Mucosal And Skin Immunity

Epithelial cells are both effectors and inducers of immune response.

Gut-Associated Lymphoid Tissues (GALT)

Crypt: Place of epithelial stem cell proliferation and differentiation

Epithelium

Contains the following:
Enterocytes: Have microvilli for nutrient acquisition
Goblet cells: Produce mucus, antimicrobial peptides and form top protective layer above epithelium
Paneth cells: Secrete antimicrobial peptides. These reside in the crypt, keeping mucus sterile
Enteroendocrine cells: Produce serotonin (for peristalsis) and mediates immune regulation

Also includes Intraepithelial Lymphocytes and Dendritic Cells.

Lamina Propria

Contains the following:

CD4/CD8 T cells
IgA/IgG Plasma cells
Dendritic cells and macrophages
Innate lymphoid cells (mostly ILC3)

Peyer's Patches

These behave like lymph nodes. For more, see here: T Cell Mediated Immunity > Peyer's Patches

Contains the following:

CD4/CD8 T cell
B cells
Dendritic cells and macrophages

Also contains M cells, which preferentially absorb antigens from lumen then transport them to dendritic cells and macrophages.

Epithelium

Intraepithelial lymphocytes are immune cells in the epithelial layer. Lymphatic vessels collect materials that drain into the mesenteric lymph node. Isolated lymphoid follicles are tiny B cell follicles under epithelium.

Protective mechanisms

Mucus: From goblet cells. Coat the epithelium to trap/eliminate microbes
Antimicrobial peptides: Paneth and other epithelial cells use these to repel microbes
Low pH: Makes it hard for microbes to survive (innate line of defense)
Lysozymes: Degrade the bacterial cell wall (innate line of defense)
Microbiome: Instigates development of Mucosa-Associated Lymphoid Tissue (MALT), produces antimicrobial peptides, and competes pathogens for nutrients
Inflammation: Mucosal barrier breach recruitments of monocytes, neutrophils, and eosinophils
IgA: Highly present in the gut

IgA

IgA is found in the gut as a dimer (bound to a J chain). The secretory component promotes Polymeric Immunoglobulin (PIG) to bind. PIG-IgA dimer travels across the epithelial cell and the J chain is cleaved, releasing the IgA monomers into the bowel lumen. Because the secretory component becomes cleaved, this is a unidirectional travel.

IgA will neutralize antigens and bind to bacterial surfaces, but will not activate complement.

IgA utility

Binds binds to toxins, viruses, and bacteria to neutralize them
Prevents pathogens from binding to entering cells
Carries pathogens back to the lumen via transcytosis
IgA/Dectin-1 interactions on M cells promotes antigen-bound IgA presentation to a dendritic cell/macrophage

Class switching

For more on class switching, see here: Humoral Immune Response > Class Switch Recombination

Matrix metalloproteinases (MMPs) activate TGF-beta, which stimulates class switching to IgA in germinal centers. MMPs are found within eosinophil granules.

Isoforms

There are two isoforms: IgA1 and IgA2. Secretory IgA is abundant in the gut as a homodimer (IgA1-IgA1 or IgA2-IgA2) while serum IgA is found in much smaller amounts in circulation.

Recognition of Pathogens in the Gut

There are a few ways this can happen.

M cells ingest antigens from the lumen and pass them off to dendritic cells.
IgG binds to neonatal Fc receptors (FcRn) and enables the antigen to be transported across the epithelium for dendritic presentation
Antigens inducing apoptosis attract dendritic cells.
Macrophages reach through lumen to ingest lumen-dwelling antigens for immune response.
Goblet cells can ingest antigens (in addition to mucus secretion).
Dendritic cells travel back and forth between the epithelial layer and the lumen, capturing antigens.

Activating Gut Immune Response

Nucleotide oligomerization domain (NOD) proteins exist in the cytoplasm and have the power to bind to bacterial cell walls. They activate the NFkB pathway which results in an inflammatory response (IL-6, IL-1, TNF-a). NODs also stimulate the autophagic pathway.

In addition, cytoplasmic sensor molecules can trigger the inflammasome pathway, leading to caspase activation.

These steps lead to ILC2 activation and promote TH2 responses (IgE switching, eosinophil activation, mucous secretion, and mast cell activation).

Effector cell localization

Effector lymphocytes (B/T cells) returning to the same mucosal tissues they were activated in. This process is mediated by integrins (on effector cells) binding to receptors on the mucosal surfaces.

Commensal Bacteria

Commensal bacteria primarily regulate the immune response.

Bacterial flagella
IgA production → Th17 cell differentiation → IL-17, IL-22 → mucus, epithelial repair, antimicrobial peptides

Butyrate (FA produced by some bacteria)
FOXP3 → TGF-beta, IL-10 → inhibits chronic inflammation

NOD ligands
Generate ILC’s and isolated lymphoid follicles

Epithelial cells
IL-33 for Type II Immunity (worms and allergens)

Colitis Study

This experiment showed that T regulatory cells make TGF-beta that reduces the immune inflammatory response. Because chronic inflammation in response to intestinal microbes can be damaging, the immune system balances this response with regulatory T regulatory cells (e.g., TGF-beta) to limit inflammation.