Mucosal immunization:
relevance to protection against
tuberculosis
Per Brandtzaeg
per.brandtzaeg@medisin.uio.no
Laboratory for Immunohistochemistry and
Immunopathology (LIIPAT), Department of Pathology,
Oslo University Hospital Rikshospitalet, Norway
The mucosae are an enormous battlefield
Mucosal effector sites provide secretory IgA (SIgA) antibodies
Section through skin
Hornified layer
Normal human colon IgAIgG
Epithelial cells
Airways and oral cavity
IgA
Mucus and cilia
Epithelial cells
Glands
Plasma cells
Gastrointestinal mucosa
Surface
epithelium
Glands (crypts)
Plasma cells
Plasma cells
At the border of hell!
H&E
80% of all plasma cells are
located in gut mucosa
An adult exports 3 g of SIgA to
the gut lumen per day
Local formation and export of mucosal immunoglobulins
Lumen
Lamina propria
Dimeric
Plasma cells IgA (pIgA)
IgA+J
Free SC
pIgR
(mSC)
SIgA
Gland
Ag
‘The IgA pump’
IgA+J
J chain
SIgM
IgM+J
IgA
Pentameric
IgM
IgG(±J)
IgG
Mucus
IgA-coated
bacteria
C
o
n
t
a
i
n
m
e
n
t
Control, not
clearance,
provides
mutualism
Brandtzaeg Nature & J. Immunol. 1974; Brandtzaeg & Prydz Nature 1984
(SIgA)
Coating of bacteria with
SIgA is an important
immune exclusion
mechanism
• SIgA-coated bacteria are
(PRR)
pIgR
IgA-producing cells
less invasive
• Less shedding of SIgAcoated bacteria
• Less horizontal spread of
SIgA-coated pathogens
(provides herd protection)
Modified from: Natalia Shulzhenko … Polly
Matzinger, Nature Med 2011; 17: 1585-93
Trachea and
bronchi:
Secretory IgA
Bronchioles
(< 1 mm):
Serum-derived
IgG
Defence of lung
parenchyma relies
largely on serumderived IgG and cellmediated mechanisms
The lung is
not a gut that
breathes
Defence of lung
The lung is
Trachea and
parenchyma relies
not a gut that
bronchi:
largely on serumbreathes
derived IgG and cellSecretory
IgA
Marcus Gereke (Braunschweig,
Germany):
mediated mechanisms
Alveolar type II epithelial cells: pneumocytes with
regulatory properties, also anti-inflammatory
Type II
pneumocyte
Bronchioles
(< 1 mm):
Serum-derived
IgG
ALVEOLUS
Gereke et al., Respir. Res. 2007; 8: 47
Homeostatic function of
mucosal vaccines
• The goal of mucosal vaccines is to stop
the pathogen at the portal of entry
• This can best be achieved by induction of
secretory IgA (SIgA) antibodies
• Protection against invasive mucosal
pathogens requires, in addition, systemic
immunity (IgG antibodies and cytotoxic T
cells)
Regionalization in
the integrated mucosal immune system
Also
Tonsils &
adenoids
(NALT)
systemic
BALT
Lacrimal,
nasal, &
salivary
glands
Bronchial
glands
Small
intestinal
mucosa
Peyer's
patches
(GALT)
Dichotomy
in the
integrated
mucosal
immune
system
Also
systemic
Tonsils
(NALT)
BALT
Mammary
glands
Large
Intestinal
mucosa
Isolated
lymphoid
follicles (GALT)
Urogenital
tract
Peyer’s
patches
(GALT)
Tonsils and adenoids are well designed for antigen trapping
Inductive sites
Tonsils &
adenoids
(NALT)
BALT
Human NALT anlagen: prenatal (19 wks).
Nasal ILFs in 40% < 2 yrs (inducible?).
Rodent NALT: postnatal organogenesis.
Human BALT in 40%-100% at young age (215 yrs); rare in adult normal lungs (>20 yrs),
but inducible (also rodent BALT is inducible)
Human palatine tonsil
Reticular crypt
Reticular crypt
epithelium
epithelium
(cytokeratin)
(cytokeratin)
BALT
GC
Peyer's
patches,
appendix Crypt
and solitary
intestinal
lymphoid
follicles (GALT)
Scanning electron-microscopy (Owen, 1988)
Inductive mucosa-associated lymphoid tissue (MALT) in human airways
Inductive sites
Tonsils &
adenoids
(NALT)
BALT
Human NALT anlagen prenatal (19 wks).
Nasal ILFs in 40% < 2 yrs (inducible?).
Rodent NALT: postnatal organogenesis
Human BALT in 40%-100% at young age (215 yrs); rare in adult normal lungs (>20 yrs),
but inducible (also rodent BALT is inducible)
Adult lung with
chronic infection
Human bronchusassocitaed lymphoid
tissue (BALT)
Submucosal glands
HLA-DR
HLA-DR
DC
DC
CD3(T)CD20(B)
CD3(T)FoxP3(Treg)
Nasal anatomy and location of regional lymphoid tissue
Waldeyer’s ring
Airway mucosa
Organized lymphoid
tissue with M cells
Olfactory region
Adenoids
Ciliated mucosa
Tubal tonsil
Skin
is extremely rich in
dendritic cells
HLA-DROlfactory
Humanregion
nasal
RFD-7 mucosa
Middle turbinate
Inferior turbinate
Palatine tonsil
Lingual tonsil
Oral cavity
Tounge
150-200 cm2
Epiglottis
Jahnsen FL, Gran E, Haye R,
Brandtzaeg P. Am J Respir
Cell Mol Biol, 2004; 30:31-37
Regional lymph drainage
through mesenteric and
cervical lymph nodes
Mesenteric
lymph nodes
Thoracic
Right
duct
lymphatic
duct
Cervical
lymph nodes
Sublingual vaccination
Regional lymph drainage
through mesenteric and
cervical lymph nodes
Mesenteric
lymph nodes
Thoracic
Right
duct
lymphatic
duct
Cervical
lymph nodes
Immune
compartments of
the lung
From: Holt et al.
Nature Rev.
Immunol. 2008;
8:142-52
Wolf et al.
J. Exp. Med.
2008 205: 105-15
CD4+ T cells only become activated once
M. tuberculosis spreads from the lungs to
the lymph nodes and starts to produce antigen
Airway luminal T cells: a newcomer on the
stage of TB vaccination strategies
Jeyanathan M, Heriazon A, Xing Z. Airway luminal T cells: a newcomer on the stage
of TB vaccination strategies. Trends Immunol. 2010; 31: 247-52
pIgR/SC knockout mice lack epithelial IgA transport
+/+
IgA IgG
–/–
Johansen et al. J. Exp. Med. 1999; 190: 915-21
Naïve mice
infected i.n.
with 106 CFUs
of BCG
Mice i.n.
vaccinated
with PstS-1
antigen
(plus CT)
and then i.n.
infected
Effect of
mucophilic
SIgA and the
ciliary
conveyer
band?
Authors from Cuba, Mexico and Malaysia
Determination of bacterial load (A)
and pneumonic area (B) in lungs of
mice which were untreated (NT) and
those treated with human secretory
IgA (hsIgA), after challenge with M.
tuberculosis H37Rv by intratracheal
route 2 hrs after inoculation.
Another group received M.
tuberculosis preincubated with hsIgA
(preinc). Well-organized granuloma of
preincubated group 2 months after
challenge with M. tuberculosis,
visualized by H&E staining (25x) (C).
• Such vaccine administration elicits both regional mucosal
and systemic immunity
• Future strategy: prime-boost approach, e.g. BCG (prime)
followed by mucosal boost, or vice versa
Acknowledgements
Laboratory for Immunohistochemistry and Immunopathology
(LIIPAT) is part of Centre for Vaccinology and Immunotherapy
(CEVI, 2001) and Centre of Excellence for Immune Regulation
(CIR, 2007), funded by the Research Council of Norway,
University of Oslo and Rikshospitalet University Hospital