials that can be used to study Crohn’s disease:
5)Mouse models of IBD
Mouse models of intestinal inflammation like IBD:
-Spontaneous colitis :Induced on monkeys, but hardly used anymore.
-If you mutate something, CKO, or transgenic animals: colitis occurs right away. It’s really important to have good balanced immune response in the intestine.
Colitis induced by agents: . induced by DSS. If DSS is given to mice, they get leaky gut. Mucus layer gets effected, in 12 hours bacteria accumulate there. = inflammation happens. TNBS: causes contact allergy, Type IV hypersensitivity in gut. TH1 reaction.
Colitis can be induced by disturbing eg. Tregs.
Parameters of disease in chemically induced colitis
Weight loss
Colon length
Colon weight
colon length and weight is checked since if inflamed, length decreases and weight increases.
Histology
Disease Activity Index (DAI)
DAI exists as a disease seriousness index in both humans and mice.
Endoscopy
Endoscopy is done to see when the disease is induced, and at that point they can treat the animals.
Cytokine profile of colon, spleen, LN
What we learned from IBD animal models
GWAS susceptibility genes + roles
Different genetic abnormalities that can result colitis
Microbiota importance
Essential role of APCs, Thelpers, Tregs, macrophages, mucosa barrier
Materials that can be used to study Crohn’s disease:
5) Study data from databases - chronic fatigue syndrome
Check genes of Chronic fatigue syndrome
Public dataset of mRNA expression - get it via an algorithm
They found 23 genes, 10 of them related with immune system.
Check similarity of Chronic fatigue syndrome/ Crohn’s disease genes.
Crohn’s do fatigue too.
Materials that can be used to study Crohn’s disease:
5) Study data from literature - MINCLE
Use literature for new findings:
In Crohn’s disease = there’s strong TH1 and TH17 immune response. It’s kind of not that specific, they produce a lot of IFN gamma and IL-17 = they are effector cells. But there’s no antigen involved.
There’s a random study about MINCLE CTL receptor, and it induces exact same response with an adjuvant. = looks very similar to IBD.
Due to literature, they found when macrophages and DCs in epithelia are activated with a stimulus like PGN/PAMPs, they become activated, and start expressing MINCLE receptor + and since they get continuously exposed to PAMPs due to bacterial wall PGN = they get Chronic inflammation/granulomas = Crohn’s.
So in Crohn’s disease = there’s some type of response like happening in adjuvants, due to continuous exposure to danger signals from the microbiome, activation of immune cells become persistent.
DAMPs/PAMPs: They really help sustaining the continuous inflammation.
Materials that can be used to study Crohn’s disease:
5) Study data from literature - DAMPs unrelated
Elder people has too much DAMPs, As a consequence, Flu vaccine works poorly in elder people, they have less T cells, less Abs, less inflammation. Inflammasome = they understood COVID-19.
Immune fitness / complexity- how to study:
Immune fitness is important: also seeing in whether your defenses work properly: Are you giving a proper response or less or too much response / is there a genetic problem? = answering those questions.
Important in IBD too = multifactorial disease.
Some people have different immune receptors “immunotypes” = more or less susceptible.
For increased risk people: you can make Integrative Personal Omics Profile (IPOP) for personalized medicine.
How to study:
Study it crossdisciplinary - Biology / Physics for eg.
Study common pathways
Imagine and create
Use complex system science = build computational models from IRL observations = create a virtual lab.
