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PCL469 > GI immunity > Flashcards

GI immunity Flashcards

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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
H1 receptor, signalling?
G1/G11 --> PLC stimulation
26
H1: expression
CNS neurons smooth muscle cells - vascular, resp, GI CVS neutrophils, eosinophils, monocytes macrophages DCs T B cells Endothelial cells Epithelial cells
27
H1: drugs
Chlorpheniramine Diphenhydramine hydroxyzine cetirizine desloratadine fexofenadine levocetirizine loratidine...
28
H1 clinical use:
Clinical rhinitis, allergic conjunctivitis Urticaria CNS disease Allergic and non-allergic disorders
29
H2 receptors : signalling
Gs family --> AC --> cAMP
30
H2 expression
Gastric parietal cells Smooth muscle CNS CVS neutrophils, eosinophils, monocytes macrophages DCs T B cells endothelial cells epithelial cells
31
H2: antihistamines
Cimetidine Ranitidine famotidine nizatidine
32
H2: clinical use
Peptic ulcer disease Gastroesophageal disease
33
Histamine release when allergy, location
- 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
Strategies to counter histamine release
- 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
2 main treatments of allergies
Mediator action Chronic inflammatory reactions
36
Mediator action: mechanism, approach
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
Chronic inflammatory reactions: Mechanism of drugs, approach
Mechanism: General anti-inflammatory effects Specific approach: Corticosteroids
38
H1 Antihistamines
Act via antagonism or inverse agonism of histamine receptors - Act on H1 receptor - spec for allergy - Two drugs against H1 receptors
39
2 gens of antihistamines
1st gen:contains alkyl amine, side effects 2nd: Piperidine, piperazine motifs, less side effects
40
Adverse effects of H1 antihistamines
- 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
H1 antihistamines - mechanism
- 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
What is H2 for?
GI pathologies Expression on parietal cell in stomach is clinically relevant
43
Stomach physiology
- Gastric pits - multiple cell types - Parietal cells - produce gastric acid - Vasculature adjacent to gastric pits (leukocyte transport there)
44
H2 receptor as a target
- 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
Mast cell activation leads to...
smooth muscle contraction, vomiting, fluid outflow - diarrhea. Antigen diffuses into vessels, elicits further allergic reactions
46
H+ in the stomach
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
Intracellular carbonic anhydrase
CO2 + H2O --> H2CO3 --> HCO3- + H+
48
Stomach pH
1
49
Peptic ulcers
Breaks in the inner lining of stomach Causes: Excessive acid production - pH too low Chronic NSAID use H pylori infection
50
Weak bases
- Hyperacidity - weak bases used - Antacids - OTC - direct neutralized by donating anions like OH or carbonate HCO3-
51
H2 receptor antagonists
Not inverse agonists - Decrease gastric secretion from parietal cells - Some are inverse though - H2 receptor antagonists largely replaced by PPI
52
Example H2 antagonist drugs
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
Proton pump inhibitors
- 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
PPI main structure
Conserved benzimidazole-sulfoxide functionalities are key to activity
55
PPI are prodrugs
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
PPI --> covalent inhibitors
- Cyclic sulfenamide produce -- associates with H/K ATPase, on parietal cells --> disulfide linkage - Covalent adduct - inhibiting ability of pump to export protons
57
PPI mechanism advantages:
- Prodrugs only activated in acidic env. - H-K ATPase - expression restricted to parietal cells
58
Adverse effects of PPI
- 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
H. pylori + peptic ulcers
Stomach - infected H. pylori - promote ulceration can lead to gastric cancer - inflammatory cascades by immune system -- gastritis - destroys mucus layer by neutrophils, epithelium
60
How bacterium survive low pH env?
- 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
Reaction with urease
urea + water --> (urease) --> carbamic + ammonia --> (water) --> carbonic acid + 2 ammonia (decarboxylation)
62
Detection of H. pylori and treatment.
- 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
Inflammatory bowel disease
- 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
IBD: Leukocytes and inflammation
- 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
Ways of treating IBD
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
New mode of IBD treatment
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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