Disclaimer: Like all SEAcontent, this serves as supplemental material.

Make sure to study the material covered in class

Mucosal immunity
Mucosal tissue: Mucus: NOT a bad thing. Slippery, viscous secretion that serves as a barrier rich in
overview protective enzymes
Mucosal tissue: mucus-producing thin tissues that are frequently exposed to
infectious/foreign substances. Ex. skin, mouth/oral, nose, lungs/airway, intestines,
reproductive areas
MALT = mucosa-associated lymphoid tissue. The majority (60-70%) of lymphocytes are
in these mucosal tissues. These mucosal tissues are in contrast to central/systemic
immunity (spleen, thymus, lymph/nodes), where the rest of the lymphocytes are
3 major types of MALT: GI tissue (GALT), respiratory tissue (NALT and lungs), skin
Each type of mucosal tissue has unique structure/function to fight the pathogens it
Mucosal protection encounters
Common protectivemost frequently
features at the various mucosal sites:
Common
Barriers tomucosal
preventfeatures: IgA secretion,
entry: physical barriersnon-canonical T cells,
(ex. skin), chemical innate(ex.
barriers lymphoid
low cells,
specific combos
stomach of adhesion
pH), cellular barriersmolecules/cytokines for immune cell homing
(ex. different cell layers—epithelial, dermal, etc.)
Secretions: mucus contains antibodies (esp. IgA), enzymes, bactericidal proteins
Mucosal Consist ofinnate,
Cellular: epithelial layer, and
adaptive, connective tissue cells
other immune
membranes layer, and sometimes lymphoid tissue
Serve as barriers between immune cells (in
tissue) and foreign substances (in lumen)
Foreign substances, pathogens, etc. are in the
lumen. The epithelial layer separates the
lumen from the connective tissue underneath,
IgA IgA secretion
where is a common
the immune cells aremucosal tissue feature
found. Epithelial
IgA
layeris is
a dimer—2 of theinfectious
critical to keep classic Y-shaped Ab connected by additional
agents out,
proteins (vs. IgG,
but if agents thethrough
do get most common Ab, which is just 1 Y)
to connective
they’reincreased
tissue, shape
Dimer attacked bystability
immunetocells
proteases (resistance to
degradation) increased survival in mucous membranes
Also, dimer shape “immune exclusion via agglutination”: there are 4
binding sites on the dimer IgA (compared to 2 binding sites on IgG), so IgA
can bind to more epitopes. Each binding site on 1 IgA can bind to a
different pathogenic cell cross-link/agglutinize pathogenic cells
together cross-linked cells are precipitated out and eliminated from
body in the normal flow of mucus
So compared to IgG, IgA has increased: stability, valency, and ability to
cross-link pathogens
Non-canonical T Non-canonical T cells are a common mucosal tissue feature
cells Non-canonical (atypical) T cells differ from standard CD4 or CD8 T cells; they don’t
undergo as much VDJrecombination, and they recognize a more specific subset of Ag
(tend to recognize pathogens they’re most likely to encounter at their sites)
Ex. gamma delta T cells, which are highly enriched in mucosal tissue and express a
different type of T-cell receptor than CD4s/CD8s
 Provides another way to develop a mucosal-specific immune response unique from
central immune responses
Innate lymphoid Innate lymphoid cells (ILCs) are a common mucosal tissue feature
cells Lymphoid in origin, like T cells, but don’t contain a T-cell receptor. But, like T cells, they
can still polarize when exposed to cytokines
Resident ILCs at mucosal tissues amplify the cytokine response from low levels of Ag-
specific T cells
ILC1—similar to Th1s (without the T-cell receptor); releases IFN-
Immune cell How do immune cells get to MALTs/know which tissue to go to? What controls
ILC2—similar to Th2s (without the T-cell receptor); releases IL-4, 5, 9, 13
homing: overview immune cell localization? The interaction of chemokines, receptors, and adhesion
ILC3—similar to Th17s (without the T-cell receptor); releases IL-17, 22
molecules determines immune cell homing to mucosal tissue
Immune cells express various cell surface receptors, including chemokine receptors
(CCR-)and adhesion molecules (integrins, selectins, etc.). Cells in lymphoid/mucosal
tissue express adhesion molecules and release chemokines (CCL-). The chemokine
receptors/adhesion molecules on immune cells interact with the chemokines/adhesion
molecules on the target tissue cells
A lot of the chemokine receptors are GPCRs;GPCRsignaling cell migration
Immune cell Lymph node homing: CCR7(chemokine receptor) = GPCRexpressed by T cells, B cells,
Each specific mucosal site has a unique combo of receptors, adhesion molecules, and
homing: specific dendritic cells. Responds/binds to CCL19and CCL21(chemokines). CCL21is expressed
chemokines combo determines tissue-specific homing of immune cells unique
examples localized
on immune
the surfaces of response
high endothelial venules and lymphatic cells. Therefore, immune
cells that express CCR7will move towards/home to tissues expressing CCL21, like the
lymph nodes
MadCAM-1: cell-to-cell adhesion molecule expressed in various tissues, ex. intestinal
mucosa. Interacts with adhesion molecules on the surface of immune cells—integrins
(LPAM-1, VLA-4) and selectins (L-selectin)
CCL28(chemokine): aka MEC (mucosae-associated epithelial chemokine). Expressed in
Immune cell various
Combination fortissues, ex. respiratory
lymph node homing mucosa. Interacts with various chemokine receptors:
CCR10on B and T cells, CCR3on eosinophils. These chemokine-receptor interactions
homing: specific CCL21/ CCR7
direct the immune cells to mucosa expressing CCL28
combinations Lymphatic cells/high endothelial venules highly express CCL21(attracts immune
cells expressing CCR7)
∴ immune cells that express CCR7localize to lymph nodes
Combinations for intestine homing
CCL25/ CCR10
Mad-CAM/alpha4 integrins
Intestinal mucosal cells highly express CCL25(attracts immune cells expressing
CCR10) and Mad-CAM (attracts immune cells expressing alpha4)
∴ immune cells that express CCR10and alpha4 integrin localize to intestine
Combinations for respiratory homing
CCL28/CCR10

VCAM/alpha4 integrins
Respiratory mucosal cells highly express CCL28(attracts immune cells expressing
 CCL27/CCR10

VCAM/alpha4 integrins
E-selectin/CLA (cutaneous lymphocyte Ag)
Skin mucosal cells highly express CCL27(attracts immune cells expressing CCR10),
VCAM (attracts immune cells expressing alpha4), and E-selectin (attracts immune
Immune cell Sinceexpressing
cells we know the combos of chemokines/receptors/adhesion molecules needed for
CLA)
homing: ∴localization to certain
immune cells tissues,CCR10,
that express we canalpha4
selectively blockand
integrin, these
CLAinteractions to prevent
localize to skin
applications immune cell infiltration to a specific tissue
Ex. natalizumab and vedolizumab are integrin antagonists—drugs that bind to alpha4
integrins (adhesion molecules on immune cells) block interaction with adhesion
molecules on the target tissue (intestines) prevents leukocyte transendothelial
GALT: immune GALT = gut-associated
migration lymphoid tissue (type of MALT)
into intestines
overview Many pathogens
Natalizumab and can potentially
vedolizumab enter
used to body
treat through
Crohn’s GIT, ex. bacterial pathogens from
food and water, and viruses (Polio)
Flow of liquids (in mouth, esophagus) remove a lot of microorganisms, and so does
acidic pH in stomach. But moving from stomach to colon, pH decreases
GALT: tissue Intestinal lumen is separated
 number/diversity from
of microorganisms increases other immune mechs
organization/ become more
connective critical
tissue (ex. propria)
(lamina mucus, bile,
by aIgA, lymphoid tissue, shedding/replacing
epithelium)
immunity layer of epithelial cells. Lamina propria is
immediately below epithelial layer and
contains many immune cells, to deal with
pathogens that cross epithelium
Goblet cells: specialized epithelial cells
that secrete mucus
Paneth cells: specialized epithelial cells
that produce antimicrobial enzymes
Crypts: indentations in the epithelial layer
Villi: projections that extend into lumen and are important for nutrient absorption.
These are effector sites: contain scattered already-activated T/B cells like Th1s,
CTLs, etc. that are ready to effect their action
Peyer’s patches: organizes immune tissue below the surface of the endothelial layer,
where Ag presentation occurs. These are inductive sites: contain naïve T/B cells,
which are activated (induced) when a specific Ag is presented to them
o Review: linked recognition—T and B cells interact together stimulates both
T and B cell response to particular pathogen
Both inductive and effector sites drain to mesenteric lymph nodes, another site of Ag
presentation activation of T/B cells (and linked recognition)
Peyer’s patches are unique feature of GALT; allow a faster Ag response since Ag
doesn’t have to travel all the way to mesenteric lymph nodes