Lecture 11: Chronic Inflammation - TB

Question 1

Causes of chronic inflammation

Answer 1

Persistent exposures:
1) Irritants - Bronchitis, Emphysema from smoke particles
2) Infections - Hepatitis B virus, TB

Abnormal immune responses:
1) Harmless environmental agents - allergies
2) Commensal microbes - inflammatory bowel disease (Crohn’s)
3) Components of the body - autoimmune diseases - rheumatoid arthritis, systemic lupus

Novel cells:
1) Wounds that don’t heal - Cancers in proliferation stage
2) Grafts/transplants - rejection of organ transplant if not completely histocompatible

Question 2

Chronic inflammation has multifactorial causes

Answer 2

lifestyle = modifiable (protective and causative)
genetic = non-modifiable

Question 3

Causative factors of chronic inflammation:

Answer 3

1) Psychological stress
2) Obesity (diet)
3) Microbial balance

Question 4

Psychological stress causing chronic inflammation

Answer 4

• Fight or flight
• SNS releasing noradrenaline from adrenal glands.
• Influences mood and increases risk for inflammatory disease - via activation of pro-inflammatory cytokines (which improve metabolism for fight of flight).

Question 5

Obesity (diet) causing chronic inflammation

Answer 5

Hypertrophic (thickened) adipose tissue release:
- pro-inflam cytokines
- saturated fatty acids which stimulate TLRs.
- ROS from malfunctioning mitchondria
- DAMPs from necrotic adipocytes (lytic when too much fat).

sFA, ROS, DAMPs recruit pro-inflam macrophages and Th1 cells.

Question 6

Microbial balance causing chronic inflammation

Answer 6

Changes to microbes associated w/ our gut and skin can be due to diet, antibiotics, and hygiene.

Pathobiants (microbe) are harmful, colonise the gut, alter mucus production, and induce pro-inflam cytokines.

Question 7

Protective factors of chronic inflammation:

Answer 7

Can counteract the pro-inflam factors through production of anti-inflammatory cytokines: IL-10 and TGFb

1) Microbial balance
2) Diet
3) Regular exercise

Question 8

IL-10 and TGFb

Answer 8

Anti-inflammatory cytokine

Question 9

Protective factor of chronic inflammation: microbial balance

Answer 9

• Symbionts and probiotics rebalance the commensal (healthy) microbes in our body. Symbionts promote Treg cells activity. Probiotics rebalance the microbes.
• Fecal transplant rebalance the gut microbes
• Helminths (worms) are anti-inflammatory and can be used to treat inflammatory gut conditions like IBD.

Question 10

Treg cell activity

Answer 10

?

Question 11

Protective factors of chronic inflammation: diet

Answer 11

Diet enriched in short-chained fatty acids and omega 3 bind to GPR43 to regulate metabolism and inflammation through mucus production and epithelial barrier production.

Question 12

Protective factor of chronic inflammation: exercise

Answer 12

• suppresses inflammatory cytokines - TNFa.
• Reduces risk of chronic metabolic and cardiovascular diseases.
• Leads to reduction in adiposity.

Question 13

Role of monocytes > macrophages acute/innate inflammation:

Answer 13

monocytes > macrophages

• recruited at the sites of damage within tissues
• phagocytes debris, DAMPS, microbes
• kills microbes via ROS
• regulate inflammation and repair

Question 14

What are the pro-inflammatory cytokines and chemokines involved in acute/innate immune system?

Answer 14

IL-6, TNF, IL-1b

Question 15

Role of proteases (Matric Metalloproteases) in acute inflammation

Answer 15

Digest ECM

Question 16

Role of ROS in acute inflammation

Answer 16

Kill microbes by attacking the lipid membrane

Question 17

Role of macrophages in adaptive/chronic inflammation

Answer 17

Macrophages act as antigen-presenting cells (APC).
- Phagocytosis of microbes and macromolecules
- process into fragments (antigens)
- present to lymphocytes (Th0 cells - naive) to regulate their activities.

Question 18

Role of B and T cells

Answer 18

Lymphocytes recognise antigen epitopes as ‘foreign’ by surface receptors.

T cells: include Cytotoxic T cells (killer; CD8) and T helper cells (CD4).
B cells: differentiate in to plasma cells lto produce antibodies.

Question 19

Cytokine: IFNg

Answer 19

Th1 cells release the cytokine IFNg.

1) Self development (increased production/calling for Th1 cells)
2) Macrophage response to intracellular pathogens.

Abnormal (pathology) –> autoimmunity

Question 20

Cytokine: IL-4

Answer 20

Th2 cells release IL-4

1) Self development of Th2 cells
2) Promote eosinophil response to Helminths (worms)

Abnormal/pathology –>Allergy

Question 21

IL-21 and IL-17

Answer 21

Th17 release IL-17 and IL-21.

1) IL-21 responds to extracellular microbes by releasing anti-microbial peptides such as defensins and GM-CSF to recruit neutrophils.
2) Self development of Th17 cells

Abnormal/pathology –> Autoimmunity

Question 22

Cytokines: TGFb and IL-10

Answer 22

Treg cells release TGF and IL-10

1) Suppress inflammation by dampening activity of other T helper cells.
2) TGFb promotes self-development of Treg cells.

Deficient function: increased inflammation, loss of tolerance.