Mechanisms of Mucosal Defense. Soma Jyonouchi, M.D. January 24, 2008. Mucosal Surfaces. The GI mucosal surfaces cover 400 m ² Thin – facilitate nutrient absorption. The Gut Associated Lymphoid Tissue (GALT) - Organized T and B cell areas
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Soma Jyonouchi, M.D.
January 24, 2008
- Organized T and B cell areas
- where antigen is collected and adaptive immune response is generated.
- Tonsils, Peyer’s patches, appendix, solitary lymphoid follicles in the large intestine and rectum.
** Dome structures extend into the lumen of the intestine.
1. Glycocalyx – Goblet cells produce mucous to create a thick barrier that covers the GI epithelium and prevents easy access.
- Pathogens become trapped in the mucous and are expelled via peristalsis.
- Mucous also acts as a reservoir for secretory IgA.
Epithelial Cell Tight Junctions - prevent the passages of macromolecules.
** Zonulin – Homology to Vibrio cholera toxin.
upregulated during the acute phase of celiac disease.
- Induces tight junction disassembly and increased intestinal permeability.
Drago et al. Scand J Gastroenterol. 2006
Fasano et al. Lancet 2000
di-peptides and tri-peptides.
2. Lysozyme – cleaves cell wall of
gram positive bacteria.
3. Defensins – 30-40 aa peptides
that disrupts the cell memebranes of
bacteria and fungi causing lysis.
- Pups delivered by C-section and raised in sterile conditions.
- decreased IgA plasma cells
- decreased lamina propria CD4+ cells
- Abnormalities reversed by placing non-germ free mice in same cage.
IgA response for different routes of vaccination
Holmgren et al. Nature Medicine. 2005
– some pathogens gain entry via M-cells
tissue as well as development of tolerance.
- marked difference compared to peripheral T-cells.
- T-cells induce apoptosis of injured epithelial cells.
frequently shared among IEL from
**Secretory Component (SC) of the receptor remains associated with IgA
- More flexible
- More susceptible to IgA1 specific proteases made by bacteria.
- Serum ratio 4:1
- Mucosal ratio 3:2 (even higher in colon)
Blue stain - IgA
Green stain - IgM
Red stain - IgG
Enhanced IgG and IgM response in the gut (fixes complement)
IgM IgG IgA
Addition of Con A
IgG IgM IgA
PP T-cells added to spleen cell cx
Spleen T-cells added to PP cell cx
TNF-α and IL-6
IL-1 IL-1 Ra
1. Chen et al. Journal of Experimental Medicine. 2003.
2. Mottet et al. Journal of Immunology. 2003.
- Pathogens have additional virulence factors (adhesion molecules, toxins)
- commensals also endocytoced by M-cells and engage TLRs
- Result: Inhibition of the
Immunoflourescence at 2 hrs
Salm + Bact
Kelly, D. Nature Immunology. 2004.
- Humoral and cellular immune response.