Lecture 8: Mucosal Immunity (Ben) Flashcards
What are some physical + biochemical barriers for pathogen penetration in the mucosa?
- Tight Junctions
- Ciliary Movement - in trachea
- Fluid/Air Movement - coughing, sneezing, etc.
- pH - unfavorable for pathogens
- Antibacterial molecules - (details in later card)
- Commensal flora
What are the pH values of the…
skin?
stomach?
vagina?
pancreatic juice?
(prob not super important)
- skin 5.5
- stomach 1.2-3.0
- vagina 4.5
- pancreas 8.0
What antibacterial molecules can be found in…
saliva/colostrum? tears, sweat + saliva?
others?
- lactoperoxidase in saliva/colostrum
- lysozyme in tears, sweat + saliva
- defensins - in many body fluids/tissues
Give some examples of GALT.
Large proportions of what cell types + molecules are found in it?
What are its 3 ‘tasks’?
- Peyer’s patches, tonsils, appendix
- more lymphocytes than elsewhere; 2/3 of total Ig
- Tasks: exclude pathogens/antigens from invasion; initiate local/systemic immune responses; induce tolerance
Describe the structure of a Peyer’s patch from luminal to basal.
- M cells at lumen
- SED - “subepithelial dome” = APCs
- TDA - T cells below SED, surrounding follicles
- Follicles - clusters of B cells within TDA
- afferent lymph vessels connect the most basal parts of the patch to nearby mesenteric lymph nodes
Describe the function of M cells in the intestine.
- transport antigens across the epithelium to dendritic cells below
- (take up luminal antigen via endo-/phagocytosis -> transport it basally in vesciles -> release it to subepithelial layer where dendritic cells are)
How can T cells be categorized by location in mucosal immunity?
- can be “scattered” as effector cells or “organized” in Peyer’s patches and isolated follicles as immune response inducers
- scattered T cells can be intraepithelial (IPL) CD8+ cells or lamina propria (LPL) CD4+ cells
What are the two “functional sites” of GALT?
- Inductive Site - Peyer’s patches + isolated follicles in which T/B cells are activated + then travel through lymph + blood back to…
- Effector Site - T cells enter epithelium/lamina propria; B cells enter lamina propria + secrete mostly IgA and some IgM
Describe intraepithelial lymphocytes (IPLs).
How many are there? What kinds of T cells?
- 10-20 IPLs per 100 epithelial cells
- many CD8+ T cells
- 50% gamma-delta T cells, many NKTs as well
Describe the effector function of an intraepithelial CD8+ cell with regards to viral infection.
- virus in lumen infects epithelial cell (e.g. enterocyte)
- infected cell presents viral peptide via MHC-I
- CD8+ cell uses Perforin/Granzyme and FasL mechanisms to kill the infected cell
How does transepithelial transport of antibodies from lamina propria to the lumen differ when the Abs are in monomeric vs. polymeric forms?
- IgA dimers + IgM pentamers transported via active receptor-mediated transport
- IgA/IgM monomers transported via passive paracellular diffusion
What cytokines are involved in differentiation of B cells into IgA-secreting plasma cells?
- IL-5
- IL-2
- TGF-B
How does T-dependent class switching to IgA take place in the mucosa?
What is the affinity of the resutling IgA
- M cells transport antigens to Peyer’s patch DCs
- DCs activate naive T cells -> CD4+ Th
- Th cells stimulate B cells with their CD40L + nearby dendritic cells provide TGF-B co-stimulation to induce class switch
- resulting plasma cell secretes high affinity IgA
How does T-independent class switch to IgA work in mucosal immunity?
What is the affinity of the resulting IgA?
How does the timescale of this class switch mechanism differ from T-dependent?
- PAMPs bind to TLR on APCs + activate them
- APCs secrete TGF-B + other cytokines which induce class switch of B-1 cells to IgA plasma cells
- resulting IgA is low affinity
- is a faster class switch via innate immunity mechanisms, acting as a “first line defense”
How is IgA transported from the lamina propria to the lumen of mucosal organs?
- binds to polyIg receptor basolateral epithelium
- is endocytosed into a vesicle
- transcytosis to apical face of epithelium
- releases into lumen along with secretory component of the receptor
What are three locations in the mucosa where IgA can function?
- Luminal mucus layer - bind/neutralize pathogens + toxins
- Intracellular endosomes - neutralize antigens
- Lamina propria - export toxins/pathogens from LP to lumen
Where are TLRs located in relation to gut epithelium?
- on basolateral surface + intracellularly in endosomes
What 5 “checkpoints” are there in the mucosa for determining whether to induce an immune response + what response to induce?
(this is a very vague classification system used in the ppt)
- Soluble vs. particulate PAMPs
- Dead vs. Alive - is microbe viable?
- Pathogen vs. Non-Pathogen - virulence detection
- Harmless Colonization vs. Harmful Invasion
- Regulatory vs. Inflammatory response
What pro-inflammatory cytokines are produced immediately upon recognition of PAMPs in mucosal immunity?
(this is info from some very vague slides that I’m not really sure how to study)
- IL-6
- IL-12
- TNF
What are the signs of microbial viability called?
What kind of response do they induce?
An example of one?
- “vitaPAMPs” such as prokaryotic mRNA
- via PRRs such as NLRP3 they induce inflammasome activation + production of IL-1B
What receptors are useful for detecting the “activity” of virulence factors such as exotoxins + secretion systems?
NLRs
nod-like receptors
Give an example of a way in which invasiveness vs. commensal tendency is determine in mucosal immunity.
(specific microbe + changes btwn invasive/harmless form)
(not sure how important this is…)
- C. albicans can transform from an inocuous yeast to invasive hyphal form
- hyphal form expresses B-glucans which are recognized by PRRs (TLR2 + Dectin 1) on immune cells
What potentially harmful salivary commensal was mentioned in the lecture?
What diseases is it associated with + how?
- P. gingivales
- associated with periodontitis, RA + atherosclerosis
- in RA -> citrullinated bacterial proteins are bound by Abs and deposited immune complexes cause arthritis
What other oral commensal prevents invasion by P. gingivales + how?
- F. nucleatum - has a cell wall factor which promotes beta-defensin expression which harms P. gingivales
