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GIGU test! > Gut Immunology > Flashcards

Gut Immunology Flashcards

1
Q

What are some early life exposures that can affect the development of the gut Microbiota?

A
  • Mode of delivery
  • Infant diet
  • Antibiotics
  • Probiotics
  • Physical environment
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2
Q

what is the difference between symbiosis and dysbiosis of the gut microbiota? and what leads to dysbiosis

A

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

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3
Q

what is GALT? how does it develop? and what is it consist of?

A

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

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4
Q

How does GALT interact with antigens?

A

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

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5
Q

What are ILFs?

A

Isolated Lymphoid Follicles that act as inductive site for immunoglobulin A production

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6
Q

What is the Barrier Function of the Intestinal Epithelium and what components do what?

A

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

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7
Q

what makes Secretory IgA crucial for defense in the gut?

A

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
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8
Q

how does the Innate immune response of Bacterial defensins work against microbes? what percentage of protection does the innate immune system contribute

A

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

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9
Q

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?

A

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

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10
Q

what is the roll of Treg in the GI?

A

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

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11
Q

How can diet affect the microbiota, and immune system?

A

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

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12
Q

Importance of SCFA? and the various types and what they do?

A

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

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13
Q

What is Central Tolerance?

A

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
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14
Q

What is peripheral tolerance?

A

Mature self-reactive lymphocytes in peripheral tissues may be either:

  • inactivated (anergy)
  • deleted (apoptosis)
  • suppressed by the Treg cells
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15
Q

why is peripheral tolerance to Ags essential in the intestine

A

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

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16
Q

Mechanism for Oral tolerance, and the impact of RA, TGF-B, and IDO

A

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

17
Q

What are the two different types of Food Adverse Reactions?

A
  • Non-immune mediated: formaly known as food intolerances

- Immune mediated: Formely known as food allergy

18
Q

Examples of Non-Immune mediated ARs

A

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

19
Q

Examples of Immune mediated ARs

A

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
20
Q

what is the type of hypersensitivity with food allergies?

A

IgE mediated (type 1)

or type III or IV (non IgE mediated mechanisms)

21
Q

Mechanism of IgE mediated food allergy

A

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)

22
Q

Mediators of Mast cells and their target effects?

A

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

23
Q

What are the main systemic and local food allergy responses?

A

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

24
Q

How do Treg cells control food allergy?

A

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

25
Q

Impact of Environmental factors on allergic sensitization: Vitamin D,A, and folate
High fat diet
Gut Microbiota
iTregs

A

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

26
Q

What are the 4 different tests to diagnoss an IgE mediated allergy?

A

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

27
Q

What is the primary tool for assessing immediate hypersensitivity reactions??

A

History of the patient

then use other tests to double check

28
Q

mechanism of Non-IgE-Mediated allergic reaction to peanuts

A

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

29
Q

process of what allergies

A

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

30
Q

Food-Dependant excercise induced anaphylaxis

A

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
31
Q

Cows Milk Allergy

A

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

32
Q

What is Celiac Disease and the main genetic predisposing factor?

A

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

33
Q

Epidemiology of CD

A

The prevelance of celiac disease in the US is 1:100

-most cases remain undiagnosed until later in life

34
Q

Significance of HLADQ2.5 and CD

A

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

35
Q

Immuno pathogenic response in CD

A

Self reactive T cells are generated and tissue diamage occurs in a type IV hypersensitivity manner
-CD4 and CD8 self reactive T cells

36
Q

Antibody response in CD

A

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

37
Q

Pathogenesis of CD

A

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

38
Q

How to test for CD

A

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

GIGU test! (40 decks)

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