Lecture 9 Flashcards
Pathophysiology of CD
Phase four: tissue damage
Different stages of intestinal mucosa damage in CD from 1 to 5
Progressive loss of SI villi and micro villi = compromised mucosal membrane
- activated TH1 cells secrete IL-21 which functions to activate B cells in lamina propria and Peyers Patches which RELEASE ANTIBODIES
- B cells release antibodies against:
— gluten (gliadin and glutenin)
— TTG
— collagen in lamina propria
— actin and endomysium .
Review slide:
B cell antibodies (auto antibodies) in CD
Antibodies normally function to:
- target specific protein for destruction via other cells or
- inhibit/neutralize target directly
In CD, activated B cells start making antibodies against structural components in the small intestine (auto/self antibodies) thinking its an antigen
- the “antigen” is actually structures of the small intestine -> causes more tissue damage
Result: antibodies target specific healthy small intestine tissue structures for destruction by the cells in the immune system
Types of B cell antibodies in CD
Anti-collagen antibodies: destroy collagen in the extra cellular matrix (ECM) of the lamina propria
Anti-actin antibodies: destroy actin in the muscle layer of the SI
Anti-endomysium antibodies: destroy the connective tissue sheath around the muscle layers of the small intestine for destruction
- antibodies against gluten proteins also produced and TTG
- these antibodies are secrete by B cells and found on both sides of the epithelial barrier (lumen AND lamina propria -> blood)
Anti gluten antibodies
Anti gluten (really anti-gliadin and anti glutenin) antibodies typically secreted into the lumen of intestine where they complex with gluten proteins to form a complex
- the anti gluten antibody + gluten complex SHOULD have a protective role and neutralize the gluten BUT INSTEAD the complex binds with CD71
- CD71 is a receptor on the apical surface of epithelial cell that is upregulated in active CD
- CD71 helps with retrotransport of gluten across epithelial barrier into lamina propria
- CD71 helps bring gluten into contact with TTG (leading to further deamidation)
Result: gluten peptides are retrotransported across the epithelial barrier -> increases gluten access into the lamina propria and perpetuates the immune response to gluten
B cell antibodies in the CD immune response (TTG)
Anti-TTG antibodies SHOULD have protective effect in CD response but:
- TTG enzyme in the lamina propria normally binds to fibronectin and in addition to its enzymatic function (deamidation), TTG ALSO plays a role in ECM assembly
- therefore, TTG can influence epithelial barrier repair processes AND epithelial cell proliferation meaning TTG plays a key role in rebuilding damaged ECM in the lamina propria and restoring the epithelial barrier
- when TTG is bound to anti-TTG antibody, it cannot perform these beneficial functions -> perpetuates tissue damage and delays wound healing
- result: barrier remains leaky and damaged
Anti-TTG antibodies are detected in the blood and trigger autoimmune reactions in the skin and the development of dermatitis herpetiformis AND can trigger pancreatic islet cell destruction and development of T1 diabetes
Pathophysiology of CD
Other factors: Zonulin and CXCR3
- increased zonulin expression in CD: increases intestinal epithelial permeability
- zonulin then binds to the surface receptor CXCR3 on the epithelial cell apical membrane
- CXCR3 also over expressed in CD
- zonulin-CXCR3 signalling acts to loosen the tight junctions between epithelial cells
— increased leaky barrier allows more gluten peptides to pass between epithelial cells and access lamina propria where they will be phagocytosed by APC and presented to CD4+ T cell
Vicious cycle: mechanisms that perpetuate the CD response
Genetics play a role in CD response: HLA-DQ2 and 8 (7 recently) BUT other genes and protein are over expressed in CD that promote aspects of the inflammatory response:
- zonulin and CXCR3
- CD71
-MIC-A
-TTG
- IRF4 (controls IL-21)
- Production of B cells
- IL-5 inhibits the activity and suppressive function of Regulatory T cells (Treg): perpetuates TH1 response
- IFNy stimulates TTG activation by stimulating Thioredoxin-1: promotes deamidation of gluten
Overall: even after gluten is removed from the diet, some of these mechanisms sustain delayed wound healing
Clinical considerations in Celial Disease: atypical celiac disease
- usually diagnoses in older children and adults: most common form of CD
- “tip of iceberg (presenting symptoms = easier to diagnose”
- main symptoms are extra intestinal:
- anemia/iron deficiency
- osteoporosis
- dermatitis (skin lesions, responsive to gluten free diet, linked to anti TTG antibodies)
- Type 1 diabetes: (why?)
- patients already have increased intestinal permeability before pancreatic islet destruction
- a majority of T1D patients have elevated serum zonulin (increases leafiness)
- gliadins potential trigger
- HLA-DQ2 haplotype is present in 50% of T1D patients
Clinical considerations in CD: diagnosing with serology testing
- no perfect antibody diagnostic marker: anti TTG is most accurate
- CD patients will products different levels and types of antibodies
- tests:
- IgG: anti gliadin
- IgA: anti gliadin and anti glutenin
- IgA: anti TTG
Serology should be measure don gluten rich diet
Serum antibody levels remain elevated 1-12 months after starting gluten free diet
Clinical consideration in CD: compliance issues with treatment
Adherence to gluten free diet is low especially in asymptotic people
WHY is adherence to GFD important?
- adherence to GFD restores intestinal structure and function which reverses any secondary deficiencies (LI, vitamin malabsorption)
MIDTERM QUESTION: despite feeling clinically well, consumption of gluten can lead to “under the surface” issues like micronutrient deficiencies, which an lead to irreversible conditions (osteoporosis, etc)
- CD is associated with increased risk of malignancy (GI cancer and lymphomas) and mortality
— study showed adherence brought CD ppls cancer risk down to some as general population - undiagnosed CD is associated with preterm pregnancies
Last slide:
- GFD REMAINS SAFEST AND MOST EFFECTIVE TREATMENT
Other treatments:
- GMO diet
- zonulin/CXCR3 antagonists
- TTG inhibitors
- cytokine inhibitors
- IRF4 and Tbet inhibition
(None work)
