course introduction: gastroenterological conditions ... · course introduction: gastroenterological...
TRANSCRIPT
Course Introduction:
Gastroenterological
conditions
Masters in Biomedical
Science
Andrew Macpherson Director of Gastroenterology
Department of Medicine, University of Bern
Principles of the course: A) Content
1.To give you the information to understand
current science and medicine underlying
digestive disease
2.To show you how science is being
translated into new medical treatment
3.To relate what you learn to real patients
and to areas where advances are badly
needed.
Principles of the course: B) For you
1.To allow you to follow your interests
2.We have tried to concentrate the lectures
and practicals so that things hang together
and it is easy to ask questions. ..... The
more the better.
3.We want you to have chance to see and
do things ‚hands on‘ as well as listen to us.
Principles of the course: Themes
A. Immune conditions of the GI tract.
B. Anatomy and clinical physiology of the GI tract.
C. Epithelial biology and medicine.
D. Functional disorders of motility or secretion.
E. Practical course: endoscopy demonstration.
F. Intestinal hormones.
G.Grand challenges: the horizons where you can
contribute.
Goals of the course:
1.That you find it interesting,
useful and enjoyable.
2.That we can inspire some of
you to undertake research in
the area.
Problems, feedback, comments ........
Marie-Louise Zbinden 031 632 8025
Kathy McCoy (078 788 3016 emergency no.)
Andrew Macpherson (079 861 3740 emergency no.)
Induction of adaptive immunity
in the GI tract
Andrew Macpherson
Department of Medicine, University of Bern
Learning goals of the lecture:
1.The dominance of the mucosal immune
system.
2. Induction of adaptive mucosal immune
responses
3.The intestinal microbiota
4. How the mucosal immune system is
compartmentalised
5.Oral tolerance
1. Dominance
of mucosal
immunity
Mucosal immunity - dominance and Achilles heel
Murine intestinal T cells = 6x107
> 50% of the total peripheral T cell
pool
Most of the immune
system is in the
mucous membranes Most infections enter
through the mucosal
routes
WHO worldwide mortality
data
Case 1 Herr A.N. Other Aet 35
Recently arrived in Switzerland from Germany
previously worked up with final diagnosis of irritable
bowel syndrome
Low weight (61kg: 1.86m) and intermittent
abdominal pain for >10 years
Ileocolonoscopy (St. Elsewhere’s University
Hospital, D) normal 2006
Hb 109g/dl, MCV normal, CRP 12mg/l, fecal
calprotectin 232mg/g
Case 1 Herr A.N. Other ileocolonoscopy
Terminal ileum
Distal 8cm Proximal to 8cm
Case 1 Herr AN Other (continued)
Diagnosis: Crohn’s disease
NOD 2/CARD 15 homozygote for 3020insC mutation
Initial treatment and course
Prednisolone 30mg/day reducing.
Symptoms settled and retained weight gain 68kg 4
weeks after completion of course.
Discussion of immunosuppression and preliminary
TMPT genotyping as future treatment modality.
2. Induction of
mucosal
immune
responses
Tonsils and
adenoids
Organs of the
immune system
Spleen
Bone
marrow
(primary)
Lymphatics
Thymus
(primary)
Lymph
nodes
Mesenteric
lymph nodes
Peyer‘s
patches
Mucosal responses to cholera toxin: the
definitive model system NAD Nicotinamide
Gs protein
of adenylate
cyclase
ADP-Gs protein
of adenylate
cyclase irreversibly
activated
d0 d10 d20
d24
15μg cholera toxin in
NaHCO3
Excellent specific
mucosal B (IgA in
mucosa) and T cell
responses
Mucosal responses to cholera toxin
Demonstration of
lymphocyte
recirculation in
rodents with
disconnected
intestinal loops
Immunisation of the intestinal loop causes
an anti-cholera response in the main
intestine and vice-versa
Specific IgA plasmablasts can be tracked
as they recirculate
Mucosal responses to cholera toxin
IgA carried into
intestinal lumen
bound to the
polymeric Ig receptor
(pIgR)
Neutralising
IgA antibody
effects in
intestinal
epithelial
monolayers
IgA, but not IgG, will
neutralise luminal
antigens following
epithelial transport
3. The
intestinal
microbiota
Antigens from non-
pathogenic
commensals and
food antigens
1014
1012/ml contents
Large intestine
(colon)
108-10/ml contents
Distal small intestine
(ileum)
1010
Pharynx and upper
respiratory tract
1011
103-9/cm2
Skin
109-10
Female lower
genital tract
Environmental
microorganisms 1014
>
Eukaryotic cells 1013
Food 200-400g/day
Human (mammalian) biological
identity... Our genes Our cells
Microbial cells Microbial genes
Mucosal immunity is
heavily shaped by
the commensal
microbiota
Germ-
free
isolators
Germ-free
mice
Mice with normal
intestinal
bacteria (SPF)
4. How the immune
system is
compartmentalised
• Mesenteric lymphatics
• Mesenteric lymph
nodes
Induction of
IgA by
intestinal
commensal
bacteria
DC carrying
bacteria do not
penetrate further
than the
mesenteric lymph
nodes so induction
is confined to the
mucosal immune
system
Colon 50µm
E.coli mono-colonized C57BL/6 mouse
Commensals are kept from
epithelial surface by mucus
E.coli
DAPI
Muc-2
Carnoy’s
fixation
to preserve
mucus
structure
The intestinal
microbial habitat
–through an
immunologic
lens
IgA helps the
barrier function
of the intestine
Mucus,
antibacterial
proteins and IgA
are all secreted to
help the epithelial
cells withstand the
barrage of
commensal
intestinal bacteria
A whole-body view of
(intestinal) host
microbial mutualism
Live microbes stratified above the intestinal
epithelium or compartmentalised within
dendritic cells of the mucosal immune system
Recirculation
of induced
lymphocytes
5. Induction of
oral tolerance
to soluble
proteins
Generation of ‘oral tolerance’
Generation of
‘oral tolerance’ –
recirculation of
regulatory T cell
populations
Regulatory T cells
induced by
commensal
bacteria only
appear in the
intestine itself
Learning goals of the lecture:
1.The dominance of the mucosal immune
system.
2. Induction of adaptive mucosal immune
responses
3.The intestinal microbiota
4. How the mucosal immune system is
compartmentalised
5.Oral tolerance
