Enterology Flashcards
1
Q
What are distinctive features of the mucosal immune system? (7)
A
- Intimate interactions between epithelia & lymphoid tissues
- Discrete compartments of lymphoid tissue
- Specialized antigen-uptake mechanisms
- Activated/memory T-cells predominate even in absence of infection
- Non-specifically activated natural effector/regulatory T-cells present
- Active downregulation of immune responses
- Inhibitory macrophages and tolerance-inducing DCs
2
Q
What are the specialized lymphoid tissues in the small intestine & colon?
A
Small intestine = Peyer’s patches
Colon = colonic patches & isolated lymphoid follicles
3
Q
Why are lymphoid-like structures directly present in the mucosal surfaces of the intestine?
A
Lymph nodes are relatively far away -> presence of lymphoid structures in the intestines allows for rapid responses
4
Q
What is the specialized antigen-uptake mechanism of Peyer’s patches?
A
M-cells
5
Q
What is the function of M-cells?
A
Selective antigen-uptake in the intestine
6
Q
What kind of T-cells predominates in the intestine? What is the advantage of this?
A
Memory cells -> primed phenotype, allows for rapid responses
7
Q
Where are memory T-cells in the intestine located?
A
Lamina propria
8
Q
How is tolerance to food antigens (mainly) maintained in the intestine?
A
Tregs
9
Q
How are intestinal epithelial cells interconnected?
A
Tight junctions
10
Q
Which three distinct areas can be distinguished in Peyer’s patches?
A
- Dome area containing DCs
- T-cell areas
- B-cell areas
11
Q
Where are DCs located in the Peyer’s patches?
A
Dome area
12
Q
True or false: Peyer’s patches and colonic patches have the same organization
A
False; Peyer’s patches have distinct tissue organization, whereas colonic patches are more loosely organized
13
Q
Which cell types can be found in the intestinal lamina propria? (4)
A
- Memory T-cells
- Memory B-cells
- High amounts of macrophages and DCs
- Relatively low amounts of monocytes
14
Q
True or false: the composition of immune cells in the lamina propria is the same across the whole digestive tract
A
False; the composition is site-dependent
15
Q
What are IELs? Where are they mainly found?
A
Intra-epithelial lymphocytes; almost exclusively found in the small intestine, very little in the colon
16
Q
What is the role of IELs?
A
Have a role in barrier function of the epithelium
17
Q
How do antigens from the intestines reach lymph nodes?
A
Peyer’s patches and colonic patches contain lymph ducts that drain to mesenteric lymph nodes
18
Q
What is the function of villi of intestinal epithelium?
A
Surface enlargement
19
Q
What are the functions of microvilli of the intestinal epithelium? (2)
A
- Enlarge surface
- Prvent bacterial attachment
20
Q
What do the villi of the duodenum look like?
A
High villi
21
Q
What are Brunners glands? Where are they found, and what are their function?
A
Glands in the submucosa of the duodenum -> secrete alkaline solutions to neutralize stomach acid
22
Q
What can be said about the folds of the jejunum as compaired to the duodenum? What happens to the folds more distally?
A
Higher folds, that lower distally
23
Q
What happens to the crypts of the ileum, the more distal you get?
A
Crypts deepen towards the ileum
24
Q
True or false: the ileum has plicae
A
False; the ileum barely has any folds
25
Where are Peyer's patches mainly found?
Ileum
26
Why are Peyer's patches mainly found in the ileum, and not more proximal?
Barely any bacteria in the duodenum/jejunum
27
Why does the colon not contain villi or folds?
No need to take up nutrients
27
Which cell type can be found at the bottom of colonic crypts?
Stem cells
27
Which cell types can be found in the intestinal epithelium? (4)
1. Enterocytes
2. Goblet cells
3. Paneth cells
4. Stem cells
27
What is the function of enterocytes?
Resorption of nutrients
28
What is the function of goblet cells?
Production of mucus
29
The colon contains [less/more] goblet cells than the small intestine
More
30
Where are goblet cells located in the small intestine?
Base of the villi
31
Where in the intestine can one find Paneth cells under physiological circumstances?
Small intestine
32
What is the function of Paneth cells?
Keeping crypts free of bacteria through the release of anti-microbial peptides
33
True or false: Paneth cells are the only intestinal cells producing AMPs
False; other epithelial cells also produce AMPs, but in far lower amounts
34
What happens when a Paneth cell is unable to clear bacteria?
Sensing of bacteria using TLRs & PRRs -> signals for assistance
35
In which instance can Paneth cells be found in the colon?
Paneth cell metaplasia -> occurs in severe colonic disease
36
How long does regeneration from crypt to villus take?
~36 hours
37
How do intestinal microbiota contribute to host physiology? (4)
1. Bacteria facilitate digestion & absorption of nutrients
2. Bacteria-derived signals are needed for normal intestinal physiology
3. Commensal bacteria limit pathogen colonization
4. Host provides a protected & nutrient-rich environment
38
Which two systems in the intestine are dependent on the presence of signals from intestinal microbiota?
1. Epithelium
2. Immune system development
39
Which constituent parts form the intestinal epithelial barrier, which limits bacterial penetration of host tissue? (5)
1. Microvillar extension -> prevent bacterial attachment
2. Epithelial tight junctions
3. Mucinous secretions by goblet cells
4. Epithelial transcytosis of IgA
5. Antimicrobial peptides
40
True or false: epithelial tight junctions in the intestine always remain tightly closed
False; they can be opened in a controlled way, but without breaking the barrier
41
What is the main component of mucus?
Polysaccharides
42
The [small intestine/colon] has a thicker mucus layer
Colon has a thicker mucus layer
43
What does a lack of mucus-production lead to?
Lack of bacterium-free zone above the epithelium -> bacterial colonization of crypts -> colitis
44
What is the daily prodyuction of IgA in the intestine? How much % of the total immunoglobulin production is this?
3-5 grams of IgA/day, 75% of total production
45
What is the role of IgA in intestinal barrier functions?
Allows for selective colonization by bacteria, whilst preventing others from attaching
46
What triggers secretion of AMPs by Paneth cells?
TLR activation
47
What is the effect of a deletion of Paneth cells?
Disturbances of commensal bacteria, leading to more drainage of commensals to mesenteric lymph nodes
48
How do M-cells selectively take up antigens?
PRRs recognize relevant antigens
49
Which three mechanisms does the intestine have for antigen-uptake across the epithelium?
1. Passive diffusion
2. M-cells
3. Macrophage uptake
50
How do macrophages take up antigens from the intestine?
Break tight junctions between epithelial cells and extend cytoplasm into the lumen to sample it
51
What is the effect of increased bacterial load on the number of macrophage protrusions in the intestinal epithelium?
Amount of macrophage protrusions increases
52
What are the epithelial barrier & antigen sampling characteristics of the small intestine? (4)
1. Presence of M-cells
2. Thin mucus layer
3. Presence of Paneth cells
4. Peyer's patches
53
What are the epithelial barrier & antigen sampling characteristics of the colon? (4)
1. Absence of M-cells
2. Thick mucus layer
3. Absence of Paneth cells
4. Isolated lympoid follicles
54
How does a cell in the intestine determine whether to respond to PRR activation or not?
Specific combinations of PRR activation produces specific cocktails of inflammatory mediators, dictating responses
55
What are the two functions of NF-κB in the intestine?
1. Production of inflammatory mediators upon activation of PRRs
2. Intestinal epithelial homeostasis
56
By which factor is NF-κB inhibited?
IκB
57
How is IκB inactivated, allowing for the activation of NF-κB?
Phosphorylation of IκB allows it to be ubiquinated -> IκB broken down in proteasome, releasing NF-κB
58
What is the function of NF-κB in intestinal epithelial cells?
Necessary for epithelial cell survival
59
What is the effect of loss of NF-κB in intestinal epithelial cells?
Disrupted epithelial barrier function -> bacteria leak in -> macrophage activation -> chronic intestinal inflammation
60
What is the effect of NF-κB in macrophages? (3)
1. Survival
2. Pro-inflammatory factor expression
3. Host defence
61
Where are most PRRs in the intestine located? Why there?
Basolateral side -> allows for sensing of bacterial tissue invasion, whilst not getting activated by intraluminal presence of bacteria
62
In which areas of the intestine are TLRs located on the apical side of epithelium?
1. Close to Peyer's patches
2. Colon
63
True or false: small intestine & colon express the same TLRs
False; they express different TLRs because they have a different microbiological profile, requiring different receptor signatures
64
What is the effect of repetitive activation of PRRs by the same pathogen?
Desensitization of epithelium, leading to hyporesponsiveness for that pathogen
65
What are the homeostatic functions of resident macrophages in the intestine? (4)
1. Elimination of invading commensal bacteria
2. Maintenance of Tregs
3. Phagocytosis of senescent and apoptotic epithelial cells
4. Transfer of antigens to migratory DCs
66
What is the effect of activation of resident phagocytes by danger molecules?
Inflammatory response
67
Which group of macrophages in the intestine is particularly prone to inflammatory reactions? Why?
Monocyte precursors from blood; these have not been conditioned for the gut environment and are hyperreactive against the antigens found there
68
What are the functions of inflammatory macrophages/moncoytes in the intestine? (3)
1. Increased phagocytosis -> elimination of invading pathogens
2. Maintenance of pro-inflammatory effector T-cells
3. Production of pro-inflammatory cytokines & chemokines
69
What hampers mucosal vaccination of the intestine? How can this be overcome?
Predominant tolerance of the intestinal mucosa against mucosal signals; can be overcome by incorporating a strong danger signal in the intestine
70
What is the function of DCs in the intestine? What characteristics do they have towards that end? (4)
Sampling of micro-environment and antigen presentation in mesenteric lymph nodes
1. Limited phagocytosis
2. Limited killing
3. High antigen-presenting capacity
4. High migration capacity
71
What is the function of macrophages in the intestine? What characteristics do they have towards that end?
Important in homeostasis/governing responses in healthy tissue
1. High phagocytosis
2. High killing
3. Low antigen-presenting capacity
4. Low migration capacity
72
What are markers of DCs in the intestine? Where are they located?
CD103+ cells in the lamina propria
73
What are markers of macrophages in the intestine? Where are they located?
CD103- CX3CR1+ cells located under the epithelium
74
The small intestine contains more [DCs than macrophages/macrophages than DCs]
More macrophages than DCs
75
True or false: the intestine contains a lot of naïve cells
False; nearly all memory cells
76
What happens when T-cells in the Peyer's patch are activated?
Migration to lamina propria
77
In which two ways can mesenteric lymphocytes be activated?
1. DCs drain to mesenteric lymph nodes and present antigen to T-cells
2. Free-floating antigens passively reach the lymph node, after which they are taken up by subcapsular macrophages/B-cells and presented to T-cells
78
Where are subcapsular macrophages located in the lymph node?
Subcapsular space
79
How to activated T-cells migrate back to the intestine?
T-cells undergo migration-dependent imprinting
80
What is migration-dependent imprinting?
Induction of specific chemokine receptors & adhesion molecules due to instruction by DCs
81
What is an important adhesion molecule for intestinal homing?
α4β7
82
True or false: tolerance in the intestine is mainly the result of the immune system ignoring antigens
False; there are T-cell responses to almost all food proteins
83
What is the effect of the presentation of food antigens by DCs in mesenteric lymph nodes & Peyer's patches?
Induction of antigen-specific Tregs
84
How long after encountering new food antigens are functional Tregs produced?
72 hours
85
What is an important marker of many Tregs in the intestine?
FoxP3+
86
How can tolerance to food antigens be overcome? Why does this overturn tolerance?
Cholera toxin -> strong danger signal
87
Which factors contribute to a regulatory environment in the intestine? (3)
1. CD103+ DCs
2. Dietary vitamin A
3. TGF-β
88
What do CD103+ DCs do to dietary vitamin A?
Convert it to retinoic acid
89
Which combination of DC-derived factors leads to the induction of Tregs in the intestine? (2)
1. Retinoic from dietary vitamin A
2. TGF-β
90
What is the effect of the presence of retinoic acid + TGF-β on inducted Tregs? Why is this beneficial?
1. Expression of CCR9
2. Expression of α7β4
Both are homing factors needed to home into the small intestine
91
Which cytokine is key in Treg function in the intestine?
IL-10
92
How deep should an intestinal biopsy be to adequately be able to judge it? Why?
Until the muscularis mucosae; allows for orientation of the biopsy
93
How many IELs should be visible in intestinal biopsies?
<20-25 IELs/100 epithelial cells
94
What is the ratio of villi length:crypt depth in adults & children?
Adults: 3:1
Children: 2:1
95
Based on which factors is celiac disease diagnosed? (5)
1. Clinical manifestations
2. Serological markers
3. Genetic testing
4. Response to gluten-free diet
5. Histopathologic examination
96
Is histopathologic examination performed in routine diagnostics of celiac disease?
No; only in children and borderline cases
97
Why is early and correct diagnosis of celiac disease important? (2)
1. Allows for initiation of gluten-free diet to avoid complications
2. Allows for identification of non-celiac disease conditions
98
From which sites do biopsies need to be taken in order to be able to diagnose celiac disease? (2)
1. Duodenal bulb
2. Distal part of duodenum
99
What are two important biopsy prerequisities for accurate celiac disease diagnosis?
1. Biopsy tissue fragments well-oriented
2. Biopsies performed when patient was on gluten-containing diet
100
What histological pattern can be observed in celiac disease? (3)
1. Disruption of villi:crypt ratio
2. Increased amounts of IELs
3. Crypt hyperplasia
101
In which way is the villi:crypt ratio disturbed in celiac disease?
Short villi (1:1) or no villi (mucosal flattening)
102
What is the primary location of ulcerative colitis?
Primarily rectal & left-sided colitis
103
Where in the digestive tract does Crohn's disease occur? Where is it most frequently found?
All across the digestive tract; most frequently terminal ileum
104
How is the diagnosis of IBD made? (4)
1. Clinical manifestations
2. Endoscopic findings
3. Imaging features
4. Microscopic features
105
What is the role of the pathologist in IBD? (2)
1. Assess distribution of disease
2. Recognize chronic changes & acute inflammation due to IBD
106
In which anatomical location is it most difficult to distinguish between ulcerative colitis & Crohn's disease?
Colon -> both can occur there and look similar
107
What are macroscopic features of Crohn's disease? (3)
1. Cobblestone aspect of the intestinal wall
2. Strictures of the intestinal wall
3. Ulcerations of the intestinal wall
108
What are microscopic features of IBD in the colon? (4)
1. Architectural changes
2. Chronic inflammation of the lamina propria
3. Acute inflammation
4. Epithelial changes
109
Which architectural changes can be observed in IBD in the colon? (2)
1. Irregular/villiform mucosal surface
2. Crypt distortion & atrophy (loss of crypts & shallow crypts)
110
How can chronic inflammation of the lamina propria be seen in IBD? (2)
1. Increase of non-aggregated plasma cells & lymphocytes in lamina propria
2. Basal lymphoplasmacytosis
111
Which presentations of acute inflammation can be seen in microscopy of the colon in IBD? (2)
1. Formation of crypt abscesses/cryptitis due to neutrophilic inflammation
2. Ulceration of the intestinal wall
112
Which epithelial changes can be observed in colonic IBD? (2)
1. Paneth cell metaplasia to the distal colon
2. Mucin depletion of epithelial cells of the mucosa
113
Which features can be used to distinguish CD from UC? (2)
1. Presence of granulomas
2. Presence of giant cells
114
What are features of IBD in the small bowel? (3)
1. Architectural disturbance
2. Inflammatory component of the lamina propria
3. Pyloric metaplasia
115
What are causes of dysbiosis of the intestinal microbiome? (4)
1. Host genetics
2. Lifestyle
3. Early colonization (bith in hospitals)
4. Medical practices
116
What is inflammatory bowel disease (definition)?
Inappropriate inflammatory response to intestinal microbes in a genetically susceptible host
117
In which ways can immune responses in IBD be inappropriate? (2)
1. Hyporesponsiveness
2. Hyperresponsiveness
118
Which kind of genetic alterations are mainly found in IBD?
SNPs
119
In which locations is CD mainly found? (2)
Locations with high microbe diversity/numbers:
1. Terminal ileum
2. Colon
120
What are histological aspects of Crohn's disease? (5)
1. Patchy
2. Transmural
3. Dense lymphocyte infiltration
4. Granulomas in 60% of patients
5. Ulcer formation
121
What are histological aspects of ulcerative colitis? (4)
1. Superficial layers affected
2. Infiltration of lymphocytes & granulocytes
3. Loss of goblet cells (empty)
4. Presence of ulcerations & crypt abscesses
122
Genes involved in which functions have been implicated in IBD? (5)
1. Immune regulation
2. Neutrophil function, phagocytosis & bacterial killing
3. Innate immune activation
4. Lymphocyte selection & FoxP3 Tregs
5. Epithelial barrier/responses
123
SNPs in which groups of genes are primarily associated with CD? (2)
1. PRRs
2. Cytokines
124
SNPs in which groups of genes are primarily associated with UC? (2)
1. Cytokines
2. Epithelial barriers
125
What are characteristics of IBD due to monogenic mutations?
Early onset and severe
126
Why is studying monogenic IBD informative for the whole group of IBD?
It can reveal pathways involved in IBD
127
Disruptions in the NOD2 pathway can lead to IBD. Does this lead to UC or CD?
CD
128
What is the physiological function of NOD2?
PRR
129
True or false: there are complete NOD2 insufficient patients
False; no complete NOD2 knockout has been found, but there are cases in which multiple SNPs severely hamper NOD2 function
130
How does CD due to NOD2 deficiency respond to treatment?
Very treatment-resistant
131
What are physiological functions of NOD2? (2)
1. Maintenance of Paneth cells
2. Physiology of APCs
132
What is the function of NOD2 for Paneth cells?
Important for the production of AMPs, particularly cryptidin
133
What is the effect of NOD2 disruption on APCs? (2)
1. Increased killing
2. Reduced TLR2 signaling -> reduced production of pro-inflammatory cytokines
134
What is the effect of disruption of IL-10 signaling in the intestine?
Small intestinal & colonic severe early-onset IBD
135
What is the effect of IL-10 deletion in Tregs in the small intestine (in mice)?
No effect -> other cells than Tregs are responsible for IL-10 production in the small intestine
136
What is the effect of IL-10 deletion in Tregs in the colon (in mice)?
IBD -> Tregs are an essential source of IL-10 in the colon
137
SNPs in which adaptive genes are mostly involved in IBD? (3)
Th1/Th17-function:
1. Innate cytokines involved in Th1/Th17 differentiation
2. Transcription factors of Th1/Th17 cells
3. T-cell derived cytokines
138
Which cytokine is fundamental in CD?
IFN-γ
139
Which cytokine is fundamental in UC?
IL-17
140
What are the treatment goals of IBD-treatment? (2)
1. Induce & maintain remission
2. Avoid complications
141
What is the initial phase of IBD treatment?
Strong immunosuppression using corticosteroids
142
Which treatment strategies are available for IBD? (5)
1. Exclusive enteral nutrition
2. Corticosteroids
3. Anti-inflammatory drugs
4. Immunomodulators
5. Biologicals aimed at involved cytokines
143
True or false: exclucive enteral nutrition has (some) effect in all IBD patients
False; only works in a subgroup of patients
144
Which anti-inflammatory drugs are used in the treatment of IBD? (2)
1. Sulfasalazine (SASP)
2. Mesalazine (5-ASA)
145
Which immunomodulators are used in the treatment of IBD? (3)
1. Methotrexate
2. Tacrolimus
3. Azathioprine
146
What is the main cytokine targeted by cytokine treatments in IBD?
TNF-α
147
What are proposed new options for IBD treatment? (4)
1. Cytokine therapies against cytokines involved
2. T-cell blocking therapies
3. Therapies blocking cell recruitment
4. Therapies blocking growth factors
148
Which involved cytokines could be targeted in IBD, in addition to TNF-α? (3)
1. IFN-γ
2. IL-6
3. IL-12
149
What is gluten?
Protein component of many grains
150
What is the function of gluten for grains?
Storage protein
151
Gluten is [soluble/insoluble] in water
Insoluble
152
What makes gluten hard to break down? (2)
1. Disulfide & hydrogen bonds, forming tight aggregates
2. Rich in proline
153
What is coeliac disease (definition)?
Gluten-induced inflammation of the GI-tract
154
What is the main effect of coeliac disease on the body?
Disturbed nutrient uptake
155
What is the treatment of coeliac disease?
Gluten-free diet
156
How many % of the Dutch population suffers from coeliac disease? How many of them are diagnosed?
~1% = 170.000 people, of which 25.000 are diagnosed -> lots of undiagnosed infections
157
Which two HLA types can be present in coeliac disease? How many % has each?
1. HLA-DQ2 = 95%
2. HLA-DQ8 = 5%
158
Which serum marker is used for the diagnosis of coeliac disease?
Anti-tissue transglutaminase IgA
159
What is the physiological function of tissue transglutaminase?
Tissue repair
159
The antibodies against TG2 in coeliac disease are [binding/neutralizing] antibodies
Binding antibodies
160
Why is the presence of anti-TG2 antibodies alone insufficient for diagnosis of coeliac disease?
These could be transiently present in other diseases
161
Which processes enable reactions to gluten in coeliac disease? (3)
1. Gluten is degraded in the intestinal lumen and passes the epithelial barrier
2. TG2 deaminates gliadin, changing its confirmation
3. The changed confirmation of gliadin allows it to bind in HLA-DQ2/-DQ8, causing antigen presentation of T-cells
162
Which adaptive responses are involved in coeliac disease? (2)
1. Induction of gliadin-specific IFN-γ producing CD4+ T-cells by presentation of gluten on HLA
2. Induction of a plasma cell response, leading to anti-TG2 antibodies
163
Which innate responses are involved in coeliac disease? (3)
1. Stress of epithelial cells leads to secretion of IL-15, leading to induction of IELs
2. Stress of epithelial cells leads to NK-receptor ligand expression, resulting in killing of epithelial cells
3. Killing of epithelial cells by cytotoxic CD8+ IELs
164
What is the role of IL-15 in coeliac disease?
Leads to induction/activation of cytotoxic IELs that kill epithelial cells
165
What causes epithelial flattening in coeliac disease?
Killing of stressed epithelial cells by NK-cells
166
A large % of the population has susceptible HLA-types, yet only a small % has coeliac disease. What maintains balance in healthy individuals?
Tregs
167
What kind of Tregs are necessary for the maintenance of tolerance to gluten? Which cytokine do they produce?
Tr1-like cells: FoxP3- IL-10 producing T-cells
168
What is the effect of disrupted IL-10 function in coeliac disease? (2)
1. IEL infiltration
2. Crypt hyperplasia
