Lecture 17: Gut Immunology Flashcards
What is GALT?
Gut-associated lymphoid tissue
- part of MALT, which works in the immune system to protect the body from invasion in the gut.
- has Peyer’s patches and isolated lymphoid tissue
Where do isolated lymphoid follicles develop after birth?
Small and large intestine
How does GALT receive antigens?
Directly from epithelial surface and dendritic cells
Microbes crossing the epithelium enter Peyer’s Patches through what cells?
M cells
-microbes endocytosed by dendritic cells from here
After dendritic cells with antigens interact with Peyer’s Patches, what happens?
Differentiation of T-cells
Differentiation of T-cell-dependent B cells maturation
What do mature B cells in the gut release?
IgA producing plasma cells
What promotes the development of mature ILFs (isolated lymphoid follicles)?
- MAMPs recognized by PRRs (pattern-recognition receptors)
- Stimulate recruitment of B and T cells
- Cryptopatches develop into mature ILFs
What are Paneth Cells?
Cells found in the small intestine that have antimicrobial properties similar to neutrophils
What are defensins?
Antimicrobial peptides that contribute to mucosal host defense of the GI system
-important role in innate immune system
Describe different types of intestinal epithelial cells.
- Goblet Cells: Produce dense mucin
- Enterocytes: absorptive cells in SI and LI
- Colonocytes
- Paneth Cells
What is the role of secretory IgA?
Maintain peaceful bacteria-host interaction
- does not activate complement system
- does not activate phagocytosis
- resistant to proteolysis
How do defensins work?
Has both hydrophobic and hydrophilic parts
-can disrupt microbial membranes and form pores
Where do most of the commensal bacteria reside?
Outside the layer of mucus covering intestinal epithelial cells
What kills commensal and pathogenic bacteria that penetrate epithelial layer?
Macrophages in lamina propria
Can dendritic cells eventually reach systemic circulation?
No
- mesenteric lymph nodes function as a barrier
- loaded DCs cannot penetrate farther than systemic circulation
What happens to B and T cells after activation?
Unlike DCs, they can leave mesenteric lymph nodes through efferent lymph and enter blood stream at thoracic duct
What is the significance of short chain fatty acids
Important source of energy for colonocytes
- from colonic microbial fermentation of dietary fibers
- stimulate production of mucus
- support effective IgA mediated response to pathogens
What does acetate stimulate?
Accumulation of IL-10 producing Tregs
What does butyrate stimulate?
Acts on Tregs
Modulate DC to enhance Treg-inducing ability
What does capsular polysaccharide A (PSA) act on?
Tregs
Improves expression of IL-10 and TGF-β
What is immune tolerance?
Sustained immune unresponsiveness to self-antigens, beneficial antigens, and commensal bacteria
-not attacking self or good bacteria
What is oral tolerance?
Suppression of immune responses to antigens administered orally
If immune or oral tolerance is disturbed, what can that lead to?
Food allergies
Celiac Disease
What is central tolerance?
Immature lymphocytes that select self-antigens in central lymphoid organs are deleted or develop into Treg cells
What is peripheral tolerance?
Self-reactive lymphocytes in peripheral tissues are inactivated, deleted, or suppressed by Treg cells
Which immature T cells are selected to become Treg cells?
T cells with high affinity for self-antigens and expresses Foxp3
Why does central tolerance not prevent responses against antigens in lamina propria?
Intestine antigens are not available in thymus
-why it is so imp for peripheral tolerance
Describe the mechanisms of oral tolerance.
1) Macrophages take antigens from intestinal lumen across epithelial barrier
2. Macrophages transfer antigens to dendritic cells in lamina propria
3. Dendritic cells with antigens go to mesenteric lymph nodes
4. DCs stimulate naive CD4 T cells into Treg cells
What are examples of non-immune mediated adverse reactions?
- Absence of an enzyme (e.g. lactose intolerance)
- Irritable Bowel Syndrome
- Food poisoning
- Recurring stress or psychological factors
What are examples of immune mediated adverse reactions?
- Food allergies
- Celiac Disease: triggered by gluten
- Sensitivity to food additives
What type of hypersensitivity is most common with food allergies?
Type I Hypersensitivity
-characterized by IgE antibodies against food allergens
Describe a secondary response to a food allergen.
After recurrent contact with an allergen, IgE-dependent secondary immune response activated
-allergen is degraded and fragments are distributed throughout the body –> response in skin, respiratory tract, and circulatory tract
What are some mediators of an early allergic reaction?
Histamine
Tryptase
Bradykinin
What are some mediators of an late allergic reaction?
Prostaglandins
TNF-alpha
Leukotrienes
Various interleukins
How do disseminated antigens trigger distal reactions?
Mechanisms dependent on histamine and platelet activating factor (PAF)
- urticaria (hives)
- bronchospasm
What cytokines are GI manifestations of food allergies dependent on?
Th2 derived cytokines: IL-4, IL-13, IL-9
What do response to local GI allergen exposure do PAF and serotonin mediate?
Diarrhea
What is the central role of Treg cells in controlling food allergies?
1) Secrete IL-10 and TGF-β to suppress Th2
2) Inhibit mast cell reactivity
3) Reduce IgE synthesis
4) Increase IgG and IgA synthesis
What vitamins suppress inflammatory responses?
Vitamin D
Vitamin A
Folate
What are some ways to diagnose an IgE mediated allergy?
Testing Type 1 Hypersensitivities:
- Skin Prick Test
- Serum-specific IgE test
- Atopy Patch
- Basophil activation test
Describe the non IgE mediated allergic reactions to peanuts.
- Peanuts stimulate production of C3a
- C3a stimulates production of macrophages, basophils, and mast cells
- PAF and histamine released
- Increase in vascular permeability and smooth muscle contractility.
How does anaphylaxis occur in those with peanut allergies?
- Mast cells are activated by IgE cross-linking FceRI
- Also mediated by IgG1 induced activation of Mf
Mediators (histamine and PAF) released by mast cells
What allergens mosty cause a wheat allergy?
α-amylase inhibitors
germ agglutinin
peroxidase
Majority of infants with an allergy to cow’s milk has what specific type of majority?
non-IgE-mediated allergy
-can take up to 48 hours to develop
What is celiac disease?
Systemic immune disorder caused by permanent sensitivity to gluten
Which HLA molecules are the predisposing factor in developing celiac disease?
DQ2 and DQ8
In Celiac Disease, what autoantibodies are found?
anti-Tissue Transglutaminase 2 antibodies
What is the purpose of Transglutaminase 2 (TG2)?
Deamination of glutamine found in gluten
What type of hypersensitivity is Celiac Disease?
Type IV Hypersensitivity
Describe how Celiac Disease works.
- Gluten molecule: has gliadin that binds with IgA.
- Gliadin/IgA compound is recognized by transferrin receptor and moved from apical side to basolateral side.
- tTG deaminates glutamine and is picked by macrophages
- Immune response starts attacking epithelial cells of GI tract
What is the best way to test for Celiac Disease?
- tTG-IgA test
