Mucosal

immunity I

Kim Murphy
kim.murphy@monash.edu
 Objec;ves
At the conclusion of the mucosal immunity
lectures you should be able to:
Describe mucosal immunity and the dierent
areas of the body to which mucosal immunity
pertains
Explain the innate and adap;ve immune systems
associated with the gut
Dene the immune systems of the respiratory
system, genitourinary system and skin
 Objec;ves
At the conclusion of this lecture you should be
able to:
Dene mucosal immunity
Comment on the anatomy and key cells of the
immune system
Describe the gut innate immune system
List how an;gen is acquired from the lumen
Describe humoral immunity associated with the
gut
 Mucosal immunology
Mucosal immunology is the study of immune
responses that occur at mucosal surfaces, such
as the intes;nes, the urogenital tract and the
lungs. These ;ssues are closely associated with
the external environment and the mucosal
immune system must provide protec;ve
immunity to pathogens but remain tolerant of
non-harmful environmental substances.

Nature (nature.com/subjects/mucosal-immunology)
Mucosal immune system

Murphy and Weaver, Fig 12.1

 General features
Immune systems at epithelial barriers have
similar anatomic organisa;on
Outer epithelial layer
Several layers or single layer
Underlying connec;ve ;ssue (contains immune
cells)
Lymphocytes, DCs, macrophages, mast cells
Distant lymph nodes
 Mucosal associated lymphoid ;ssue
Mucosal ;ssues contain unencapsulated,
organised secondary lymphoid ;ssues
T cells, B cells, DCs, macrophages
Called the Mucosal Associated Lymphoid
Tissue (MALT)
Regional immune systems contain specialised
cell types and/or molecules that are not
abundant at other sites
Anatomy review
 Innate immunity
Epithelial cells are a key component of the
innate immune system of the GI tract
Dierent types, all derive from a common
precursor
Mucus secre;ng cells (secrete defensins)
Absorp;ve cells (secrete cytokines)
Paneth cells (secrete an;bacterial pep;des)
Microfold (M) cells (an;gen sampling)
Tight junc;ons
 Innate immunity
The gut contains heavily glycosylated mucins
Major component of mucus
Can have two layers
Outer layer is less dense
Inner layer is more dense and a]ached to the
epithelium
Is responsive to environmental s;muli
Defensins; an;-microbial, form pores
Innate immunity

Abbas et al, Fig 14.2

 Innate immunity
Gut DCs and macrophages inhibit
inamma;on and aim to maintain
homeostasis
Intes;nal macrophages can phagocytes and
kill microbes and secrete an;-inammatory
cytokines
Induced by TGF-
Innate lymphoid cells (ILCs) produce IL-17 and
IL-22
 Adap;ve immunity
Major form of adap;ve immunity in the gut is
humoral immunity
Major role for IgA
Minor role for IgM and IgG
Protec;ve cell mediated immunity is provided
mainly by TH17 cells
Regulatory cells are numerous and shows how
commi]ed the mucosal immune system is to
tolerance
Anatomy of the adap;ve immune
system in the GI tract
Peyers patches
Unencapsulated
B:T ra;o ve
;mes higher than
in lymph node
An;gen delivery
can be
independent of
lympha;cs
Mesenteric
lymph node

Abbas et al, Fig 14.1

 Microfold (M) cells
Basal surface forms a
pocket of lymphocytes and
has close contacts with DCs
and Ms
DCs and Ms take up
an;gen and present them
to T cells
An;gen loaded DCs then
migrate from the sub-
epithelial dome to the T
cell area

Abbas et al, Fig 14.3

 M cells
The DCs meet nave,
an;gen-specic T cells
and prime them
DCs and primed T cells
ac;vate B cells to
undergo class-switching
to IgA
This process are increased
in the presence of
pathogenic organisms
 An;gen can be acquired other ways
M cells only cover a limited surface area
Various other mechanisms may include:
Soluble an;gens
Through gaps
M cells outside the Peyers patches
Direct invasion
Through FcRn (neonatal Fc receptor)
An;gen capture by macrophages
An;gens can be acquired in other ways

Murphy and Weaver, Fig 12.10

Murphy and Weaver, Fig 12.10
 Mesenteric lymph nodes
Collect lymph-borne an;gen from the small
and large intes;nes
Site of dieren;a;on of eector and
regulatory lymphocytes
Sites of B cells dieren;a;ng into IgA-secre;ng
plasma cells
Cells that dieren;ate here will (oken) home to
the lamina propria
 Waldeyers ring
Murphy and Weaver, Fig 12.6

May be removed due

to recurrent infec;ons,
but this does have an
eect on immune
responses
Homing to the gut

Abbas et al, Fig 14.5

 Homing to the gut
Gut homing phenotype is imprinted by DCs
through re;noic acid
IgA-secre;ng plasma cells and eector T cells
express 47 and CCR9
Gut homing
T cells can respond to invading pathogens
B cells can secrete an;bodies that are
secreted into the lumen
 Humoral immunity
Humoral immunity cri;cal to mucosal
immunity
Mainly IgA; neutralising
Secretory immunity
Accumulate in the gut
Very common immunodeciency
Some IgG and IgM
Humoral immunity
Class switch can be T-
dependent and T-
independent
mechanisms
Soluble cytokines and
membrane proteins
TGF-
Commensals cri;cal

Abbas et al, Fig 14.7

 Humoral immunity
IgA-secre;ng plasma
cells are widely
dispersed in the lamina
propria
Secreted into the lumen
by the poly-Ig receptor
Also able to transport
IgM

Murphy and Weaver, Fig 4.33

Humoral immunity

Abbas et al, Fig 14.8

 Role of IgA in mucosal immunity

S-IgA can bind and neutralise toxins

S-IgA binds pathogens and prevents
their a]achment to host epithelium
Intranasal infec;ons with Inuenza
Intes;nal infec;ons with Vibrio cholerae,
Salmonella typhimurium
Gastric infec;on with Helicobacter
sIgA func;ons

Murphy and Weaver, Fig 12.12

 Development of specic IgA
Circula;ng T cells are of a nave phenotype (CCR7+
47- T cells )
When pathogen enters small intes;ne an immune
response is triggered causing the pathogen to be taken
up and transported across specialised M cells
In the Peyers patches DCs take up process and present
pep;des derived from pathogen to the CCR7+ 47- T
cells
Once ac;vated T cells take on the phenotype CCR7-
47+ T cells
CCR7- 47+ T cells home to MAdCAM-1 expressed on
the endothelium of blood vessels in the lamina propria
of the small intes;ne
 Development of specic IgA
In the lamina propria ac;vated T cells produce
cytokines such as TGF- that drive IgA produc;on
by plasma cells
IgA bound with poly-Ig receptor allows it to be
endocytosed by the mucosal epithelial cells
Aker cleavage of poly-Ig the residual receptor
remains bound around sIgA and this protects it
from proteoly;c diges;on in the lumen of the
intes;ne where it binds pathogen
Pathogen bound by IgA is prevented from
a]aching to the epithelial cells lining the villi
 IgA deciency
The most common primary immunodeciency
disorder is IgA immunodeciency
Prevalence: 1 in 500 people (Caucasian), 1 in 6000
(African American), 1 in 15,000 (Japanese)
Even more common in people with coeliac disease
(about 2% with coeliac disease are IgA decient)
Normal B cell numbers, normal CD4+ and
CD8+ T cells and neutrophils
Not one cause
 IgA deciency
Many people with IgA deciency appear to
have no symptoms
May be at increased risk of severe respiratory
infec;ons
IgD:IgM ra;o
Increased risk of severe reac;ons to blood
transfusions, increased risk of atopy
 Humoral immunity
Equal amounts of IgG and IgM is found in
intes;nal secre;ons
Less than IgA (in intes;ne)
High IgG (some;mes higher levels than IgA) found
in other mucosal sites such as airway or rectum
IgG is transported through the neonatal Fc
receptor (FcRn)
Bidirec;onal transport
 Passive humoral immunity
IgA is secreted into colostrum and mature
breast milk
Through the poly-Ig receptor
Passive immunity for breast-fed infants
The plasma cells originate from various ;ssues
Most IgA plasmablasts express CCR10; breast
;ssue expresses CCL28
Reduces risk of diarrhea and sepsis
 Review
Mucosal immune system is large, par;cularly
gut immune system
Innate defenses are key in preven;ng
infec;on
Physical and chemical
Humoral immunity is cri;cal, par;cularly IgA
Role for IgG and IgM (and larger role outside of
gut)
 Ques;ons
What is mucosal immunity?
How is the gastrointes;nal immune system
organised?
What is the role of the innate gut immune
system in preven;ng pathogenic infec;ons?
How is the adap;ve immune system exposed
to an;gens from the gut?
What role do an;bodies play in protec;ng us
from gastrointes;nal diseases?
 References
Abbas, Lichtman and Pillai. Cellular and
molecular immunology (8th ed). Elsevier
Saunders, Canada, 2015. Chapter 14.
Murphy and Weaver. Janeways
immunobiology (9th ed). Garland Sciences,
New York, 2017. Chapter 12.