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GI II Exam 3 > Mucosal immunity > Flashcards

Mucosal immunity Flashcards

1
Q

Most pathogens gain access by passing through

A

mucosal surfaces

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2
Q

Challenge in the GI tract

A

Eliminate pathogenic organisms
Limit the growth of commensals, but don’t kill them
Don’t mount an immune response to food

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3
Q

differences in the gut immune responses Vs. the “traditional” immune responses

A

traditional immune responses:

  • Healthy tissue protected by systemic immunity
  • surface wound introduces bacteria that activate macrophages to make inflammatory cytokines
  • Cytokines released by macrophages produce an inflammatory immune response
  • Infection is terminated, leaving a damaged and distorted tissue for repair
  • Repaired and healthy tissue

Gut immune response:

  • Healthy tissue protected by mucosal immunity
  • Bacteria gain access to lamina propria by endocytosis, activate macrophages but do not cause inflammation
  • local effector cells respond to limit infection, dendritic cells travel to mesenteric lymph node to activate adaptive immunity
  • Effector B Cells and T cells that are highly specific for the invading bacteria colonize the infected area
  • infection is terminated with either minor tissue d amage or no need for repair
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4
Q

Lamina Propria of the Gut:

A

Population is dynamic
- size depends on the antigenic environment
- Germ free animals have very few lamina propria cells
- Animals in highly infectious environments the
population greatly expanded

Antigen presenting cells:

  • Chief APCs are the dendritic cells
  • Macrophages also abundant in the diffuse

Natural Killer (NK) and Lymphokine-Activated Killer (LAK) cells

Mast cells
Contribute to local host defense by producing important mediators of inflammation
Induce chemoattraction of inflammatory cells to mucosal tissues

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5
Q

Goblet cells in GALT

A

Mucus secreting- barrier function and antibacterial, mucin glycoproteins

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6
Q

Epithelial cells in GALT

A

Barrier and antibacterial functions

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7
Q

Paneth cells in GALT

A

Antibacterial secreting cells

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8
Q

M cells in GALT

A

Antigen sampling

Microfold cells (M cells):
Specialized epithelial cells
Do not secrete mucus or have microvilli
Take up microorganisms and antigens from the gut and transfer them to the Peyer’s patches (basal surface)
DCs inside can take up and present Ag
T cells and B cells activated locally
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9
Q

GALT stratification

A

minimize direct contact between bacteria & epithelial surface
Mucins, Anti-bacterial proteins, IgA

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10
Q

GALT compartmentalization

A

confine bacteria to intestinal sites and limit systemic exposure
Action of phagocytic cells in the lamina propria
Homing of activated lymphocytes to mucosal surfaces

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11
Q

Small intestine is heavily invested with lymphoid tissue

A

Peyer’s Patches

  • 5-200 B cell follicles with - - Germinal centers
  • Only in small intestine

Isolated Lymphoid follicles

  • Single follicle, mostly B cells
  • Small and large intestine

Appendix

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12
Q

Intra-epithelial lymphocyte

A

Special type of CD8+ T cell (1 per every 10 epithelial cells)
Limited range of antigen specificities

CD8+ T cell binds MHC 1 to see if the item is foreign or not

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13
Q

Dendritic cells resident in lamina propria

A

Capture pathogens independently of M cells

Less likely to activate Th1 response

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14
Q

Lymphocytes return to mucosal tissue as effector cells

A

Occurs in ways that minimize inflammation

These effector cells can now recirculate to any mucosal tissue

In nursing mothers, plasma cells from other mucosal sites will migrate to mammary glands.

This ensures that breast milk IgA represents all the antibody responses from all mucosal tissues

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15
Q

Adaptive Immunity in the mucosa

A

Humoral immunity and * IgA

    • Neutralizing
    • Enhance innate immune factors
  • Th17 dominant cell-mediated immunity
    • Th17 plays a role in gut colonization
    • IL-17 and IL-22 are characteristic cytokines

Suppression of cell-mediated immunity

    • High percentage of *** FoxP3+ Tregs
    • Presence of regulatory CD103+ DCs
    • TGF-β, IL-10, and IL-2 are characteristic cytokines
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16
Q

Food allergies

A

Food potentially immunogenic, inflammatory reaction ensues

Sometimes allergen can be transported to another part of the body causing a skin reaction

IgE mediated: food-specific IgE

  • Acute or chronic cutaneous symptoms or anaphylaxis
  • Most prevalent in young children

Non-IgE mediated: Th2-cell mediated

  • Chronic skin and/or GI symptoms
  • Eosinophilic disorders

Mixed: both

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17
Q

IgE mediated allergic reactions

A

Anaphylaxis (Edema)
Urticaria (increase in blood flow/ vascular permeability)
Seasonal allergies (sneezing)
asthma (bronchoconstriction, mucus, inflammation)
food allrgy (vomiting, diarrhea, pruritis, etc.)

18
Q

Sensitization (Priming) and repeat exposures to allergen

A

1st time: no allergic symptoms
2nd time: sensitized. mild
3rd and more: hypersensitized, overt allergic symptoms

19
Q

Immediate hypersensitivity

A

Cross linking of FcR1 on mast cells by IgE causes mast cell activation
Immediate hypersensitivity
Varying severity - runny nose to asphyxiation
Early phase (minutes after repeat exposure to allergen)

and late phase (6-24 hours after repeat exposure to allergen)

20
Q

Why Do Food Allergies Arise?

A

Inappropriate Digestion Hypothesis

  • Normal: di & tri-peptides, non-immunogenic
  • Abnormal: longer peptides, some maybe immunogenic
  • Caused by: genetics, diet, drugs, toxins, age?

Hygiene Hypothesis

Microflora Hypothesis

21
Q

Hygiene Hypothesis

A

Lack of early childhood exposure to infectious agents, including parasites, increases susceptibility to allergic diseases

“Poorly developed” immune systems – can’t perceive real danger

Fail to induce Th1 polarized responses early in life, grow up more prone to Th2 responses

Increase due to better hygiene, vaccination, increased use of drugs and antibiotics

Some studies have shown that children exposed to more infections at a younger age have reduced propensity for allergic reactions

22
Q

IBD

A

Autoimmune disease partially mediated by the absence of Treg cells

Inflamed, ulcerated, damaged bowel
* Crohn’s disease
affects the entire thickness of the bowel wall
most frequent, but not restricted, to the terminal ileum
* Ulcerative colitis
restricted to the colonic mucosa
Recent study demonstrated that Celiac and Crohn’s share genetic risk loci

23
Q

Differences between Crohns and Ulcerative colitis

A

Crohns: anywhere along the digestive tract
inflammation may occur in patches
pain commonly in RLQ
colon may be thickened and may have a rocky appearance
ulcers along the digestive tract are deep and may extend into all layers of the bowel wall
Bleeding from the rectum during bowel movements is NOT common

Ulcerative colitis: large intestine is typically the only affected site
inflammation continuous
pain common in LLQ
colon wall thinner, continuous inflammation
mucus lining may have ulcers, but they do not extend beyond the inner lining
bleeding from rectum during bowel mvts

24
Q

IBD treatment

A

IBD and colitis result from autoreactive T cells in the lamina propria

The disease can be treated by transfer of CD4 CD25 Treg cells, which home to mesenteric lymph nodes and the colon

CD4 CD25 Treg cells proliferate and inhibit the pathogenic effector T cells

After inflammation resolves, CD4 CD25 Treg cells remain in clusters with dendritic cell and pathogenic effector T cells

25
Q

Immunologic Abnormalities in IBD

A

Defective Treg cell function
- FoxP3 and IL-2 or IL-2R deficiencies result in inflammatory bowel disease

Dysregulated innate immune response

  • Defective defensin expression
  • Inadequate negative immune regulation to commensal organisms

Abnormal cell-mediated immunity

  • Overactive Th17 response
  • Granulomatous inflammation by IFN-γ-producing Th1 cells

Defective autophagy

26
Q

Epithelial Host Defense- Regulated Expression of TLRs and NLRs

A

The first susceptibility gene identified for Crohn’s disease was a NOD family member NOD2, a receptor for the muramyl dipeptide structural unit of bacterial peptidoglycan.

Expression of TLRs and NLRs (nod-like receptor) is restricted in the gut and the location of receptors is altered. Furthermore, the functional response of these receptors is biased towards an anti-inflammatory response. The purpose of these alterations is to limit inflammation in the gastrointestinal tract.

27
Q

Celiac Disease - Introduction

A

Celiac disease is an immune-mediated disease mediated by T cells
Estimated frequency 1:100 to 1:150
Associated with other autoimmune diseases
Type 1 diabetes, autoimmune thyroid

  • Clinical symptoms can vary from abdominal pain, diarrhea, growth failure, anemia, osteoporosis, or asymptomatic
28
Q

celiac disease antibodies and triggers

A

Antibodies to tissue transglutaminase (IgA) are seen in individuals with celiac disease
- 10% of type 1 diabetics will develop celiac disease autoantibodies

Gluten is the environmental trigger
- Found in wheat, rye, and barley

Treatment is lifelong dietary avoidance of gluten (gluten-free diet)
- Found in pastas, bread, most marinated meats, salad dressings, & beer

Gluten-free diet completely reverses clinical and histological findings

29
Q

Celiac Disease is an autoimmune disease

A

Inflammatory autoimmune disease of gut mucosa
Genetic and environmental factors
CD4 T cells, chronic inflammation, atrophy of intestinal villi, malabsorption of nutrients, diarrhea
Genetic predisposition
- 75% monozygotic twins
- Strong association with HLA-DQ2 or 8

Gluten specific T cells found in gut of celiacs but not healthy controls
BUT peripheral blood T cells from celiac and non-celiac patients contain cells that react to gluten in culture

30
Q

What happens to gluten in the gut

A

gluten is degraded in the gut lumen to give a resistant fragment
gluten fragment enters gut tissue and is deaminated by transgluatminase

In celiac: Naive CD4 T cell responds to deaminated peptides presented by HLA-DQ
inflammatory effector T cells cause villous atrophy

31
Q

one of the first thing that starts to damage tissue in celiac disease

A

intra-epithelial lymphocytes

32
Q

genetics of celiac disease

A

All Celiac disease patients have HLA - DQ2 or DQ8
30% of the Caucasian population has DQ2
3-5% of DQ2/DQ8 individuals develop Celiac disease
HLA genes are necessary but not sufficient to develop disease

33
Q

Gluten is broken down into

A

Gliadin (alpha, gamma and omega)- alcohol soluble

Glutenins (alcohol insoluble)

34
Q

Tissue Transglutaminase (TTG)

A

TG recognizes certain motifs: QXXF and QXPF → EXXP and EXPF

Deamidation creates a negative charge on specific aa residues to better
fit in DQ pockets.
No evidence that TG antibodies cause disease.

35
Q

Celiac Disease Antibodies

A

Tissue Transglutaminase

  • IgA – sensitive and specific
  • IgG – check if IgA deficiency

Endomysium (IgA)

Gliadin (IgA & IgG)

Deamidated Gliadin

36
Q

Gluten Free Diet

A

Very difficult to maintain a completely gluten free diet
“Hidden Gluten” – protein filler in sausage, soups, soy sauce, & ice cream
Cross-contamination – gluten free products encounter gluten during milling & storage
50 mg/day of gluten for 3 months can cause intestinal changes (this amount can come from 250 grams of gluten free food)
- No change in clinical symptoms or autoantibodies levels

37
Q

Novel Therapies for Celiac disease

A

Enzyme Therapy

  • Bacterial prolyl endopeptidase can digest the 33-mer of gliaden
  • Pretreatment of gluten containing food with these peptidases

Zonulin Antagonists

  • Zonulin is a protein that increases intestinal permeability
  • Zonulin antagonist (AT-1001) has been used in a small clinical trial resulting in no increased intestinal permeability after a gluten challenge (Paterson BM, Aliment Pharmacol Ther 2007)

Inhibiting DQ2/DQ8 antigen presentation
- Small molecules to block basic binding pockets of gluten peptides

38
Q

Immunodeficiencies that can affect the GI tract

A

Selective IgA deficiency

IPEX

39
Q

Selective IgA deficiency

A 
Most common primary immunodeficiency
Majority are asymptomatic
People are relatively healthy - 
- Compensated for by IgM, IgG
- Could reflect developed countries, few parasitic infections

Caucasians: 1/500 persons little or no IgA

African-Americans: 1/10,000

Japanese: even lower

40
Q

Immune dysregulation, polyendocrinopathy, enteropathy X-linked disease (IPEX)

A

Arises due to mutations in the transcription factor Foxp3
The phenotype in humans results in a loss of functional Treg cells
Lack of T cell inhibitory activity results in widespread autoimmunity
Symptoms include intractable watery diarrhea, failure to thrive, dermatitis, and autoimmune diabetes
Immunoglobulin levels are normal with the exception of IgE which is elevated

41
Q

Building on hygiene hypothesis – “microflora hypothesis”

A

Western lifestyle alters gut microflora which leads to allergies and other inflammatory diseases

GI II Exam 3 (14 decks)

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