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GIGU > Gut Immunology > Flashcards

Gut Immunology Flashcards

1
Q

What results with dysbiosis of gut microbiota?

A
  • Immune disorders
  • Intestinal diseases
  • Metabolic diseases
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2
Q

What regulates the microbiota?

A

Cross talk between the host immune system and microbiota is critical for GALT and ILT development which then regulates the microbiota

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3
Q

What regulates the maturation and enlargement of GALT and ILCs?

A

Microfloura of the gut

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4
Q

What type of immunoglobin is found in the intestine mucosa?

A

IgA

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5
Q

How do bactericidal defensins protect the intestine?

A
  • Bactericidal Defensins make the inner mucous layer impervious to bacterial colonization
    • They contain positively charged AA’s and hydrophobic side chains which allow for the defensin to interact with microbial membranes resutling in the formation of pores
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6
Q

What provides 98% of pathogens encountered by the body?

A

Innate immune system

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7
Q

What are ILF’s, when do they develop, and where?

A
  • Single B cell follicles that act as an inductive site for IgA production
  • After birth
  • SI and LI
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8
Q

What is the primary way that the body is exposed to Ags?

A

GALT

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9
Q

How do PP’s and ILF’s receive Ag’s?

A

Directly from the epithelial surface via Ag-transporting DC’s. They lack afferent lymphatic vessels like other lymph nodes

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10
Q

How do microbes cross the epithelium and enter PP’s and what happens next?

A

Enter via M cells and from there the microbe is endocytosed by DC’s in the subepithelial dome.

  • The Ag loaded DC’s induce differentiation of T cells and T cell dependent B cell maturation to produce IgA producing plasma cells
  • B cells mature in the germinal cell, and IgA is in the dimeric form since it is secretable
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11
Q

What is the significance of MAMP’s?

A

They get recognized by PRR ,pattern recognition receptors, on intestinal cells and then DC’s next to cryptopatches stimulate recruitment of B and T cells causing the Cryptopatches to develop into mature ILF’s.

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12
Q

What does PRR mediated recognition of MAMP’s stimulate?

A
  • proliferation of intestinal epithelial cells in crypts increasing their depth and density of paneth cells in the SI
  • Intestinal epithelial cells to release of Defensins
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13
Q

Describe the structure of the intestine barrier.

A
  • Goblet cells produce mucin which arranges into a highly dense cross linked inner proteoglycal gel and a less dense cross linked outer mucous layer
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14
Q

What three types of cells continually sense the microbiota to induce production of AMP’s? Where are they located?

A
  • Enterocytes SI
  • Colonocytes LI
  • Paneth cells base of SI crypts
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15
Q

How does IgA maintain a “peaceful abcteria host interaction”?

A
  • IgA doesn’t activate complement or phagocytes in an Fc receptor dependent manner
  • IgA is resistant to proteolysis
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16
Q

What do pathogens have to go through in order to be picked up by DC’s and presented to T and B cells? (How do we get to adaptive immunity?)

A
  • Commensal and pathogenic bacteria reside outside of the layer of mucous covering IEC’s and are killed by defensins.
  • Although some bacteria can penetrate the enterocyte epithelial layer, and end up getting killed by macrophages within the lamina propria.
  • If bacteria can make it past that and penetrate the specialized follicle associated epithelium with M cells (ontop of the PP’s ) they get killed by macrophages but also can get picked up by DC’s and interact with B and T cells within the peyers patch or drain to near lymph nodes
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17
Q

What happens following activation of Ag activated B and T cells? (NB)

A

They leave the mesenteric LN through the efferent lymph and enter the blood stream at the thoacic duct and then home back to the intestinal mucosa

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18
Q

What is the role of Treg cells in the GI?

A

They suppress Th1 2 and 17 responses.

This is due to the limited expression of pro inflammatory cytokines by APC’s and excess secretion of TGF-B resulting in the differentiation of naive t cells into T reg cells. 10% of t cells in GALT are Treg

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19
Q

Under nutrition is associated with defects in ____&___.

A

Innate and adaptive immunity.

Microbiotia and immune systems co-evolve

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20
Q

What is the significance of dietary carbs being fermented by commensal bacteria to acetate PSA and butryate?

A
  • Acetate stimulates accumultaion of IL 10 producing colonic Tregs
  • Butyrate directly acts on T regs or through modulating DC fxn to enhance their Treg inducing ability
  • Capsular polysaccharide A derived from b. fragilis and MAMP’s can directly act on Tregs via TLR2 to promote Treg fxn by enhancing expression of IL 10 and TGFB
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21
Q

What do SCFA’s do?

A
  • stimulate production of mucous
  • support an effective IgA mediated response to gut pathogens
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22
Q

What is immune tolerance?

A

sustained immune unresponsiveness to self Ags beneficial Ags and commensal bacteria

23
Q

What is oral tolerance?

A

Suppression of immune responses to Ags that have been administered previously orally.

24
Q
  • Recap:*
  • What is central tolerance?*
A
  • Occurs w/n the lymphoid organs, prevents autoimmunity
  • Immature lymphocytes specific for self Ag’s are deleted, developed into Treg cells or can change BCR specificity (only B cells)
25
Q
  • Recap:*
  • What is peripheral tolerance?*
A
  • Mature self reactive lymphocytes in the peripheral tissue undergo anergy (deactivated), apoptosis or get suppressed by Treg cells
26
Q

why do we need peripheral tolerance in regards to the GI system?

A

Central tolerance does not apply with intestine antigens as these antigens aren’t available in the thymus where central tolerance is occuring. Peripheral tolerance is needed to make sure we have tolerance to food antigens and commensal organisms.

27
Q

What are the mechanisms of oral tolerance?

A
  • Macrophages DC’s and Treg cells are crucial
    • DC: takes up AG directly from intestine lumen
    • Macrophages: transfer Ags to DCs in the lamina propria
    • Ag loaded DCs can move from LP to mLNs
  • In the mLN DCs stimulate naive CD4 cells to differentiatie into incuded CD4 CD25 FoxP3 Treg cells with RA TGF-B and IDO release
28
Q

What do RA, TGF-B and IDO do in regards to Tregs?

A
  • RA: induces Treg differentiation
  • TGFB: mediates Foxp3 upregulation
  • IDO exerts immunosuppressive functions causing anergy of effector T cells inducing proliferaiton of Tregs
29
Q

Describe the non immune mediated ARs.

A
  • Absence of an enzyme needed to fully digest food, such as in lactose intolerance
  • IBS: chronic condition causing cramping, constipation and diarrhea
  • Food poisoning
  • Recurring stress or physiological factors
30
Q

what are immune mediated ARs?

A
  • Food allergy and Celiac disease
  • Sensitivity to food additives
  • Celiac disease: chronic digestive condition triggered by eating gluten
    • GI symptoms but not at risk of anaphalyxis
31
Q

What is the mechanism for primary allergen encounters?

A
  • The allergen is ingested and the adaptive immune response by B cells makes plasma cells to produce IgE to the allergen
  • IgE enters circulation and binds FcRe (CD23) ono mast cells in the tissues
  • NO response is mediated
32
Q

What happens with a secondary allergen exposure?

A

Cross linking btw allergen and IgE causes mast cell degranulation that relesases vasoactive amines, cytokines chemokines and lipids

Type 1 hypersensitivity

33
Q

What two substances mediate diarrhea in response to allergen exposure?

A

Platelet Activating Factor and serotonin

34
Q

How are Treg cells important in controlling food allergy?

A

Treg cell derived IL10 and TGFB suppresses Th2 immunity which inhibits mast cell reactivity reduces IgE synthesis and can increase IgA and IgG synthesis

35
Q

What do vitamin D, A and folate do in regards to allergic sensitization?

A

They suppress inflamatory responses

36
Q

What does a high fat diet promote?

A

Inflammation, the fat interferes with the epithelial cell membrane

37
Q

What are the four ways to diagnose an IgE mediated allergy?

A
  • Skin prick test
  • Serum specific IgE test
  • Atopy Patch
  • Basophil activation
38
Q

What is the skin prick test?

A
  • It assesses for type one hypersensitivites
  • testing is done on arms for adults and back on kids
    • a grid is marked and small amounts of substances are injected into the dermis
    • if there is redness and swelling at the injection sites within 20-30 minutes they are positive for the allergy
39
Q

The primary tool for assessing immediate hypersensitivity reaction is _____. (NB)

A

History!

40
Q

What is a wheat allergy?

A
  • IgE mediated allergy- alpha amylase inhibitors, wheat germ agglutinin and peroxidase are important allergens
  • Affects skin GI or respiratory tract:
    • wheat dependent exercise induced anaphalyxis
    • occupational asthma (bakers)
    • rhinitis
    • contact urticaria
41
Q

Food dependent exercise induced anaphylaxis?

A
  • Urticaria or angioedema with upper respiratory obstruction and hypotension precipitated by exercised
  • Ingestion of foods or medications before exercise can be a predisposition factor
    • occurs w/m 2 horus of eating allergen
    • onset occurs during the exercise
42
Q

Cow’s milk allergy?

A

Non-IgE mediated or IgE mediated, majority are non IgE

  • reactions are delayed and takes ~48 hours after consumption to occur
  • If IgE mediated it occurs immediately
  • Treatment is to remove dairy products from diet
43
Q

How does non IgE mediated allergic reaction to peanuts lead to shock?

A
  • they contribute to shock by producing C3a stimulating macrophages basohpils and mast cells to release PAF and histamine in a C3aR dependent way
  • PAF and histamine increases vascular permeability and smooth mm contractility
44
Q

How does nut induced anaphalyxis occur?

A
  • The B cells and the allergen stimulate IgG1 which stimulates MØ activation via FcyR1 releasing PAF
  • IgE is a major contributor which stimulates mast cells to release histamine and PAF
  • Complement activation via C3a and C5a activates mast cells to again cause release of PAF and histamine
45
Q

What are non GI findings with Celiac’s disease?

A
  • Failure to thrive
  • Delayed puberty
  • Autioimmune disorders
  • Inflammation
  • Neurological disorders
  • Metabolic disorders
46
Q

What are the two main genetic predisposing factors for celiac disease?

A

HLA-DQ2 and DQ8, they have a key role in adaptive immune responses against gluten peptides

47
Q

What is the prevalence of celiac disease in the US?

A
  • 1:100 and most cases remain undiagnosed until later in life
  • Present at any age in both sexes
48
Q

Describe gluten

A
  • Proline rich protein that is not digested well due to a lack of prolyl endopeptidases
  • It is also rich in glutamine residues and those that are 10-50 aa in length are left completely undigested
49
Q

What happens when gluten is deaminated and what does it?

A
  • Formation of negatively charged glutamic acid residue done by TG2
50
Q

How is gluten presented in HLADQ2.5? What one do CD patients express?

A
  • Bind HLA class II on APC’s, negative glutamate residues act as the anchor residues of the peptide loaded into the HLADQ2.5.
  • Majority of CD patients express the heterodimer encoded by HLA-DQB1 *02 (Beta chain_ and HLADQA1*05 (alpha chain) alleles
51
Q

What type of hypersensitivity is CD?

A

type four

  • Causes T cell mediated inflammatory response in SI damaging the mucosa leading to malabsorption and chronic inflammation will occur if the patient continues to eat gluten
52
Q

Pathogenesis of Celiac Disease? (Very long)

A
  • Gluten peptides are resistant to intestine proteases and can reach the LP
  • Cross linking and deamidation of gluten peptides by TG2 creates potent immunostimulatory epitopes that get presented by HLA-DQ2.5 on APCs
  • Activated gluten specified CD4 t cellls secrete TH1 cytokines like IFN-y that induces release of MMPs resulting in remodeling of mucosa and villous atrophy
  • Th2 cytokines are also made causing production of autoAB to gluten and TG2
  • IL-18 IFN-y and IL-21 play role in maintaining Th1 response
  • IL-15 links adaptive immune to innate serving as a growth factor for T cells
53
Q

How do you test for CD?

A
  • Measure IgA Ab to tTG it has a high sensitivity and specificity
  • Measuring total serum IgA is needed bc it can help distinguish if it is IgA deficiency or CD
  • Intestinal biopsy is recommened to confirm
54
Q

What do you look for in genetic testing with CD?

A
  • looking for HLA alleles DQ2 or DQ8 and 95% of patients with CD have DQ2
  • If they are lacking both of these CD is not the diagnosis

GIGU (17 decks)

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