W10L12 - Immunity of the Epithelium Flashcards
Regional Immune System
Immune cells and molecules serving a specialised function of an anatomical sight
Epithelium
- barriers
- much of which interact with outside world
- mucosal epithelium: gastrointestinal, bronchopulmonary, genitourinary
- cutaneous epithelium - skin
Contact with pathogenic microbes
- immune response
Also contact with non-pathogenic microbes (commensals)
- tolerate (non-response), live in harmony
GI Tract Epithelium Immunity
Number of lymphocytes (50 x 10^9) is 5 times more than in circulation
More antibodies made than anywhere else
Large, wet and warm surface area (absorption of nutrients)
Single cell epithelial layer with underlying connective tissue
Trillions of bacteria (many types)
80% of all immune system located in GI tract
Skin Epithelium Immunity
Number of lymphocytes (20 x 10^9)
Large, dry and cool surface area (direct contact with atmosphere)
Thick multi-layered epithelium before underlying connective tissue
Not as many bacteria on surface (limited number of types)
Innate Immunity of the Epithelium
Barriers
- epithelial cells have tight junctions preventing microbes from passing
- skin epithelium made of layers of stratified squamous cells (keratinocytes)
- mucus produced on surface of mucosal epithelium
Chemicals
- mucin in mucus
- gastric acid
- defensins
- cytokine production (inflammation)
- surfactant protein A and D on alveoli of lungs
Cells
- microvilli and cilia on epithelial cells
- M (microfold) cells imbedded into epithelium of GI tract
- DC (langerhans cells), macrophages
- epithelial cells expressing TLR = production of cytokines
- innate lymphoid cells (e.g. NK cells)
- mast cells and eosinophils
Defensins
Small cysteine rich cationic proteins found in both vertebrates and invertebrates
Active against bacteria, fungi and some viruses
18-45 amino acid
Function by binding microbial cell membrane forming a pore like defect
Several types (α, β and θ) in humans only α and β defensins
α defensins
- primarily expressed in neutrophils and NK cells
- paneth cells of small intestine also express α defensins to regulate microbes in intestinal lumen
β defensins
- most widely distributed, secreted by leukocytes and epithelial cells
Regulation of the Innate Immunity of the GI Tract
Some macrophages in the GI tract express IL-10 after phagocytosis of microbes (IL-10 is anti-inflammatory)
- this phenotype is induced by local TGF-β
- prevents response to commensal microbes
DC and Macrophages in lamina propria have low expression of TLR 4 (response to LPS on gram neg bacteria)
TLR expression is regulated
- TLR5 recognises bacterial flagellin is only expressed on baso-lateral surface of intestinal epithelial cells, not on lumen surface so only invading bacteria recognised
- TLRs in intestinal cells either low in expression or have a higher threshold of activation compared to other epithelium
Adaptive Immune System of the GI Tract
Major form of adaptive immunity is production and secretion of sIgA
- IgA binds and prevents bacteria as well as other microbes from invading the epithelium
- major function of sIgA is to neutralise microbes in the gut lumen
- B cells in the GI tract undergo class switching to IgA
- other IgA B cells tend to home in on the GI tract
Major T cells are the Th17 T helper cells
Major control mechanism is through Tregs
- limits inflammation
- tolerance of commensal microbes and food
- IL-10 producing Tregs are more common in GI tract than anywhere else
Structures of the Adaptive Immune system of the GI Tract
Gut-associated lymphoid tissue (GALT)
- mucosal-associated lymphoid tissue (MALT) of the GI tract
Peyer’s patches
- mainly in distal ilium
- lymphoid follicle structure: germinal centre containing B cells, follicular T helper cells, follicular DC, macrophages. Germinal centre is surrounded by IgM/IgD naïve B cells
- not encapsulated
- area between follicles and epithelium is called the dome (DC, Macrophages, T and B cells)
Ratio of B cells to T cells is 5x higher than in lymph nodes
- ag delivered to Peyer’s patches directly (not via lymphatics) - local immune response
M (Microfold Cells)
Specialised cells in epithelium overlaying Peyer’s patches
- shorter than surrounding epithelium
- short, irregular microvilli (microfolds)
Endocytose/phagocytose antigens and transport to underlying DC, macrophages and lymphocytes
- molecules that bind microbial structures
- don’ process ag
- vesicles deliver intact Ag to basolateral membrane for exocytosis
- DC and B lymphocytes in dome region take up Ag
Important link between lumen of intestine and immune system of intestine
Main ag delivery system for GI tract
Some microbes have adapted M cells for invasion (Salmonella typhimurium)
Mesenteric Lymph Nodes of GI Tract
100-150 LNs in the mesentery
Same function at GALT (differentiation of B cells to IgA plasma cells)
Development of effector T cells and Treg
Homing of cells back to GI lamina propria
Tonsils
Part of GI and Respiratory tracts (oral cavity, microbes): lingual and palatine
Encapsulated lymphoid tissue (similar to Peyer’s patches)
Under multi-layered stratified squamous epithelium (unlike Peyer’s patches)
In response to infection they enlarge and produce mainly sIgA
Lymphocytes Homing to the GI Tract
Effector T cells, IgA B cells and IgA plasma cells circulate back to the GI
Changes to adhesion molecules and chemokine receptors during activation in GALT and lymph nodes
- main adhesion molecule to get expressed on T and B cells after activation is α4β7 integrin which binds to MadCAM-1 (mucosal addressin cell adhesion
molecule 1) expressed on venular endothelial cells in lamina propria of gut
- chemokine CCR9 gets expressed on T and B cells homes in on ligand CCL25 on intestinal epithelial cells
- MadCAM-1 and CCL25 restricted to gut
T Cells in the GI Tract
T cells are found in lamina propria, submucosa and in Peyer’s patches
- most intraepithelial T cells are CD8+ cells (cytotoxic T cells)
- most lamina propria T cells are CD4+ cells (T help)
DCs and Macrophages are abundant and either stimulate effector T cells for immune response or induce regulatory T cells to suppress an immune response
Most CD4+ T cells in the GI are Th17 cells.
- produce IL-17 and IL-22
- receptors for these cytokines are found on intestinal epithelium
Th2 cells
- response to helminth infection through IL-4 and IL-13
- IgE response, enhanced mucous secretion
Th1 cells
- increased numbers in conditions such as inflammatory bowel disease
Treg Cells
Abundant in GALT
Prevent immune response to commensal microbes
DCs and macrophages produce retinoic acid and TGF-β
- response to gut microbial flora
- promote FoxP3 expression
- suppress Th1 and Th2
Dominant mechanism of Treg in GI is the production of IL-10 to suppress immune response
Inflammatory Bowel Disease
E.g. Crohn’s disease and ulcerative colitis
Defective regulation of immune response to commensal microbes
- innate immunity to commensals: defective defensin expression leading to increase invasion across intestinal epithelium
- abnormal Th17 and Th1 responses: genetic polymorphisms in IL-23 receptor gene, Th1 cells producing IFN-ɣ stimulating inflammatory response
- defective Treg: failure to develop Treg (Foxp3 gene mutations) results in reduced regulation of immune response
