Gut Immuno Flashcards
1
Q
What is the function of the immune system in the intestine?
A
Must discriminate between harmful pathogens and tolerance to harmless microflora and diet antigens
2
Q
What is associated with a growing number of intestinal diseases?
A
Disruption of gut microbiota
3
Q
What early-life exposures contrinbute to colonization of infect intestines?
A
Maternal Microbes Infant Diet Abx Probiotics (enrichment) Environmental Microbes
4
Q
What are examples of gut microbiota symbiosis?
A
Immune tolerance
Intestinal homeostasis
Healthy metabolism
5
Q
What are examples of gut microbiota dysbiosis?
A
- Immune disease (asthma, MS)
- Intestinal disease (IBS)
- Metabolic disease (DM, obesity)
6
Q
What is the largest immune organ in the body?
A
Gut-associated lymphoid tissue (GALT)
7
Q
What do GALT consist of?
A
Peye’s patches and isolated lympoid tissue (ILT)
8
Q
What is critical for GALT and ILT development–> regulate microbiota?
A
Cross-talk between host immune system and microbiota
9
Q
When/where do ILT develop?
A
after birth in small and large intestines
—>dynamic response of gut immune system to microbiota
10
Q
How is the body expose to microbial and diet antigens in the gut?
A
GALT
11
Q
How do peyer’s patches and ILT receive antigens directly from the epithelial surface?
A
antigen-transporting dendritic cells
12
Q
Why do peyer’s patches and ILT receive antigens directly from the epithelial surface?
A
They lack afferent lymphatic vessels (incoming)
13
Q
How are B cells and T cells recruited in the gut?
A
Microbe-associated molecular patterns (MAMPs) on intestinal epithelial and DCs are recognized and stimulate recruitment
14
Q
How do ILF mature?
A
MAMPs recognized–>recruit B and T cells–> cryptopatches develop into mature ILFs
15
Q
What are ILFs?
A
Single B-cell follicles that act as inductive site for IgA production
16
Q
What occurs when MAMPs are sensed?
A
Stimulates proliferation of intestinal epithelial cells in crypts–> increase depth, increase density of Paneth cells in SI
17
Q
How are defensins primed for release?
A
sensing of MAMPs
18
Q
What contribute to antimicrobial action and mucosal defense in GI?
A
Defensins (antimicrobial peptides)
19
Q
What occurs when DC in peyer’s patches interact with local lymphocytes?
A
induce diff of T cells and T-dependent B cell amturation in germinal cells–> IgA-producing plasma cells so IgA can transpor into intestinal lumen
20
Q
What cells produce mucin that organizes into dense proteoglycal gel on intestinal epithelial cells?
A
Goblet cells
21
Q
What continually sense microbiota and induce production of antimicrobial peptides (AMPs)?
A
Eneterocytes, colonocytes, Paneth cells in bases of SI crypts
22
Q
WHat are major classes of AMPs in GI?
A
Defensins
23
Q
How does secretory IgA maintain peaceful bacteria-host interaction?
A
IgA:
- does not activate complement
- does not activate phagocytes
- resistant to proteolysis by peptidases in GI
–> why major fxn of GI is exclusion (if + completement, damage intestines)
24
Q
How is the inner mucous layer impervious to bacterial colonization?
A
High density and concentration of bactericidal defensins
25
What provides protection against 98% of pathogens encountered in body?
innate immune system
26
How do defensins produce pores in pathogen membranes?
have charged and hydrophobic aa chains that interact with microbial membranes--> pores-->kill pathogen
27
Where do the large number of commensal bacteria reside in the gut?
outside the layer of mucus that covers intestinal epithelial cells
28
What happens to commensal and pathogenic bacteria that penetrate the intestinal epithelial layer?
Rapidly killed by macrophages in lamina propria
29
How can activated B and T cells (via DC) return to intestinal mucosa?
Activation by DC with bacteria that invaded Peyer's patches--> leave mesenteric LN via efferent lymph--> bloodstream at thoracic duct--> back to intestinal mucosa
30
Describe how DC pick up bacteria in the gut
Bacteria that penetrate M cells overlying Peyer's patches are RAPIDLY KILLED by macrophages, but can be picked up by DC
31
What do DC do with bacteria that penetrated Peyer's patches?
Migrate to draining mesenteric LN--> activate T and B cells, + IgA-producing plasma cells
32
Why can't DC reach the systemic circulation from the gut?
LN function as a barrier so DC with either pathogenic or commensal bacteria can't penetrate to reach bloodstream
33
What make up 10% of T cells in GALT?
Treg cells (anti-inflammatory)
34
What is the function of Treg cells in the GI?
limited pro-inflamm cytokines and excess TGF-B (from lamina propria)---> diff of T cells into Treg cells--> SUPPRESS Th1, 2 and 17 responses
*****ANTI-INFLAMMATORY
35
How can dysbiosis occur?
Changes in diet and environmental factors
--> change composition of microflora and connections of epithelial cells
36
What are examples of short-chain fatty acids?
butyric acid, propionic acid, acetic acid
37
What is produced by colonic microbial fermentation of undigested (or partially) dietary fibers?
short-chain fatty acids (SCFAs)
38
Why is an infant born of C-section more likely to have GI disorders within first few years of life?
Wasn't exposed to mother's microflora---> infant has underdeveloped gut microflora
39
What recognize MAMPs?
Pattern recognition receptors (PRRs)
40
How do IgAs work in gut?
Form single layer on top of epithelial cells, multiple bind to bacteria
--> if bacteria try to penetrate, create respiratory burst--> release of toxins that destroy pathogens
41
How to antigens from diet interact with cells in the gut?
Go to subepithelial dome of M cells and Peyer's patches where they are picked up by DC--> migrate to draining mesenteric LB--> interact with T and B cells
42
What is undernutrition associated with?
defects in innate and adaptive immunity
43
Recurrent enteric infections predispose you to?
nutrient deficiencies and impaired intestinal mucosal barrier fxn---> increase susceptibility to inf even more
44
Why is malnutrition so harmful to the gut?
Microbiota acts as barrier to pathogen infection--> disrupted by malnutrition
45
Generally, what is the function of SCFA?
promote Treg diff and sIgA production
46
Fxn of acetate
+ accumulation of IL-10 and colonic Tregs
47
Fx of butyrate
acts directly on Tregs or via modulation of DC--> enhance Treg-inducing ability of DC
48
What acts on Tregs via TLR2 (promotes fxn, enhances IL-10 and TGF-B)
Capsular polysaccharide A (PSA)
49
What fxn do SCFAs have on mucus and IgA
- support effective IgA-mediated response to gut pathogens
| - stimulates production of mucus (maintains barrier)
50
Define immune tolerance
sustained immune UNRESPONSIVENESS to self-AG, beneficial AG and commensal bacteria
51
Define oral tolerance
suppression of immune responses to Ag that have been administered previously by oral route
52
What occurs due to failure of induced tolerance to food protein (oral tolerance)?
food allergy, celiac disease
53
What is the most prevalent food-induced pathology?
Celiac disease
54
Define central tolerance
immature lymphocytes specific for self AG--> encounter Ag in central lymp organs-----> are deleted, change B cell specificity, develop into Treg cells
55
Define peripheral tolerance
Mature self-reactive lymphocytes in periphery--> inactivated (anergy), deleted, suppressed by Treg cells
56
Generally, why is peripheral tolerance required over central in the gut?
Intestine Ag not available to cells in thymus (can't be changed by central tolerance)
57
What happens to the large number of developing lymphocytes that react against self-Ags and Ags from food/ commensal bacteria?
Eliminated in thymus via CENTRAL tolerance
OR express Foxp3 if high affinity for self-Ags--> become natural Treg cells (nTregs)
58
What normally prevents deleterious immune responses against self-Ag in the body?
Central tolerance (developing cells eliminated or neutralized in thymus that react to self-Ag)
59
Why can't central tolerance work in the gut?
Intestinal Ags can't go to thymus, so it can't prevent responses against Ag in the lamina propria
60
Depletion of what cells inhibits oral tolerance?
CD25+ Treg cell
61
What cells can activate oral tolerance?
CD4+ CD25+ Treg cells (produced in thymus)
62
What mechanism showed + of suppressor fxn that predated Foxp3 and nTreg cells?
induction of T cells with active suppressor fxn in oral tolerance
63
What cells critical for oral tolerance?
Macrophages, DC, Treg cells
64
Describe the overall mechanism of oral tolerance
Macrophages directly take up Ag from intestinal lumen--> transfer Ag to DC in lamina propria--> go to mesenteric LN--> stimulate native CD4+ T cells~~~~ converted to CD4+ CD25+ Foxp3+ Treg cells
65
How are CD4+ T cells induced to CD4+ CD25+ Foxp3+ Treg cells?
release of retinoic acid, TGF-B and IDO via DC s
--> acid induces Treg cell diff
--> TGF-B mediates Foxp3 upreg
--> IDO immunosuppressive fxn causes anergy of effector T cells (induces prolif of Treg cells)
66
Fxn of IDO in oral tolerance
immunosuppressive fxn causes anergy of effector T cells (induces prolif of Treg cells)
67
Fxn of retinoic acid in oral tolerance
induces Treg cell differentiation
68
Fxn of TGF-B in oral tolerance
mediates Foxp3 upregulation in Treg differentiation
69
Non-immune mediated food adverse rxn
Food intolerance
70
Immune-mediated food adverse rxn
food allergy
71
Toxic vs Non-toxic
Toxic:
-bacterial superantigens and staph food poisioning
Nontoxic:
-pharm, psychosomatic, enxymatic= non-immune mediated
-IgE mediated (type 1) and Non-IgE mediated (type 3/4)
72
Examples of non-immune mediated adverse rxn
Absence of enzyme needed to fully digest food
IBS
Food poisoning
Recurring stress or psych factors
73
Examples of immune-mediated adverse rxn
food ALLERGY, celiac disease via specific immune response (exposure to given food)
Sensitivity to food additives
74
What is a chronic digestive condition triggered by the protein gluten?
Celiac disease
---> NOT AT RISK for anaphylaxis d/t mostly GI sx
75
What are most common forms of immune-mediated adverse food reactions?
Type 1 hypersensitivity
76
What is the mechanism behind food allergy (generally)?
Development of IgE against food allergens
77
Describe the general mechanism of type 3/4 hypersensitivities (food allergy)
macrophage activation by allergen-antibody complexes in FcyR dependent manner
--> also + of allergen-specific T cells
78
What can lead to food allergies?
genetic disposition, environmental factors that inhibit oral tolerance
79
How many people do food allergies affect?
5% young children, 3-4% adults
--> increasing prevalence
80
What are sx of food allergies?
skin sx, GI and resp sx
81
How does a food allergy turn into anaphylaxis?
After ingestion and degradation, allergen fragments are internalized in GI and distributed throughout body
82
Describe the primary allergen encounter
Ingested allergen--> adaptive immune response via B cells (Th2) --> mature into plasma cells--> produces IgE to allergen (IL-4-> IgE) --> IgE in circulation--> bound by mast cells in tissues (FcRe/CD23)
83
Describe the secondary allergen exposure
Cross-linking of allergen to mast cell causes it to release vasoactive amines, cytokines, lipids----> vascular SM contraction, endothelial vasodilation, leukocyte chemotaxis and activation
84
Define allergic sensitization
IgE-associated food allergies that appear in early childhood
85
What individuals produce IgE production upon allergen contact to GI, resp or skin?
Those who are genetically predisposed
86
What causes IgE-dependent secondary immune response in allergy pathway?
Repeated allergen contact--> activates allergen-specific T cells that induce IgE response
87
What factors are important for primary sensitization and boosting of secondary immune responses?
things that affect integrity of EPITHELIAL BARRIER and extent of ALLERGEN DIGESTION
88
What mast cell-derived mediators cause early allergic reaction?
- Preformed: HISTAMINE, TNFa
- Bradykinin, PAF
- Granule associated: tryptase, chymase, peroxidase
*******already make in mast cells
89
What mast cell-derived mediators cause late allergic reaction?
IL-1, 2, 3, 4, 5, 6
GM-CSF
TNFa
*****must be synthesized
90
What is the function of histamine in allergic rxn?
SM contraction, vascular permiability
91
What are the fxns of TNFz and IL-1 in allergic rxn?
endothelial cell inflammation
92
What is the fxn of tryptase in allergic rxn?
anaphylais, urticaria
93
What is the fxn of prostaglandin E2 in allergic rxn?
Pain, vascular permeability
94
What is the fxn of IL-5 in allergic rxn?
sputum eosinophils
95
What is the fxn of bradykinin in allergic rxn?
Vasodilator, SM contraction
96
What cells are central to both local and systemic food allergy sx?
Mast cells
97
Systemic allergen reactions
urticaria (hives), bronchospasm
98
What mediates systemic allergen rxns?
Histmaine, platelet activating factor
99
What are GI manefistations of food allergies dependent on?
Th2-derived cytokines (IL-4, 9, 13)
100
What is necessary for local sx of food allergies?
mastocytosis (accumulate in skin/organs)
101
What mediate local acute GI sx (diarrhea) to allergen exposure?
platelet activating factor (PAF), serotonin
102
Systemic vs Local mediators via mast cells
Systemic: Histamine, PAF
Local: Serotonin, PAF
103
Role of Treg cells in control of food allergy
IL-10 and TGF-B suppress Th2 immunity--> inhibit mast cell reactivity--> REDUCE IgE synthesis--> may increase IgG and IgA
104
What compounds suppress inflammatory responses in allergic sensitization?
Vitamin D
Vitamin A
Folate
105
What aspect of diet promotes inflammation?
High-fat diet
106
What are IgE, basophils and mast cells involved in?
Allergy
107
How does gut microbiota suppress allergic immune response?
- Induce Treg cells
| - Directly suppress basophils and mast cells
108
What is the fxn of Th2 in allergy?
central to generating IgE and allergic effector cells
109
How to diagnose type 1
| hypersensitivitiy allergy
1: skin prick test (in facility in case of anaphylaxis)
2: Serum-specific IgE test
3: Atopy patch (eczema)
4: Basophil activation test (BAT)-more research setting
110
What indicates a postitive skin prick test?
redness and swellin 20-30 min after exposure to allergen
111
What is the primary tool for assessing immediate hypersensitivity reactions?
History
d/t blood or skin prick test not conclusive, must combine to dx allergy
112
Are blood tests more or less sensitive vs skin prick test for allergy dx?
less sensitive, but neither conclusive
113
What is considered the gold standard for food allergy dx?
oral food challenge
114
What is an example of an allergen-specific IgE that is used to dx allergy via blood test?
Peanut-specific IgE
115
Describe the pathway of a peanut allergy
Allergy--> DC attach to peanut-specific T cells--> T cells converted to Th2 cell--> release IL-4, 5, 13--> B cells activated--> produce peanut-specific IgE--> attach to mast cells--> release histamine (early) and serotonin (late) that affect local and systemic sx
116
Describe Non-IgE-Mediated allergic rxn to peanuts
Peanut and other nuts contribute to shock via production of C3a--> + macrophages, basophils, mast cells to release PAF and histamine via C3aR-dependent pathway (not IgE)
117
What is central part of food-induced anaphylaxis
mast cells + by IgE cross-linking of FcERI
118
What is central part of peanut-induced anaphylaxis?
IgG1-induced activation of Mf
119
Which response to B cells + Allergen is bigger: IgG1, IgE or complement activatoin?
IgE
120
What are the 3 possible pathways of nut-induced anaphylaxis?
IgG1--> Allergen-Ab complexes activate macrophages via FcyR1--> release PAF
IgE--> allergen to mast cell via FcERI--> release PAF and histamine
Complement activation--> C3a/C5a--> activates mast cells via their complement receptors--> histamine and PAF
121
What are the most important allergens in wheat allergy?
Alpha-amyalse inhibitors
Germ agglutinin
Peroxidase
122
What do wheat allergies affect?
skin, GI, resp
--> wheat-dependent, exercise-induced anaphylaxis
--> occupational asthma (baker's asthma)
--> rhinitis
--> contact urticaria
123
Does prevalence of wheat allergy increase or decrease with age?
progressively increases with age (0.4% occurrence in US)
124
Describe sensitization to wheat allergy
Eye/Nasal/Oral/Skin exposure + genetics + microbiome + environmental factors--> Th2 and IgE
125
Food-Dependent Exercise-Induced Anaphylaxis
ingest certain foods (seafood, celery, whea, cheese) before physical activity (within 2 hours) enhances absorption of undigested immunoreactive allergens into circulation
******can also occur with aspirin and NSAIDs
126
How long do non-IgE mediated allergic reactions take to develop?
up to 48 hours, still involve immune system
127
Is cow's milk allergy IgE or non-IgE mediated?
can be either, but majority of infants non-IgE
128
Do infants suspected of non-IgE milk allergy need testing for IgE to milk?
no
129
What is non-IgE milk allergy wrongly labelled as?
symptoms of lactose intolerance
130
Does an infant with suspected IgE milk allergy need testing for IgE to milk?
Yes, via skin prick or blood test
131
What is celiac disease?
Systemic immune disorder caused by permanent sensitivity to gluten
- --> GI sx
- --> higly variable non-GI sx (failure to thrive, delayed puberty, autoimmune, inflamm, neuro and metabolic disorders)
132
What are the main genetic predisposing factors for celiac disease?
HLA-DQ2 and DQ8
---> + adaptive immune responses against gluten peptides
133
Serum autoantibodies against what enzyme are specifically associated with celiac disease?
tissue transglutaminase 2 (TG2)
-----> deaminases glutamine residues of gluten
134
There is a strong link between celiac disease and
autoimmunity
---> 15-20% CD patients have or will develop autoimmune diseases
135
Describe silent CD presentation
95% undiagnosed, most relatives of patients with known CD
---> most found to be positive for anti-gTG2 antibodies
136
What is the prevalence of CD?
1%, most remain undiagnosed but can present at any age
137
What antigen is proline-rich and poorly digested in SI?
gluten (rich in glutamine)
---> 10-50 aa left incompletely digested
138
Tissue damage in CD occurs in a manner similar to what hypersinsitivity?
type 4
--> chronic inflammation with continued gluten ingestion
139
Describe antibody response in CD
Gluten (anti-TG2 Ab)--> T cell-mediated inflammatory response in proximal small bowel--> damages mucosa--> malabsorption
140
If everyone has gluten peptides, why doesn't everyone have CD?
Only CD patients have HLA-DQ2.5
141
Pathogenesis of CD
Gluten peptides--> cross-link and deamidation via TG2--> presented via HLA-DQ2.5 or 8 on APCs--> activate CD4 T cells--> Th1 cytokines (INFy)--> release of MMPs by myofibroblases--> mucosal remodeling and atrophy
142
How do autoantibodies to gluten form?
Th2 cytokines drive production of auto-Ab to gluten and TG2
143
What cytokines mediate Th1 response in CD?
IL-18, IFNy, IL-21
144
What links adaptive and innate immune responses in CD and as growth factor for T cells?
IL-15
145
Who to test for CD?
children that present with failure to thrive, GI sx, non-GI sx
--> IgA Ab to transglutaminase (tTG)```````high sensitivity
146
Why is AGA test no longer recommended for CD dx?
inferior accuracy
147
What is helpful to identify unusual case of seronegative CD?
intestinal biopsy, recommended to confirm dx of CD
148
When is CD virtually excluded as dx?
if lack HLA DQ2 or 8 alleles
