Gut Immunology Flashcards
What are some early life exposures that can affect the development of the gut Microbiota?
- Mode of delivery
- Infant diet
- Antibiotics
- Probiotics
- Physical environment
what is the difference between symbiosis and dysbiosis of the gut microbiota? and what leads to dysbiosis
Symbiosis:
- Immune tolerance
- Intestinal homeostasis
- Healthy metabolism
Dysbiosis:
- Immune disease
- intestinal disease
- Metabolic diseases
all these can be caused by early life exposures that disrupts the development of the immune system
what is GALT? how does it develop? and what is it consist of?
Gut Associated Lymphoid tissue (GALT)
-largest immune organ in the body
consists of Isolated Lymphoid Follicles and Peyers Patches that develop after birth
Its main function develops and communicates with the immune system to regulate the microbiota
How does GALT interact with antigens?
PP and ILF lack afferent lymphatic vessels therefore they receive Ags directly from the the epithelial surface from DCs
these DC induce differentiation of T cells and T cell dependant B cell maturation to develop IgAs to help fight ags
also development of Mature ILFs from the presentation of DC containing Microbe associated molecular patterns to further recruit T cells and B cells
What are ILFs?
Isolated Lymphoid Follicles that act as inductive site for immunoglobulin A production
What is the Barrier Function of the Intestinal Epithelium and what components do what?
single layer of Intestinal epithelial cells
Goblet cells: produce mucin that is organized into a dense more highly cross linked inner proteoglycan gel
Enterocytes, colonocytes, and paneth cells all sense microbiota to induce the production of antimicrobial peptides
Defensins are the major class of AMPS in the GI
what makes Secretory IgA crucial for defense in the gut?
maintains a peaceful bacteria-host interaction
- does not activate complement
- does not activate phagocytes
- resistant to proteolysis by peptides produced in the stomach, small intestine, and pancreas
how does the Innate immune response of Bacterial defensins work against microbes? what percentage of protection does the innate immune system contribute
these Defensins have clusters of positively charged amino acid side chains and hydrophobic amino acid side chains that allow for them to interact with the microbial membranes that results in the formation of membrane wormholes and pores that kill the bacteria
the innate immune sytem is responsible for providing protection against 98 percent of the pathogens we encounter
after activation of B and T cells once presented with a DC how do they get back to the intestnal mucosa, what about the DC?
since DCs loaded with commensal bacteria can traffic to the mesenteric LN the LN act as a barrier that does not allow the DC to get farther in the systemic circulation
the activated B and T cells can leave the mesenteric LN through the efferent lymph, enter the blood stream at the thoracic duct and home back to the intestinal mucosa
what is the roll of Treg in the GI?
important in keeping a limited expression of pro-inflammatory cytokines by APCs and an excess of TGF-B result in differentiation of naive T cells into Treg cells which suppress Th1, Th2, and Th17 responses
How can diet affect the microbiota, and immune system?
changes in diet can have a major impact on the gut microflora, affecting its symbiosis and cause Dysboisis
Short chain fatty acids (SCFAs) such as butyric, propionic, and acetic acids are produced by microbial fermentation of undigested or partially digested dietary fibers that can effect the host immune system
therefore,
Malnutrition, and undernutrition can lead to a decreased immune function due to loss of gut microbiota leading to increased infections and impaired absorption
Importance of SCFA? and the various types and what they do?
Undigested dietary carbohydrates are fermented by gut commensal bacteria to produce SCFA: acetate, propionate, and butyrate
Acetate: stimulates the accumulation of IL-10 and Tregs
Butyrate: has similar effects by either directly acting on Tregs or through modulating DC function to enhance their Treg inducing abillity
The capsular polysaccharide A (PSA): derived from B. fragilis can also directly act on Tregs through TLR2 to promote Treg function by enhancing expression of effector molecules including IL-10 and TGF-B
SCFA: also support effective IgA mediate response and stimulate production of mucus
What is Central Tolerance?
Immature lymphocytes specific for self Ags may encounter these Ags in the generative (central) lymphoid organs and are either
- deleted
- change BCR specifity (b cells only)
- Develop into Tregs
What is peripheral tolerance?
Mature self-reactive lymphocytes in peripheral tissues may be either:
- inactivated (anergy)
- deleted (apoptosis)
- suppressed by the Treg cells
why is peripheral tolerance to Ags essential in the intestine
since intestine ags are not available in the thymus, the central tolerance does not prevent responses against such Ags in the lamina propreia
-this is because the T cells wont see these antigens when being developed initially
therefore, additional layers of peripheral toleranve are needed to ensure tolerance to Ags such as foods and commensal organisms to not ellict an immune response
Mechanism for Oral tolerance, and the impact of RA, TGF-B, and IDO
1) macrophages directly uptake small or soluble Ags from the intestinal lumen by sending their cellular processes out into the lumen across the epithelial barrier
2) macrophage then transger the acquired Ag to DC in the lamina propria
3) Ag-loaded DCs move from the LP to the mLN in a chemokine dependant process
4) the DC then stimulate naive CD4 T cells to differentiate into induced CD4 CD25 Foxp3 Treg cells via the release of retionic acid, TGF-B and indoleamine 2,3-dioxygenase (IDO)
- RA directly induces Treg cell differentiation
- TGF-B mediates Foxp3 upregulation
- IDO exerts immunouppresive functions causing anergy for effector Tcells and proliferative Treg cells
What are the two different types of Food Adverse Reactions?
- Non-immune mediated: formaly known as food intolerances
- Immune mediated: Formely known as food allergy
Examples of Non-Immune mediated ARs
Absence of an enzyme needed to fully digest a food
-lactose intolerance
Irritable bowel syndrome
-chronic condition can cause cramping, constipation, and diarrhea
Food poisioning:
-toxins such as bacteria in spoiled food can cause severe digestive symptoms
Recurring stress or physiological factors:
-sometimes the mere thought of food may make you sick
Examples of Immune mediated ARs
Food allergy and celiac disease arise from a specific immune response that occurs reproducibly on exposure to a given food
Sensitivity to food additives:
-sulfites used to preserved dried fruit, canned goods and wine can trigger asthma attacks in sensitive people
Celiac disease:
- chronic digestive condition is triggered by eating gluten, a protein found in wheat and other grains
- some features of true food allergy
- symptoms are mostly gastrointestinal
- people with celiac disease are not at risk of anaphylaxis
what is the type of hypersensitivity with food allergies?
IgE mediated (type 1)
or type III or IV (non IgE mediated mechanisms)
Mechanism of IgE mediated food allergy
Primary allergen encounter
-ingested allergen creates an adaptive immune response by B cells that mature into plasma cells to make IgE to allergen
-IgE enters circulation and is rapidly bound to FcRe (CD23) on mast cells in the tissures
(whole process Allergic sensitization)
Subsequent exposure
-cross linking causes mast cell degranulation that releases: vasoactive amines, cytokines/chemokines, and lipids
(IgE dependant secondary immune response)
Mediators of Mast cells and their target effects?
Histamine
-SM contraction, vascular permeabillity
TNF-A and IL-1:
-Endothelial cells and inflammation
Tryptase:
-trypsin like activity, anaphylaxis, and urticaria
Prostaglandin E2 (PGE2): -pain and vascular permeabillity
PGD2 and Leukotrines:
-SM contraction and vascular permeability
Bradykinin:
-Vasodilator, SM contraction
IL-5:
-Sputum eosinophils
What are the main systemic and local food allergy responses?
Mast cells are central to both local and systemic manifestations of food allergy
Ag disseminated systemically can trigger reactions of urticaria and bronchospasm through mechanisms dependant on histamine and platelet activating factor (PAF)
Gastrointestinal manifestations of food allergy dependant on Th2 derived cytokines including IL-4, IL-13 and IL-9
Mastocytosis is necessary for local symptoms
PAF and serotonin mediate the local acute gastrointestinal rsponse (diarrhea) to allergen exposure
How do Treg cells control food allergy?
Treg cell derived IL-10 and TGF-B suppress Th2 immunity and inhibit mast cell reactivity, reduce IgE synthesis and may increase IgG and IgA synthesis
Impact of Environmental factors on allergic sensitization: Vitamin D,A, and folate
High fat diet
Gut Microbiota
iTregs
Vitamin D, A, and Folate all suppress inflammatory responses
A high fat diet promotes inflammation
Gut microbiota can suppress allergic immune response through the induction of Treg cells and suppress basophils and mast cells
iTregs suppress Th2 cells that are central to generating IgE and allergic effector cellls
What are the 4 different tests to diagnoss an IgE mediated allergy?
Skin prick test:
-provides an immediate information about the presence of IgE sensitization to specific alergens
Serum specific IgE test:
-requires blood to be sent to a laboratory and can be tested to allergen extracfts or individual allergen components
Atopy Patch:
-testing has been developed over the last decade to understand the relationship between IgE sensitization and the cell mediated response that characterizes atopic eczema but is not widely used
Basophil Activation test (BAT):
- have been used in the research setting and their application for clinical use is in development
What is the primary tool for assessing immediate hypersensitivity reactions??
History of the patient
then use other tests to double check
mechanism of Non-IgE-Mediated allergic reaction to peanuts
can contribute to shock due to the production of C3a
-stimulates macrophages, basophis, and mast cells to release PAF and histamine in a C3aR dependant manner
Mast cells activate the IgE cross linking of FceRI play the central role in food induced anaphylaxis
OgG also induce activation of Macrophages that lead to release of PAF
both ways lead to anaphylaxis
process of what allergies
Classic food allerygy
-most important allergens are the alpha-amylase inhibitors, germ agglutin and peroxidase
affects the skin, GI or respiratory tract
- wheat dependant excercise induced anaphylaxis
- occupational astham
- rhinitis
- contact urticaria
prevelance of IgE to wheat progressively increases with age
Food-Dependant excercise induced anaphylaxis
occurs within 2 hours of eating the allergic food but the onset occurs during physical activity
- Ingested foods are digested in the intestine and no immuno reactive allergens entered into the circulation
- Excercise and or asprin enhance absorption of undigested immuno reactive allergens into the circulation
Cows Milk Allergy
Children aged less than 3 years
- can be either non IgE mediated or IgE mediated
- majority is non mediated IgE mediated CMA
Non mediated IgE CMA occurs 48 hours after ingestion,
- commonly wrongly labeled lactose intollerance
- do not need testing for IgE to milk
IgE mediated reactions occur immediatey after ingestion
-will need specific tests to milk
all dairy products must be removed from the diet of a breastfeeding mother
What is Celiac Disease and the main genetic predisposing factor?
Systemic immune disorder caused by permanent sensitivity to gluten
- can be associated with gastrointestinal findings
- highly variablle non gastrointestinal findings
HLA-DQ2 and DQ8 are main genetic predisposing
factor
-important in orchesftrating adaptive immune responses to gluten peptides
serum autoantibodies to the ubiquitous enzyme tissue transglutaminase 2 are specifically associated with the disease as well
Epidemiology of CD
The prevelance of celiac disease in the US is 1:100
-most cases remain undiagnosed until later in life
Significance of HLADQ2.5 and CD
Peptides with a specific spacing of proline and glutamic acid (gluten) will bind HLA class II on APCs
these people express HLADQ2.5 heterodimer
thus leading to an immuno response
Immuno pathogenic response in CD
Self reactive T cells are generated and tissue diamage occurs in a type IV hypersensitivity manner
-CD4 and CD8 self reactive T cells
Antibody response in CD
anti TG2 abs
-transglutiminase 2
these antibodies will be active in the pressence of gluten and lead to chronic inflammatory resoponse
-also leads to malabsorption due to the T cell mediated response in the small bowel
Pathogenesis of CD
Cross linking and deamidation of gluten peptides by transglutiminase 2 creates potent immunostimulatory epitopes that present to HLA DQ2.5 or 8 APCs
Activated CD4 T cells secret Th1 cytokines such as IFN-Y that will release myofibroblasts resulting in mucosal remodeling and villus atrophy
Th2 cytokines are produced driving production of auto-abs to gluten and TG2
-IL-15 then will promote growth facter of T cells causing proliferation
How to test for CD
test people with Failure to thrive and persistent diarrhea, GI symptoms, and Non-GI symptoms of malabsorption
Because of the inferior accuracy of the anti-gliadin antibody test they are no longer recommended
use the tTG-IgA test
- measurement of IgA to tTG
- sensitivity of 93% and 98% specificity
can also determine if the Total serum IgA is low
Biopsy to confirm testing
also can do genetic testing for HLA alleles DQ2 and DQ8
-exclude CD if the paitent has neither of these
