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PCL469 > GI immunity > Flashcards

GI immunity Flashcards

1
Q

Levels of immune protection

A

Physical barriers
Chemical enzymatic defense - macrophages
Cell based immunity

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2
Q

How do DCs work

A

Dendritic cells encounter PAMPs - pathogen associated molecular patters, and pathogen-derived antigens at site of infection
- TLR stimulation via PAMPS in the DCs coupled with Ag uptake
- Antigen loaded/PAMP-experienced DC travel to lymph nodes
- Mature into professional antigen presenting cells
PAMPs provide, mature and presentable signal

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3
Q

What would happen without PAMPs activating DCs?

A

Antigens, even self- would be chronically on display by mature DCs that can initiate downstream immunity.

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4
Q

What components does mature DC have?

A

MHC molecule - presents the antigen
CD80 - signals adjacent T-helper cells

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5
Q

How are B cells activated - humoral immunity?

A

also APC
bind antigen via B-cell receptor
BCR: antigen complex internalized and presented to CD4+ T cells
- CD4+ T cells promote (via cytokines) B cell differentiation –> plasma cells/memory cells –> stimulate IgE production

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6
Q

What is the role of IgE

A

Sensitization of mast cells

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7
Q

What is a mast cell

A
  • Contains granules - have cytotoxic and inflammatory factors
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8
Q

How is mast cell activated by IgE + allergies

A
  • IgE produced by plasma cells bind to mast cells and trigger degranulation
  • initiate anti-pathogen inflammatory cascades
  • When allergy, IgE is against a harmless environmental antigen, mast cells will degranulate without pathogen
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9
Q

How a mast cell is activated, overview

A
  • DC bind CD4+ T cells to deliver antigen-specific cytokine signalling to B cells
  • signalling instruct B cell differentiation into IgE producing plasma cells
  • IgE is against same antigen that DC presenting
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10
Q

Fc domain

A

Fragment crystallizable domain - of IgE binds to high-affinity receptors FceRI - displayed on mast cell surface

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11
Q

FceRI clustering and IgE + Mast cell

A
  • IgE bound to FceRI converts the surface of the mast cell to an antigen-specific sensor
  • Ligation of multivalent antigen via IgE bound to mast-cell FceRI - causes clustering of FceRI
  • Clustering: induces stimulatory intracellular signalling events –> promote degranulation
  • mutivalent antigen - scaffold, more effective
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12
Q

What do mast cells produce?

A

Variety of antimicrobial/inflam agents when crosslinking of surface-bound IgE
- Histamine - can damage host, toxic to microorganisms
- Histamine acts indirectly: promotes recruitment of additional leukocytes to site of immune insult

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13
Q

2 main products of degranulation

A

Toxic mediator
Lipid mediator

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14
Q

Toxic mediators

A

(Histamine
Heparin)
Toxic to parasites
Increase vascular permeability
Cause smooth muscle contraction
Anticoagulant

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15
Q

Lipid mediators

A

Prostaglandins -D2, E2
Leukotrienes - C4, D4, E4
- Smooth muscle contraction
- Chemotaxis of eosinophils, basophils and Th2 cells
- Increase vascular permeability
- Stimulate mucus secretion
- Bronchoconstriction

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16
Q

Pathology + Mast cells

A
  • Swelling and fluid/mucus production – allergic disease
  • REsult from increase blood flow into tissues from histmine - vascular permeability
  • Beneficial responses when Ag harmful
  • Unwanted when against harmless material
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17
Q

3 pathways were mast cell affects

A

GI tract
Eye, nasal, airways
Blood vessels

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18
Q

Mast cells in GI tract

A

Increase fluid secretion, and peristalsis
Result: Expulsion= diarrhea, vomiting

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19
Q

Mast cells: Eyes, nasal passages, airways

A

Decrease airway diameter, increase mucus
Congestion, blockage of airways - wheezing, coughing
Swelling, mucus secretion in nasal passages
Ocular itching
Sneezing

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20
Q

Mast cells + Blood vessels

A

Increase blood flow
Increase permeability
Increase fluid in tissues
Increase flor of lymph to nodes
Increase cells + proteins in tissue
Increase effector response in tissue
Hypotension
Anaphylactic shock

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21
Q

Allergies + mechanism

A

Adaptive immune response - mounted against harmless antigens
Mechanism - depends on IgE
IgE - recognizes harmless antigen
- Inflammatory immune response via specialized granulocytes == mast cells at dermis/epidermis

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22
Q

What can suppress degranulation?

A

Co-engagement of FceRI and inhibitory receptors (CD33) –> supress degranulation
if drug has TNP + CD33 ligand
when both FceRI + CD33 activated in mast cell - degran inhibited

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23
Q

Histamine biosynthesis

A

Histidine (electrically charged side chains) –> decarboxylated into histamine - beta-aminoethylimidazole + CO2
Important!! enzyme: Histidine decarboxylase

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24
Q

Histamine receptors - how many

A

4 major subtypes - H1-H4
H1 - airway
H2 - GI

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25
Q

H1 receptor, signalling?

A

G1/G11 –> PLC stimulation

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26
Q

H1: expression

A

CNS neurons
smooth muscle cells - vascular, resp, GI
CVS
neutrophils, eosinophils, monocytes
macrophages
DCs
T B cells
Endothelial cells
Epithelial cells

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27
Q

H1: drugs

A

Chlorpheniramine
Diphenhydramine
hydroxyzine
cetirizine
desloratadine
fexofenadine
levocetirizine
loratidine…

28
Q

H1 clinical use:

A

Clinical rhinitis, allergic conjunctivitis
Urticaria
CNS disease
Allergic and non-allergic disorders

29
Q

H2 receptors : signalling

A

Gs family –> AC –> cAMP

30
Q

H2 expression

A

Gastric parietal cells
Smooth muscle
CNS
CVS
neutrophils, eosinophils, monocytes
macrophages
DCs
T B cells
endothelial cells
epithelial cells

31
Q

H2: antihistamines

A

Cimetidine
Ranitidine
famotidine
nizatidine

32
Q

H2: clinical use

A

Peptic ulcer disease
Gastroesophageal disease

33
Q

Histamine release when allergy, location

A
  • Histamine - released by mast cells
  • Binds to H1 receptors on immune/endothelial cells
  • Leads to local inflammation
  • Effect adjacent to mucus membranes
  • Systemic histamine is still possible
  • Anaphylactic shock if not treated
34
Q

Strategies to counter histamine release

A
  • Drugs can act by decreasing mast cell ability to release histamine
  • or target downstream effects mediated by histamine
  • most first-line drugs target receptors recognizing histamine
35
Q

2 main treatments of allergies

A

Mediator action
Chronic inflammatory reactions

36
Q

Mediator action: mechanism, approach

A

Mechanism: 1.Inhibit effects of mediators on specific receptors
2. Inhibit synthesis of specific mediators
Approach:
Antihistamines, beta-agonists, leukotriene receptor blockers, lipoxygenase inhibitors

37
Q

Chronic inflammatory reactions: Mechanism of drugs, approach

A

Mechanism: General anti-inflammatory effects
Specific approach: Corticosteroids

38
Q

H1 Antihistamines

A

Act via antagonism or inverse agonism of histamine receptors
- Act on H1 receptor - spec for allergy
- Two drugs against H1 receptors

39
Q

2 gens of antihistamines

A

1st gen:contains alkyl amine, side effects
2nd: Piperidine, piperazine motifs, less side effects

40
Q

Adverse effects of H1 antihistamines

A
  • Ligate (inhibitory) muscarinic, alpha-adrenergic, dopaminergic, serat. receptors - CNS side effects
  • Leads to side effects
  • drowziness, tachycardia, pupil dilation, reduced mucous prod
  • risk of abuse
  • 2nd gen - less able to cross BBB, more selective for H1 rec
41
Q

H1 antihistamines - mechanism

A
  • Inverse agonists
  • H1 in consitiutively active state (balance between active and inactive state)
  • Antihistamines stabilize inactive state of H1 receptor
  • Prevents ligation by histamine, and constitutive signalling
    Gq/11 –> GTP –> PLC –> constriction
42
Q

What is H2 for?

A

GI pathologies
Expression on parietal cell in stomach is clinically relevant

43
Q

Stomach physiology

A
  • Gastric pits - multiple cell types
  • Parietal cells - produce gastric acid
  • Vasculature adjacent to gastric pits (leukocyte transport there)
44
Q

H2 receptor as a target

A
  • H2 expressed on cells within GI tract
  • In stomach, stimulation H2 receptors - increases gastric acid secretion
  • Histamine released by mast cell
  • but also produced by entero-chromaffin-like cells in the stomach
45
Q

Mast cell activation leads to…

A

smooth muscle contraction, vomiting, fluid outflow - diarrhea.
Antigen diffuses into vessels, elicits further allergic reactions

46
Q

H+ in the stomach

A

Parietal cell - epithelial cells in stomach
- Export H+ via H+/K+ ATPase pump to decrease pH
- Ligation of H2 receptor - histamine –> stimulates cAMP –> AC –> PKA
- result in increase H+/K+ ATPase
- H+ are produced by intracellular carbonic anhydrase

47
Q

Intracellular carbonic anhydrase

A

CO2 + H2O –> H2CO3 –> HCO3- + H+

48
Q

Stomach pH

A

1

49
Q

Peptic ulcers

A

Breaks in the inner lining of stomach
Causes:
Excessive acid production - pH too low
Chronic NSAID use
H pylori infection

50
Q

Weak bases

A
  • Hyperacidity - weak bases used
  • Antacids - OTC
  • direct neutralized by donating anions like OH or carbonate HCO3-
51
Q

H2 receptor antagonists

A

Not inverse agonists
- Decrease gastric secretion from parietal cells
- Some are inverse though
- H2 receptor antagonists largely replaced by PPI

52
Q

Example H2 antagonist drugs

A

Cimetidine - was one of first blockbuster drugs
- Smith Kline, French in 70s
- Was one of first treatment available for patients with peptic ulcers
- Has alkyne group

53
Q

Proton pump inhibitors

A
  • PPI - replaced H2 receptor antagonists in clinic
  • Direct blockage of H+/K+ ATPase pump on parietal cells
  • Prevents acid secretion from source
  • better than H2: because not only histamine can promote secretion of gastric acid
54
Q

PPI main structure

A

Conserved benzimidazole-sulfoxide functionalities are key to activity

55
Q

PPI are prodrugs

A

Require acid to:
- activating a benzimidazolium ion form
- Intramolecular cyclization - results in spiro - intermediate
- Intermediate collapses –> rearrangement of ring system
- Result: disulfide bond formation with available cysteine from the proton pump

56
Q

PPI –> covalent inhibitors

A
  • Cyclic sulfenamide produce – associates with H/K ATPase, on parietal cells –> disulfide linkage
  • Covalent adduct - inhibiting ability of pump to export protons
57
Q

PPI mechanism advantages:

A
  • Prodrugs only activated in acidic env.
  • H-K ATPase - expression restricted to parietal cells
58
Q

Adverse effects of PPI

A
  • reduce stomach acid pH
  • if suppresed chronically
  • Hypochloryhydria = pH too high
  • Hypergastrinaemia and hyperplasia relation:
    increase exposure of parietal cells to hormones (gastrin) –> produced in stomach - less negative feedback
  • Polyps - cancerous
59
Q

H. pylori + peptic ulcers

A

Stomach - infected H. pylori
- promote ulceration can lead to gastric cancer
- inflammatory cascades by immune system – gastritis
- destroys mucus layer by neutrophils, epithelium

60
Q

How bacterium survive low pH env?

A
  • Sophisticated survival –> uses urea– in stomach
  • creates ammonia to buffer local environment
  • Urease enzyme in H. pylori–> produced ammonia
  • Basic, quenches HCl
  • Lead to stomach epithelium and ulceration –> destroyed
61
Q

Reaction with urease

A

urea + water –> (urease) –> carbamic + ammonia –> (water) –> carbonic acid + 2 ammonia (decarboxylation)

62
Q

Detection of H. pylori and treatment.

A
  • Use 13C isotopic assay
  • Test via breath test
  • PCR test on stool sample usually
  • PPI not clear role –> synergy between PPI + antibiotics
  • PPI can contributed to H-pylori mediated pathology –> promote basification of stomach
  • bacteria migration
63
Q

Inflammatory bowel disease

A
  • inflammation of digestive tract
  • Crohn’s disease: - affect large and small intestines no clearly defined cause
    symptoms: Chronic diarrhea, abdominal pain, fever, weight loss
  • Ulcerative colitis - restricted to large intestine, similar symptoms to Crohn’s.
64
Q

IBD: Leukocytes and inflammation

A
  • Loss of mucus layer in intestinal tract of IBD patients increases epithelial permeability
  • Enables gut microbiome to interact with leukocytes in lamina propria –> immune reaction
  • Leukocytes - macrophages – produce inflammatory cytokines when contacting microbe-derived material
    due to TLR stimulation
  • Inflammatory cytokines increase leukocyte recruitment to gut, exacerbates inflammation
65
Q

Ways of treating IBD

A
  1. Mesalazine - 5 ASA, first line
    unclear mechanism
  2. Sulfasalazine - metabolized to 5 ASA
  3. Corticosteroids - second line, more aggressive treatment
    Methotrexate, biologicals mAb (anti-TNFa), surgery in extreme cases
66
Q

New mode of IBD treatment

A

Fecal microbiota transplantation
- Altered comp of gut microbiota –> cause of IBD, maybe
- Transplantation - of still from healthy donor
- efficacy in patients with C. difficile infections
- Additional research required for efficacy approval

PCL469 (6 decks)

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