Lc5: Mucosal immunity Flashcards
Malt
- Largest immune system of body
- Differs from systemic immunity
- Exposed to very large amounts of antigens
- MALT is guarded by a thin selectively permeable epithelial layer
- Mucosal tolerance
o Respond to pathogens
o Tolerate commensals
o GI
o Respiratory
o Urogenital
o Eye
o Exocrine glands
intestinal epithelium
enterocytes
goblet cells
paneth cells
entroendrocrine cells
M-cells
entrocytes
- Enterocytes most common cell in the gut
o Absorb nutrients
Passive diffusion
Carrier-mediated
Paracellular diffusion
o Maintain barrier function
Tight junctions
Desmosomes
Adherens junctions
o Secrete AMPs (beta-defensins)
goblet cells
- Goblet cell –> mucus secreting
o More in colon than small intestine
o 2 layers of mucus in colon
Deep layer is impermeable to bacteria
In crypts of SI the mucus is also more dense to protect stem cells
o Mucus traps AMP to kill bacteria
o MUC2 most common mucin
Mucins have many O-linked oligosaccharides
Mucins can be secreted or membrane bound
Mucin expression and quality is controlled by cytokines (etc.)
o GC-associated antigen passages allows for antigen delivery to DCs (tolerance antigens)
paneth cells
deep crypt secretory cells of the SI
o To protect stem cells
o Secrete AMPs
Lysozyme
Alfa-defensins (HD5 and HD6) make pores on bacterial membranes
RegIII (lectins)
o Secrete factors for stem cell function (Wnt3, Egf)
o Not found in colon (counterpart of Paneth cells are the deep crypt secretory cells)
entroendocrine cells
detect nutrients and release hormones for digestion
o 1% of epithelium of GI
o Found in SI and colon
o 12 types
o 20 hormones (serotonin, etc.)
o Role in immunity sensors of microbial metabolites
o Release cytokines and peptide hormones in response to PAMPs
Influence barrier function
Increase IgA production
Stimulate crypt cell proliferation
o GLP-1 secretion (anti-inflammatory)
M-cells
o Only present above the dome regions of Peyer’s patches follicle associated epithelium
The regions need to be in contact with antigens
Low IgA
Few Paneth cells
Few goblet cells
o Capture antigens (or whole bacteria and viruses) and deliver them to APCs (DCs and B-cells) found in their basolateral pockets
Phagocytosis
Receptor-mediated endocytosis
Fluid-phase pinocytosis
o Have short-irregular microvilli
o Large fenestrated membranes
o Have glycoprotein 2 (GP2) which binds type 1 pili on gram(-) bacteria
antigen/nutrient delivery
- Enterocyte absorption of nutrients
- M-cells
- GAPs in SI (GC-associated antigen passages)
- Trans-epithelial dendrites
- Paracellular transport
- Barrier breach
peyer’s patches
- Aggregates of secondary lymphoid tissue in the submucosa
- Covered by FAE
- Lots of DCs
- Large B cell follicles and adjacent T cell areas (mainly CD4+ but there are also cytotoxic T cells)
mesentric lymph nodes
- Collect lymph-borne antigens from SI and colon
- Site of differentiation of effector and regulatory lymphocytes that home back to the lamina propria
- Similar functions as GALT (including Peyer’s):
o B cells IgA plasma cells
o Naïve T cells effector
o Naïve T cells Tregs
DC types
- CD103(+)CD11c(+) are the classical DCs in the gut mucosa
- CD103 and sirpalfa define subsets of CD11c(+) DCs
o Sirpalfa(+) support induction of Tregs
o Sirpalfa(-) can cross present to allow for induction of cytotoxic T cells
Both induce Th17
o CD103(-)Sirpalfa(+) induce Th1
macrophages
- Resident in lamina propria and unlikely to play a major role in priming naive cells
- They engulf and clear bacteria, secreting cytokines, and maintaining intestinal homeostasis
- Some phagocytose and kill microbes while secreting anti-inflammatory cytokine IL-10 (occurs within local TGF-β environment)!!!!!!
ILCs
- Enriched at barrier surfaces (PP or lamina propria in gut)
- Lack antigen-specific T-cell receptors
- Rapidly respond to host- or microbial-derived stimuli
- Three subsets producing different cytokines
o (IL12/15/18) –> ILC1 –> IFN-y
o (IL25/33) –> ILC2 –> IL-5 and IL-13
o (IL1b/23) –> ILC3 –> IL17 and IL22 (and IL-2 which can induce Tregs) - Modulate adaptive immunity by producing soluble mediators with (in)direct effects
- Communication between ILC3s, macrophages and Treg cells in the intestine, which reinforces tolerance and tissue homeostasis
gut homing
- Effector lymphocytes in GALT or MLN are imprinted with integrin and chemokinereceptor dependent gut-homing properties
o α4β7 binds MadCAM (on lamina propria venules)
o CCR9 binds CCL25 (intestinal epithelial cells), produced by IECs - DCs in GALT and MLNs provide signals for increased expression of α4β7 and CCR9 on effector cells
o This requires retinoic acid (RA) secretion by DCs - DCs in GALT and MLNs express retinaldehyde dehydrogenase (RALDH)
o IECs also express RALDH and can synthesize retinoic acid
intrepithelial lymphocytes
- Specialized lymphocytes in paracellular space between IEC
- Participate in tissue surveillance and barrier function
- Predominantly CD8+ cytotoxic cells
- Limited diversity of antigen receptors; may be evolved in this way to recognize microbes that are commonly encountered at the epithelial surface
- Ready to kill IEC that are damaged, infected or stressed, by potent expression and secretion of granzymes
Th differentiation factors
- Microbial antigen type and APC type
- Strength of TCR stimulation and co-stimulation
- Cytokine gradients
- Induction of lineage-specific transcription factors
o Th1 > T-bet
o Th2 > GATA3
o Th17 > RORγt
o Treg > Forkhead box P3 (FoxP3) - Th17 and Treg cells are the two largest population of CD4+ T cells in the gut in homeostasis
- The commensals affect the mucosal immune system in such way that homeostasis is achieved by enforcing an equilibrium between both
Th17
- SFB binding to gut epithelium causes production of serum amyloid A which induces IL-1, IL6 and TGFbeta release by macrophages which causes Th17 differentiation
- Citrobacter cause release of Il23 and IL1beta which causes the homeostatic Th17 to become inflammatory they switch produce IFN-γ and GM-CSF when stimulated by IL-23 and IL-1β
- Homeostatic Th17 produce cytokines IL-17A, IL-17F, and IL-22
- Receptors for IL-17 and IL-22 are expressed on IECs
- IL-17A and IL-22 induce expression of proteins for barrier function > protect host from bacterial invasion
o mucins and AMPs by IECs
o tight junction formation between IECs
Treg
- Suppress immune responses and induce a tolerant response to commensal antigens and food
- Express high levels of IL-2 receptor α chain (CD25) and FOXP3, required for development and function
- FOXP3+ Tregs among CD4+ T cells is about twofold greater in the intestine than in other tissues
- Clostridium bacteria produce SCFAs which cause Treg differentiation
- CD103+ DCs and macrophages produce RA and TGFbeta which induce Treg differentiation and inhibit Th1 and Th2 differentiation
humoral immune response at mucosa
- Primarily directed at neutralizing luminal microbes
- Mediated mainly by IgA produced in lamina propria and transported into lumen by poly-Ig receptor
- Selective induction of IgA isotype switching in B cells is partly responsible for the abundance of IgA-producing plasma cells, IgG and IgM are also secreted into the lumen but in smaller quantities
- 2 g IgA per day, 60-70% of total Ab production
IgA isotype switching
- T-cell dependent (TD) and T-cell independent (TI) mechanisms to induce activation -induced deaminase, enzyme mediating switch recombination
- TGF -β / RA plays important role (DC derived)
- TD: high -affinity IgA
- TI: low -affinity IgA
IgA and sIgA
- IgA is a dimer molecule
- The J chain connects the 2 IgA molecules and is ligand for the polymeric Ig receptor (pIgR) expressed on the basolateral surfaces of IECs
- The most common IgA is secretory IgA (sIgA)
- sIgA is found in the secretions of the intestines, lungs, tear glands, the urogenital system, and the mammae
sIgA effector functions
- SIgA can recognize and neutralize gut bacteria
o Specific interaction with antigen-binding Fab segment of SIgA
o Non-specific interaction with Fc and secretory component segments of SIgA - Thereby preventing commensals and pathogens from invading through the mucosal epithelial barrier
- Fab-specific binding
o anchoring of intraluminal bacteria to mucus
o attenuation of bacterial motility, growth, and adhesion to gut epithelium - Fab-independent glycan-mediated binding
o glycans in the secretory component bind to bacteria
o reduce their motility, thereby preventing them to reach the epithelium - SIgA promotes the growth of beneficial bacterial, such as Bacteroides species glycans on Fc regions and secretory component serve as carbon sources for the microbes
neuroimmune interaction
a. IL-6 (enteric neuron) –> reduce Treg differentiation
b. VIP (EN) –> binds to VPAC2 on ILC can promote or reduce barrier function
c. CSF1 (EN) –> increased differentiation and survival (these macrophages then produce BMP2 which causes colonic motility)
d. Environmental stress –> IL33 –> serotonin (EC cells) –> increased motility via enteric neurons
e. Bacterial products –> TLRs on enteric glial cells –> neurotrophic factors –> ILC3 –> IL22 production (inflammation)
f. Microbiota –> increase AHR –> altered neuronal expression profile and colonic motility
