• Balance between tolerance and immune response
• Portals of antigen entry
• Generally thin and permeable (to exchange gases, nutrients, and sensory molecules)
• Vulnerable to infection due to permeability

1. Anatomical: mucus, ciliated cells
2. Mechanical: tight junctions, air/liquid flow, mucus movement by cilia
3. Chemical: low pH, enzymes, fatty acids, bile/bile salts, enzymes (lysozymes, pepsin)
4. Microbiological/Immunoregulatory: Commensals and normal flora

• To recognize what is a threat and what is not (self vs. non-self)
• Ability to control/disrupt what is infection and stop dissemination
• First contact with antigens and environment; "first responders"

1. Transcytosis: M cells
2. Exploitation of gap junctions
3. Fimbriae/adhesion molecules/adhesins

1. Epithelial surface: Macrophages, neutrophils, dendritic cells
2. Interstitial space/basement membrane: Fibroblasts, dendritic cells, macrophages, and neutrophils
3. Endothelial layer: Monocytes, neutrophils, T cells, dendritic cells

1. Urogenital tract (uterus, bladder, vagina)
2. Gastrointestinal tract (stomach, intestine, esophagus, oral cavities)
3. Respiratory tract (sinus, trachea, lungs)
4. Glands: mammary, lachrymal, salivary

1. Structured induction sites (organized lymphoid tissue): Peyer's patches, isolated lymphoid follicles, mesenteric lymph nodes, tonsils, etc.
2. Diffuse effector sites (loosely organized sites): Lamina propria (LP), intraepithelial lymphocytes (IELs)

1. Scattered lymphoid cells - effector sites
2. Intraepithelial lymphocytes
3. Villus
4. Epithelium
5. Lamina propria (LP)
6. Lymphatic drainage
7. Crypt
8. Organized tissues - Induction sites
9. M cell
10. SED
11. Follicle
12. TDA
13. Peyer's patch
14. Afferent lymphatic
15. Mesenteric lymph node

1. Follicle-associated epithelial cell
2. Dendritic cell
3. M cell
4. IgA
5. Follicle
6. Peyer's patch
7. Paneth cell
8. T cell
9. Plasma cell
10. Macrophage
11. Goblet cell
12. Crypt
13. Lamina propria

Enterocytes

Basement membrane

Lamina propria (LP)

What are goblet cells? Where are they located, and what are their roles during infection?

Specialized epithelial cell that maintain mucosal barrier by:

1. Secreting mucin (intestinal: MUC2, respiratory: MUC5)
2.  Secrete AMPs, cytokines, and chemokines
3.  Deliver substances to the LP

Expansion -> resolution via tolerogenic responses (T cell tolerance)

Hyperplasia of goblet cells (Th2: helminths) can lead to obstruction

Peyer's patches are comprised of

_______________ that are surrounded by areas of ___ cells situated beneath a subepithelial dome (SED), which is rich in ____________ and __________, which is covered by an ________-containing ______________________.

comprised of B-cell follicles (B) surrounded by areas of T cells situated beneath a subepithelial dome (SED) rich in macrophages and dendritic cells (DCs), which is covered by an M-cell containing follicle-associated epithelium (FAE).

Where does T cell activation happen in the mucosal tissues?What do naive T lymphocytes do once activated by DCs? Where do they go, and where do they come from?

1. Transported via efferent lymphatic vessels to blood
2. If the set of induced homing molecules on the lymphocyte matches the set of counter-receptors on endothelial cells of the postcapillary venule within a certain tissue, these effector lymphocytes extravasate 
3. Lymphocytes are further directed to their effector compartment by various chemokines and adhesion molecules

• Transient, secondary lymphoid organs
• Made in B cell follicles during T-dependent Ab response
• Mature B cells activate, proliferate, and differentiate
• Produce long-lived, Ab-producing plasma cells and memory B cells for protection against re-infection
• Mediates somatic hypermutation of genes encoding BCR for high-affinity Ag binding
• Class switching of activated B cells change from IgM to IgA/G/E via class-switch recombination (intra-chromosomal DNA rearrangement of Ig heavy-chain locus)

• Most abundant isotype
• Inhibits adhesion of bacteria/viruses to epithelial cells, also neutralizes toxins/viruses intra- and extracellularly
• Class switching to IgA happens in NALT
• Eosinophils support the class switching of IgA, maintains mucus secretion, influence the microbial composition of the intestine, promote PP development

• Can down-regulate phagocytic ability of polymorphonuclear lymphocytes (PMNs)
• Down-regulates pro-inflammatory responses 
• Opsonization of bacteria enables clearance and resolution via Kupffer cells (liver macrophages)

• Serum IgA is present in relatively lower amounts in systemic lupus erythematosus.
• Has greater affinity for H-ficolin 

• Generally induce T cell responses in the bloodstream and serum IgG production
• Mucosal administered vaccines induce IgA + systemic response 

1. Cryptopatches
2. Isolated Lymphoid Follicles (ILFs)
3. Peyer's patches

• Non-recirculating lymphocytes (tissue-terminal)
• Phenotypically and transcriptionally distinct from circulating memory T cells 
• First line of protection
• They act similar to memory T cells: upon stimulation, they proliferate and secrete cytokines

1. Infection: tonsils, lung, liver, genital tract 
2. Cancer: head/neck, breast, lung, melanoma
   Both have increased T_RM cells as disease decreases 
3. Autoimmunity: skin (alopecia, vitiligo, psoriasis)
   Increased T_RM cells as disease increases 

• Specialized CD8 T cells = intraepithelial lymphocytes (IELs)
• In constant contact with intestinal epithelial cells and other intraepithelial lymphocytes (IELs) for immune balance and protection 
• CD8s are cytotoxic: patrolling and killing 
• Maintenance, activation, and contribution to host immune response to preserve a healthy epithelial barrier

• Thin layer of connective tissue that forms part of mucosal surfaces (respiratory, GI, urinary tract)
• has immune cells (especially macrophages and lymphoid-derived cells) to protect mucosal surfaces from external insults 
• Contains blood vessels, lymphatic vessels, elastic fibers, and muscle

• Smallest and most abundant lymphoid aggregates in the mammalian gut (GALTs)
• Found mostly in ileum and colon
• Beneath the crypts at the base of intestinal villi
• Very few cells: ILC3 and CD11c⁺CXCR1⁺ myeloid cells
• NO B/T CELLS

• Single B cell follicle that often contains a GC and a network of CD21/CD35-expressing fibroblastic stromal cells
• Beneath specialized dome (formed by DCs and some CD4) containing M cells that transport antigen from intestinal lumen to leukocytes underneath 
• Establishes microbe colonization and immunological tolerance 

1. Lymphocyte recruitment
2. M cell development
3. FDC network formation

• Have many B cell follicles with germinal centers 
• Interfollicular regions of T cell zones and DCs
• lyso-DCs and lyso-macrophages

• Fibroblastic reticular cells (RFCs) define T cell zones, help trafficking T cells with interfollicular regions, interaction coordinators between APCs-DCs and naive T cells

• Peyer's patches
• Sampling of luminal antigens for surveillance via endocytosis
• Recruit and transport particles through cell interior and across barrier into the LP via transcytosis
• Characteristic membrane ruffles on cell surface
• Deep pocket to allocate B cells (direct interaction is required for maturation of M cell functionality)
• Do not secrete mucus or digestive enzymes
• No glycocalyx or microvilli; readily accessible to enteric antigens
• NOT EXCLUSIVE TO THE GUT!
• DO NOT PRESENT ANTIGEN; ONLY DELIVERS ANTIGEN

• Receptor-mediated uptake of a ligand on one side of the cell, vesicular transport across the cell, and exocytosis of the vesicle contents on the opposite side.
• IgA enhances transcytosis

1. M cells take up antigen via endocytosis and phagocytosis
2. Ag is transported across M cells in membrane-bound vesicles and released at the basal surface (LP side)
3. Ag is bound by DCs which then present the Ag and activate T cells for an adaptive immune response
4. Plasma cells secrete dimeric IgA from LP, across epithelia, cleaved to go back into lumen (through Ig receptor via transcytosis)

• Epithelial cells with high abundance of eosinophilic granules 
• Main component: AMPs (but also cytokines, chemokines, defensins, etc.)
• Modulates immune homeostasis, microflora, and small intestine physiology (crypts of Lieberkuhn cells)
• Prevents microbiota translocation
• Long-lived: persist for over 30 days

IBD, Chron's disease, necrotizing entercolitis

Disruption of Paneth cells leads to dysregulation of microbiota translocation: leads to immune response against commensal bacteria 

• Elevated cytokine production from hyperactive T cells (IL-1, IFN-g) 
• Th1 and Th17 phenotypes
• Increased leukocyte adhesion
• CD4⁺FoxP3⁺ Treg cells may play a role

CD4 Th1 response (IC pathogens)

and Th17 (EC pathogens)

CD4 Th2 responses

EC pathogens, allergies, asthma

IFN-g

Requires IL-12 for differentiation 

Associated with M. tuberculosis, viral infection, and tumors

IC pathogen clearance

IL4, IL5, IL13

Requires IL4 for differentiation

Parasitic and viral, asthma, allergies (fungal)

EC pathogen clearance

Involve eos and mast cells

IL-17 

Requires TLR4 signaling and IL23 for differentiation

AI disease association

EC pathogens

Protective and deleterious lung responses

• Immune homeostasis
• Development, induction, expansion, and function of T cells
• Diversifies IgA repertoire
• Secondary and lymphoid structure development

Dysbiosis leads to AI and inflammatory diseases through T cell subpopulation imbalances (including Th1, Th2, Th17, and Treg cells)

Bacteroides fragilis PSA protected mice from H. pylori-induced colitis 

***PSA promotes Tregs to prevent immune responses against microbiota

Mucosal (local)

1. Inductive: Peyer's patches, isolated lymphoid follicles (ILFs), and MLN (mesenteric lymph node)
2. Effective: Lamina propria lymphocytes (LPLs) and intraepithelial lymphocytes (IELs)
3. Gut, nervous system, lungs, skin, etc.

Systemic:

1. Lymphatic system, circulatory system
2. Bone marrow, liver, muscles (non-mucosal organs and tissues)