Organ-specific immunity: GUT - Disease Flashcards
This deck contains the lectures about IBD and coeliac disease
What is dysbiosis?
Big shifts in microbiota occurring in individuals
Which factors contribute to dysbiosis? (4)
- Host genetics
- Lifestyle
- Early colonization
- Medical practices
Name examples of host genetics in dysbiosis
Mutations in NOD2, IL23R, ATG16 and IGRM
Name examples of lifestyle in dysbiosis (2)
- Diet
- Stress
Name an example of early colonization in dysbiosis
Birth in hospital leading to altered exposure to microbes
Name examples of medical practices in dysbiosis
- Vaccination use
- Antibiotic
- Hygiene
How can dysbiosis affect disease? (2)
- Upregulation of pro-inflammatory Th subsets (Th1, Th2, Th17)
- Reduced regulatory T cells (reduced regulation)
What is the paradigm in IBD?
There is dysbiosis leading to severe immune disease
What does inflammatory bowel disease result from?
An inappropriate inflammatory response to intestinal microbes in a genetically susceptible host
What does ‘inappropriate’ mean in the definition of IBD?
Deregulated immune responses
What does ‘intestinal microbes’ mean in the definition of IBD?
Commensals
What does ‘genetically susceptible host’ mean in the definition of IBD?
Individual genetic variation. There has to be a specific genetic predisposition that is different in individuals that develop IBD
What are the two major clinical forms of IBD?
- Crohn’s disease
- Ulcerative colitis
What can be said about the pattern of inflammation in Crohn’s disease?
- Patchy inflammation
- Can affect every part of the GI-tract
What can be said about the pattern of inflammation in Ulcerative Colitis?
- Inflammation localized only in the colon
- Always one stretch of tissue
What are the characteristics of Crohn’s disease? (5)
- Patchy
- Transmural
- Dense inflammation of lymphocytes
- Presence of granuloma’s
- Ulcer formation
What does ‘transmural’ mean?
Affecting all layers of the bowel wall
What do granuloma’s in CD tell us?
Immune system is not functioning properly
What are the hotspots for CD?
- Terminal ileum
- Colon
Why are the terminal ileum and colon the hotspots for CD?
This is where you have the biggest density and diversity of microbiota
What are cobblestones and how are they formed?
Healthy pieces of tissue that are bulging out, because there is strictering tissue (scar tissue) next to it. Because this stretchiness is lost in these pieces of tissue, it pushes the healthy/softer tissue out
What are the characteristics of Ulcerative Colitis? (4)
- Superficial (mucosal) layers (only top layer)
- Infiltration of lymphocytes, granulocytes
- Loss of goblet cells (typical for UC → they are empty → mucus out of the cells)
- Presence of ulcerations and crypt abscesses
True or false: ‘Histologists can not make a distinction between Crohn’s disease and Ulcerative colitis based on granuloma formation.’
False. Granuloma formation never occurs in Ulcerative colitis
How do you classify diversity in IBD?
Genetics
What is monogenic disease?
Disease caused by inheritance of single gene mutations (genes that are completely non-functional)
What is the difference between monogenic disease and SNP-associated dysfunction?
- Monogenic disease: genes are completely non-functional
- SNP: functional change. Gene is not completely non-functional
Cytokines are predominantly important in CD/UC?
CD
Immune-genes are predominantly important in CD/UC?
UC
Describe the factors involved in an immune regulation pathway in IBD (3)
- IL10RA, IL10RB (two receptors form one chain)
- IL10 (ligand)
- STAT3 (phosphorylation)
Which factor is involved in neutrophil function and phagocyte/bacterial killing?
NFkB
Why is NOD2 important?
It’s a PRR molecule important for innate immune activation
Three questions to consider when studying/adressing the heterogeneity in IBD
- Which pathways are essential to prevent IBD?
- What type of inflammation emerges from a particular defective pathway?
- What microbial changes relate to this?
Examples of monogenic disease in IBD (3)
- Defective IL10R gene
- Defective IL10
- Defective neutrophil function
Which risk increases when someone has defective neutrophil function?
Risk of infection
When do classical people start to suffer from IBD?
Peak age 25
When do patients with monogenic disease start to suffer from IBD?
Super early in age
What can cause intestinal inflammation in monogenic immune disorders? (2)
- Defective host defense
- Hyperactive host defense
Example of IBD-like disease due to defective host defense
Chronic granulomatous disease due to defective neutrophil function
Example of IBD-like disease due to hyperactive host defense
Interleukin-10 RA deficiency due to defective regulation via IL-10 signaling
Name pathways arising from gene discovery in IBD (5)
- NOD2
- Autophagy (ATG16L1; IRGM; ATG5)
- Defective barrier
- IL-10 signaling
- Adaptive immunity: IL23, IL23R, Th17, IL17
Where are polymorphisms in NOD2 most associated with CD?
In CD affecting the ileum
What are the two most important normal functions of NOD2 that can be deregulated due to polymorphisms?
- NOD2 promotes the production of AMP by Paneth cells
- Chronic NOD2 stimulation in APC down regulates pro-inflammatory cytokine production
What happens when you delete NEMO in mice?
Insufficient NFkB signaling and increased TNF-induced apoptosis
Where does the TNF come from during TNF-induced apoptosis in the absence of NFkB?
Macrophages that do have intact NFkB signaling, causes spontaneous and severe chronic intestinal inflammation
What do mice deficient for IL-10 develop?
Enterocolitis to commensal Helicobacter hepaticus
What is celiac disease?
Loss of tolerance to dietary gluten
Which part of the intestine is inflamed in celiac disease? What does this cause?
Proximal small intestine is inflamed, nutrient uptake is perturbed
What is gluten?
Protein component of wheat, barley and rye
What is gluten normally used for in plants?
Source of protein to nourish embryonic plants during germination
What are the characteristics of gluten as a storage protein? (3)
- Insoluble in water
- Disulfide and hydrogen bonds (aggregates)
- Proline-rich (resistance to degradation)
What are the elastic properties of gluten used for in the food industry?
- The fermentation of bread
- Texture of pasta
Histology: What are the hallmark features of epithelial damage and duodenal inflammation in Celiac disease? (4)
- Duodenal crypt hyperplasia
- Duodenal villous atrophy
- Increased numbers of CD8+ MHCI restricted Intraepithelial lymphocytes (IEL)
- Gliadin-specific IFN-y secreting CD4+T cells in the LP
Serum and genetics: What are the hallmark features of epithelial damage and duodenal inflammation in Celiac disease?
- Anti-tissue transglutaminase-2 (TG2) antibodies (binding antibodies - NOT neutralizing)
- Genetic susceptibility HLA-DQ2/HLA-DQ8
What is the normal function of transglutaminase-2?
Tissue damage: enzyme becomes activated and repairs
Which immune cells drive disease chronicity in Celiac disease?
Gluten (in particular gliadin) specific memory CD4+ T cells
How do gluten (in particular gliadin) specific memory CD4+ T cells drive disease chronicity in Celiac disease? (4)
- Gluten diffuse across the epithelium
- TG2 enzyme binds gluten and deamidates/changes conformation of gluten
- Deaminated gluten peptide can fit in this HLA-DQ2/DQ8 groove
- Inflammatory T cell differentiation
How does this TG2-gliadin complex drive disease in Celiac disease?
Due to the conformational change, the complex is suddenly recognized as non-self, because gliadin is attached to it
Which cytokine is predominantly produced in Celiac disease?
IFN-y, but also IL-21
Which antibody is predominantly formed during Celiac disease?
IgA
Which antibodies are produced by Celiac patients if they are IgA deficient?
IgG
Which innate cytokines are involved in Celiac disease? (3)
- IL-15
- IFN-a
- IL-21
Which cytokine would you never find in IBD, but is prominently found in Celiac disease?
IL-15
Summary: Which innate immune responses are characteristic for Celiac disease?
- Stressed innate epithelial cells secreting IL-15 and expressing NK-receptor ligands
- Cytotoxic intraepithelial lymphocytes lyse epithelium
Summary: Which adaptive immune responses are characteristic for Celiac disease?
- Inflammatory gluten-specific HLA-DQ-restricted CD4 T cells secrete IFN-y
- Plasma cells secrete anti-TG2 antibodies
What causes the villus atrophy in celiac disease?
Killing of innate epithelial cells expressing NK-receptor ligands
Summarize the celiac disease pathogenesis (3)
- CD4-T cell derived IFN-y causes epithelial stress and activates cytotoxic IEL.
- IL-15 production by epithelial cells co-stimulates cytotoxic IEL
- Cytotoxic CD8+ IEL kill epithelial cells.
What does the absence of IL-10 signaling in CD11c+ APC cause?
Celiac disease-like pathology
- Crypt hyperplasia
- Increased IEL numbers
- Increased numbers of CD4+ and CD8+ T cells in LP
Mice model: what is required for tolerance to dietary gluten?
Intact IL-10 regulation
25% of the dutch population is HLA-DQ2+, however only 1% develops celiac disease. Why?
Theory: Tregs maintain balance in healthy individuals
