Immune Responses in Digestive and Metabolic Disorders

Immune Responses in Digestive and Metabolic Disorders

Immune responses in digestive and
metabolic disorders

@ Mike Baldwin / Cornered
V
CARTOONSTOCK-
BALDWIN
Search ID: mban5028

"Might be celiac disease. We'll have to
wheat and see."

TROUBLE IS I
DRINK LOTS OF BEER
TO TRY TO FORGET
THE GOUT !
DOCTOR
CARTOONSTOCK
Search ID: mfIn277

Dr Chris Nile
Level 7 (7.006)
christopher.nile1@newcastle.ac.uk

Aims of the Document

• To describe the aetiology and pathogenesis of select examples of inflammatory
  gastrointestinal diseases:

• Coeliac disease
• Crohn's disease
• Ulcerative colitis

• To describe the aetiology and immunopathogenesis of select examples of metabolic
  disorders

• Gout

• Type 2 Diabetes

• To describe the immunopathogenic relationship between metabolic disorders and
  other inflammatory diseases

Supporting Materials

• IAH Theme 1 Lectures/Tutorials
• Parham P. The Immune System (4th edition) 2014 Garland
• Murphy KP et al Janeway's Immunobiology: (9th edition) 2016 Churchill Livingstone

Coeliac Disease Overview

• Has features of both an allergic response and autoimmune disease
• Causes abdominal distension, malabsorption, diarrhea, anaemia and intestinal
  cancer (in some patients)
• Characterised by inflammation of the upper region of small intestine caused by
  response to gluten
• Gluten: a complex of proteins found in wheat, barley and oats
• 1% of the UK population have coeliac disease
• Management: elimination from diet

Normal jejunum
Celiac jejunum
Figure 16.36 The Immune System, 4th ed. (@ Garland Science 2015)

Histological Features of Coeliac Disease

• Loss of villi (villous atrophy)
• Increase in renewing epithelial cells
  (crypt hyperplasia)
• Severe inflammation (Inflammatory
  infiltrate)
• Tissue damage

Molecular Basis of Immune Recognition of Gluten in Coeliac Disease

• Pathogenesis entirely dependant on foreign antigen (gluten) but
  features of autoimmune disease
• Aberrant priming of IFN-y producing CD4+ T cells by antigenic peptides
  derived from a-gliadin (major protein in gluten)
• For immune recognition a-gliadin must undergo deamidation by tissue
  transglutaminase (tTG) - converts glutamine to glutamic acid

Peptides naturally produced
from gluten do not bind to
MHC class II molecules

An enzyme, tissue
transglutaminase (TG),
modifies the peptides so
they now can be processed and
bind to the MHC
class Il molecules

The bound peptide activates
gluten-specific CD4 T cells

The activated T cells can kill
mucosal epithelial cells by
binding Fas. They also secrete
IFN-y, which activates the
epithelial cell to produce
cytokines and chemokines that
recruit other inflammatory cells

tTG
Fas
FasL
IFN-Y
Figure 14.25 Janeway's Immunobiology, 9th ed. (@ Garland Science 2017)

Genetic Predisposition to Coeliac Disease

• Extremely strong genetic predisposition
• Major genes are on the Human leukocyte antigen region (HLA) -highly
  polymorphic
• 95% of coeliac disease patients have the HLA-DQ2 class II MHC allele
• 80% concordance in monozygotic (identical) twins
• 10% concordance in dizygotic (non-identical) twins
• 6 x higher incidence in individuals with Down's syndrome
  - why? unclear
• But most HLA-DQ2+ individuals in the population do not get coeliac disease
  - other genetic and environmental factors contribute to susceptibility

HLA-DQ
HLA-A
HLA-B
1
HLA-DR
HLA-DP
1
HLA-C
-
class |
class III
class II
Chromosome 6p 21.31
MHC class I
Complement MHC class II
proteins and
cytokines

Inflammatory Bowel Diseases (IBDs)

• Chronic inflammatory diseases with features of autoimmune disease
• Crohn's disease (CD)
• Ulcerative colitis (UC)

Inflammatory Bowel Disease (IBD)
Normal
Crohn's Disease
Ulcerative Colitis
"cobble-
stoning"
fat
wrapping
· ulceration
surviving
mucosa
(pseudo-
polyps}
fissure thickened wall
loss of
haustra
crypt
distortion
histology specimen
scope view
cobblestoning
pseudopolyps

Incidence of Crohn's Disease

Crohn's disease incidence per 100,000 person-years
<9
9-10
10-12
>12

Incidence of Ulcerative Colitis

Ulcerative colitis incidence per 100,000 person-years
<15
15-16
16-18
>18

Incidence and Prevalence of Inflammatory Bowel Disease in UK Primary Care (2000-2018)

• Crude incidence estimates of 'IBD overall' = 28.6/100,000 person per year
• Crohn's disease = 10.2/100,000 person per year
• Ulcerative colitis = 15.7/100,000 person per year
  Pasvol et al, BMJ (2020):10,7

Crohn's
Disease
Ulcerative
colitis

Crohn's Disease (CD) Characteristics

• Inflammatory lesions (including granulomas) that can involve the entire GI tract
• Inflammatory lesion is 'transmural' involving all layers of the intestine: epithelium,
  lamina propria and other layers
• Chronic and episodic (exacerbations and remission not linked to therapy)
• Frequent complications: thickened and fissured bowl leads to obstruction and
  fistulation
• The pathogenesis involves a dysregulation of mucosal immune function
• ~ 60% of patients with CD have oral manifestations (oral Crohn's) - cheilitis, oral
  ulceration (deep), fissuring and glossitis - Might be the first sign of the disease

Unique Immunological Properties of Mucosal Surfaces

Distinctive Features of the Mucosal Immune System: Anatomical

• Intimate interactions between mucosal epithelia and lymphoid tissues
• Discrete compartments of diffuse lymphoid tissue and more organized
  structures such as Peyer's patches, isolated lymphoid follicles, and tonsils
• Specialized antigen-uptake mechanisms, e.g., M cells in
  Peyer's patches, adenoids, and tonsils

Distinctive Features of the Mucosal Immune System: Effector Mechanisms

• Activated/memory T cells predominate even in the absence of infection
• Multiple activated 'natural' effector/regulatory T cells present
• Secretory IgA antibodies
• Presence of distinctive microbiota

Distinctive Features of the Mucosal Immune System: Immunoregulatory Environment

• Active downregulation of immune responses (e.g., to food and other
  innocuous antigens) predominates
• Inhibitory macrophages and tolerance-inducing dendritic cells
  Figure 12.2 Janeway's Immunobiology, 9th ed. (@ Garland Science 2017)

Microbiomes of Host Mucosal Surfaces

Firmicutes
Bacteroidetes
Actinobacteria
Proteobacteria
Other phyla
esophagus (43)
mouth (56)
stomach (25)
skin (48)
colon (195)
vagina (5)
Figure 12.4a Janeway's Immunobiology, 9th ed. (@ Garland Science 2017)

Protective Effects of Mucosal Biofilms

• In health commensal species dominate
• Synthesise antimicrobial substances e.g.,
  lactobacilli make lactic acid and antimicrobial
  peptides (baterocins)
• Stimulate epithelial cells to make their own
  antimicrobial peptides
• Compete with pathogens for ecological niches
• The microbiota influences the development of
  mucosal tissue and the immune system
  - Studies in germ free mice have demonstrated
  the importance of the gut microbiota in gut tissue
  development and training of the immune system
  (see review article)

Intestinal Immunologic Defects in Germ-Free Mice: Intestinal Organ Development

Table 1
Intestinal immunologic defects in germ-free mice
Intestinal organ development
Site
Phenotype in Germfree mice
Peyers Patches
fewer, less cellular
Small Intestine
Lamina propria
thinner, less cellular
Germinal centers
fewer plasma cells
Isolated lymphoid follicles
smaller, less cellular
smaller, less cellular
Mesenteric Lymph nodes
Germinal centers
fewer plasma cells

Intestinal Immunologic Defects in Germ-Free Mice: Cellular Defects

Cellular Defects
Cell Type
Phenotype in Germfree mice
Intestinal epithelial lymphocytes
CD8+T cells
fewer, reduced cytotoxicity
proportional decrease in number
Lamina propria lymphocytes
CD4+ T cells
decreased Th17 cells (Small intestine)
increased Th17 cells (Colon)
Mesenteric lymph nodes
CD4+CD25+T cells
reduced suppressive capacity

Intestinal Immunologic Defects in Germ-Free Mice: Molecular Immune Deficiencies

Molecular immune deficiencies
Molecule
Phenotype in Germfree mice
Angiogenin-4
reduced expression
Paneth Cells
RegIII
reduced expression
B cells
Secretory IgA
reduced production
Intestine
ATP
reduced
MHC class II
reduced expression
Intestinal epithelial cells
TLR 9
reduced expression
IL-25
elevated
Round and Mazmanian. Nat Rev
Immunol. 2009 9(5): 313-323
reduced expression of Foxp3

Mucosal Immune System - Organisation

Scattered lymphoid cells
Organized lymphoid tissues
Intestinal lumen
lamina propria lymphocyte
intestinal
epithelial
cell (IEC)
- intraepithelial lymphocyte
Peyer's patch
lamina
propria
isolated
lymphoid
follicle
afferent lymphatic
to mesenteric lymph node
Figure 11-4 Immunobiology, 7ed. ( Garland Science 2008)

• Immune cells (both effector and regulatory) scattered throughout intestinal mucosa
  (even in absence of disease)
• Areas with organised secondary lymphoid tissues (GALT - gut associated lymphoid
  tissues) e.g. Peyers patches and isolated lymphoid follicles
• GALT drains into mesenteric lymph nodes

Mucosal Immune System - Surveillance and Rapid Response

Surveillance

• Immune cells and epithelial cells
  sample antigens
• Intraepithelial lymphocytes
• dendritic cells with intraepithelial
  protrusions
• Microfold cells (M cells)
• Regulatory Immune cells can stop
  unwanted responses to commensals
  and innocuous materials

Rapid Response

• Specialised epithelial cells secrete
  antimicrobials (e.g. Paneth cells)
• Localised Plasma cells secret IgA
• Rapid communication between local
  dendritic cells and T/B cells in
  secondary lymphoid tissues due to
  organisation

Gastrointestinal mucosal immunity
Comensal bacteria
?
Intranpithelial
lymphocytes
M cell
Intestinal
ngithelia cell
Mucus
Goblet call
Dendritic
coll
Crypt
Payer 8
patch
Lymphatic
drainage
Follicle
Lamina
propria
Dendritic
coll
B cell
Macroprags
Plasma cell
Pareth
T. CHI
Anti-microbial calls
peptides
Mast call
Image - cellular and molecular immunology 8th edition
Mesentery
Mesenteric
lymph node
Intestinal
lumen
Mucosal
epithellum
Afferant
lymphatic
IGA

Crohn's Disease (CD) Pathogenesis

• Model of CD pathogenesis has been proposed
  in which this condition develops in three
  temporally distinct phases*
• The trigger - bacterial antigens penetrate
  gut epithelium (commensals - microbial
  dysbiosis - cause or consequence?)
• A defective innate immune response to
  the bacterial antigens and impaired
  clearance
• £
  A subsequent prolonged compensatory
  adaptive immune response (chronic
  inflammation - granuloma formation)
• Leads to damaging inflammation at mucosal
  surfaces

Crohn's disease
Healthy
Stage 1: Penetration of foreign material
Bacteria in gut lumen
Mucin ? MUC19
anti-microbial peptides
>defensins
Mucus layer
Epithelial barrier
C
NODE
-
NOD2
Paneth
cell
Stage 2: Impaired clearance of material
Pattern recognition
receptors (e.g. TLRs)
Pattern recognition
receptors (e.g. TLRs)
?ATG16L1
IRGM
NOD2
NOD2
Strong pro-inflammatory
cytokine secretion
Diminished pro-inflammatory
cytokine secretion
Macrophage
Neutrophil
accumulation
and bacterial
clearance
Poor neutrophil
accumulation
00:00
Impaired bacterial
clearance
Resolution
Stage 3: Compensatory adaptive responses
Macrophage
IL-23R Lymphocyte
Granuloma
Pro-inflammatory cytokine
secretion + crohn's disease
*Sewell GW, Marks DJ, Segal AW. The immunopathogenesis of Crohn's disease: a three-stage model.
Curr Opin Immunol. 2009; 21: 506- 513.