MCB 169

Lecture 19
November 7, 2013
Lecture Notes Mucosal/Gut Immunology
I.

Mucosal tissue organization

a. Lumen, where food passes through (think: the inside of a tube)

b. Single-layer columnar epithelium
i. Projections: villi
ii. Crypts essentially the opposite of villi, except instead of extending
into the lumen, they extend into the connective tissue layer. The crypts
consist of paneth cells which make antimicrobial products and stem
cells which give rise to all intestinal epithelial cell types.
c. Fibrous connective tissue where many immune cells reside called the
Lamina Propria (LP)
d. The terminal ileum has M cells, which surround lymph node-like structures
called Peyers patches.
e. Goblet cells secrete mucins, which make up the mucus layer.
II.

Commensals:
a. Our body contains 1014 microbes that are non-pathogenic; thus, we call these
organisms commensals
i. Most reside in gut, but also skin and other mucosal surfaces
ii. Consist of mostly bacteria, but also fungi, worms, and viruses
b. Many of these organisms are beneficial to the host
i. Produce / metabolize nutrients

ii. Create barrier to pathogenic organisms / fill niche to block pathogenic

organisms
iii. Essential for proper immune system development / maturation
iv. Can alter character of immune response (e.g. certain bacteria induce
different Th or Treg responses)
1. E.g. Segmented filamentous bacteria (SFB) promote Th17
differentiation
a. Associated with rheumatoid arthritis, multiple sclerosis,
type 1 diabetes in mouse models
III.

Innate immunity in the gut

Tight junctions, mucus and antimicrobial peptides are all products of the epithelial
cell layer that promote its barrier function to preventing microbes from penetrating
the epithelial layer
a. Cell types
i. Gut epithelial cells
1. Absorb nutrients
2. Create barrier to block microbes through tight junctions
3. Can secrete anti-microbial peptides and cytokines
ii. Goblet cells
1. Interspersed among epithelial cells
2. Secrete mucus
a. Mucus forms a dense, thick protective barrier that coats
the intestinal lumen and prevents commensal or
pathogenic organisms from getting too close to the
epithelium
b. Induced by commensals
iii. Gut epithelial stem cells
1. Located in the crypts
2. Constantly divide and push cells upward, replenishing cells in
the epithelium
iv. Paneth cells
1. Located deep in the crypts
2. Critical for innate immune defense
3. Protect stem cells
a. Produce anti-microbial peptides
i. Alpha-defensins
b. Reg-III: This C TYPE LECTIN is up regulated on
paneth cells after TLR signaling. It binds to
peptidoglycan region on bacteria inhibiting the bacteria.
This causes sterile zone called the demilitarized zone
(DMZ) closest to the epithelial cell layer. Reg-III can
also be induced by IL-22 secreted by Th17 like innate
lymphoid cells.
v. Sentinel cells:

1. Macrophages
a. Found throughout lamina propria
2. Dendritic cells
a. Found underneath epithelium
i. Extend processes into lumen to probe for
antigens
b. Many found throughout lamina propria
c. Many located in intestinal lymph nodes (mesenteric
lymph nodes, MLN) and intestinal lymphoid follicles
d. Have a tolerogenic profile
i. Express TGF-, which induces regulatory T
cells
ii. Express the small molecule retinoic acid, which
diffuses into the nucleus and binds retinoic acid
receptors (RARs)
1. Programs T and B cells to express guthoming molecules
a. 47 integrin
b. Chemokine receptors (CCR9)
vi. Innate-like cells (ILCs)
1. Innate equivalents of TH1, TH2, TH17 cells
2. Secrete similar cytokine profile, but respond quickly and do not
proliferate as rapidly
IV.

Sites of gut immune responses

a. Mesenteric lymph node (pictured above in purple)

i. Transparent sheet surrounding gut (mesentery)
b. Peyers patches (pictured above in green)
i. Found in ileum, the last part of the small intestines

ii. M cells, found in the epithelium, transport antigens into the underlying
Peyers patch by transcytosis
iii. Lymph-node like structure
1. T cell zones
2. B cell zones
3. No lymphatics
4. No subcaspular sinus (SCS)
V.

Adaptive Immunity in the gut

a. B cells
i. Antibody-secreting plasmablasts and plasma cells (think of them as
effector B cells)
1. Found in lamina propria
2. B cells programmed to express gut-homing molecules such as
cytokine receptor CCR7 and Integrin 47 which binds to its
ligand MAdCAM1
3. Class-switch to IgA induced by TGF- and retinoic acid
a. Secreted IgA is main defense against gut bacteria
b. Dimer, held together by J chain
c. Poly Ig receptor on epithelial cells transports IgA across
epithelium into lumen
4. T cell independent IgA production lower affinity, to
commensals
5. T cell dependent IgA production high affinity to pathogens
b. T cells
i. Intraepithelial lymphocytes (IELs)
1. Special type of memory cell that home to epithelial cells and sit
in between
2. Respond to epithelial cells that become infected (usually by
killing them)
3. CD4, CD8, or
ii. TH17 cells
1. Extremely abundant in gut (probably due to abundant TGF-,
which combined with IL-6 induces TH17 cells)
2. Produce cytokines:
a. IL-17
i. Very good at inducing neutrophils
b. IL-22
i. Improves barrier: makes epithelial junctions
tighter
ii. Induce anti-microbial peptide production by
epithelial cells
iii. Induced Tregs
1. Dampen immune response to food Ag, microbes, etc.
2. Hugely abundant in gut (probably also due to abundant TGF-,
which alone induces Tregs)

VI.

Disease
a. Inflammatory Bowel Disease
1. Crohns disease
a. Transmural inflammation (across entire intestinal wall)
b. Can get fusions between different parts of the intestines
c. Can affect small intestine and large intestine
2. Ulcerative colitis
a. Inflammation is only across part of the wall
b. Affects only the colon
3. Genetic markers and susceptibility genes:
a. NOD2 mutation