141. Mucosal Immunology

Question 1

What are the 2 compartments of GALT?

What are 4 unique aspects of GALT?

Answer 1

Inductive Site - antigen sampling/presentation
Effector Site - armed/ready to respond (LN, LP, Plasma cells, IgA)

1. Microfold (M) Cells
2. Preferential production of secretory IgA
3. Paneth Cells
4. System promotes immune tolerance to oral antigens

Question 2

How does the gut produce a physical barrier? what is antigen exclusion? What are the regional differences in physical barrier between large and small intestine?

Answer 2

Goblet cells produce mucins and trefoil factors = highly viscous layer to exclude luminal bacteria (Antigen exclusion)
Epithelial Cell tight junctions prevent transport
Small intestine: more protective mucins/mechanisms, Paneth Cells
Large intestine: mucus + Goblet cells (Lypd8 binds flagellated bacteria)

Question 3

IgA - what cells produce it? How is it secreted to lumen?

• what are its functions?
• What is the effect of selective IgA Deficiency?

Answer 3

Produced by plasma cells in LP, dimerizes, bind secretory factor on epithelial cell - moves transcellularly, secreted to lumen
Fx: confines commensal bacteria to mucus layer, binds invasive pathogens, neutralizes microbial toxins/pro-inflammatory mediators, neutralizes antigens in epithelial cell endosomes, uptake of luminal antigens, transport of antigens from LP to lumen

IgA deficiency: most common immunodeficiency, affects IgA based screening tests (Celiacs), other antibodies compensate (intestinal sIgM), may influence development of autoimmunity/allergy (less immune response, modulates Tregs, regulates commensal flora)

Question 4

What is the function of Paneth cells?
What can Goblet cells secrete?
What are the regional distributions of Paneth and Goblet cells?

Answer 4

Paneth: base of small intestine crypts - protect intestinal stem cells by secreting antimicrobial peptides
Goblet cells: produce mucus and trefoil peptides - antimicrobial properties

Paneth cells ONLY in small intestine
Goblet cells in BOTH small and large intestine

Question 5

How does GALT perform antigen uptake and lymphocytic trafficking?

Answer 5

Antigen Uptake at Induction Site
M cells - pockets to endocytose antigens and present to APCs
Peyer’s Patches - lymphoid follicles
DC - sample luminal antigens (from M cells, goblet cells or itsself); APC
Epithelial Cell - APC

Lymphocytic Trafficking

1. Induction Site: luminal antigen sampling at Peyer’s Patches
2. Lymphatic migration to mesenteric lymph nodes
3. Effector Sites: recirculate back to gut (reside in LP)

Question 6

How is the immune system induced? Where does activation occur?

Answer 6

Antigens from epithelial cells to DC - present to naive T/B cells - activated, proliferate/differentiate
Activation in Peyer’s Patches, Mesenteric LN (migration0)

Question 7

Effector Immunity

• how do effector cells home to GI tract?
• what GI cell groups act as effectors?

Answer 7

Effector cells upregulate chemokines for homing (alpha-4-beta-7: binds MADCAM1 on mucosal endothelial cells - target for IBD therapy; CCR9 binds CCL25 on GI epithelial cells)

1. LP Cells (IgA plasma cells, activated B cells, CD4 T Cells, macrophages/DCs)
2. Intraepithelial Lymphocytes (CD8 T Cells, some CD4 (more innate CD8))

Question 8

How do epithelial cells act as part of innate immunity?

Answer 8

1. Physical/Immune barrier for GI tract
2. Front line of immune recognition
3. PRRs bind PAMPs of viruses/bacteria - triggers cytokine production - immune cell recruitment
4. Cross-talk with microbiome to enhance epithelial cell fx

Question 9

How is Oral Tolerance established in GALT?

Answer 9

1. Antigen Exclusion/Ignorance: antigens cannot get to immune areas (mucus layer/IgA binding)
2. Active immune response produces inhibition/anergy: tolerogenic DCs induce Treg response

Tolerance must be DEVELOPED (allergies in kids) and MAINTAINED (allergies in geriatrics)

Tolerogenic DCs: CD103, CD116, Wnt-beta-catenin (regulates BALANCE b/w inflammatory/regulatory response)

Question 10

How does immune tissue interact with gut microbiota?

What is dysbiosis? What diseases does dysbiosis contribute to? How can you manipulate dysbiosis to tx disease?

Answer 10

Immune tissue development REQUIRES normal gut colonization = antigenic education (balance)

Dysbiosis: intestinal flora altered from healthy equilibrium at baseline (pathogenic bacteria proliferation)
- contributes to IBD, DM, Obesity, Food Allergy
IBD: B. fragilis normally delivers mLc’s to immune cells via OMV secretion = Treg production = protects against UC [Atg16L1 gene = no response to OMV = less UC protection]
Allergy: neonatal abx exposure = higher allergy risk (clostridia protect)

Tx: Fecal microbiota tx - good for recurrent C Dif Colitis (maybe obesity, autoimmune disease, CNS conditions)
Vaccine development (oral administration?)