Inflammation

Question 1

What cells initiate the inflammatory response and where are they found?

Answer 1

1. Tissue-resident mast cells (same as basophils)
2. Tissue-resident macrophages (monocytes are precursors)

Found in body tissues e.g. CT

Question 2

What is the role of cells which initiate the IR?

Answer 2

They detect damage and insult - first to respond

Question 3

What does inflammation trigger?

Answer 3

An immune response (innate and adaptive).

This triggers maturation of APCs to activate T cells.

Question 4

What stimuli give rise to inflammation?

Answer 4

1. Physical (cut or burn)
2. Chemical (acid, alkali)
3. Immunological (hypersensitivity)
4. Bacterial (pathogenic microbes)

Question 5

Describe the 2 lines of defence of the human body, against invading microbes

Answer 5

1st line = physical barriers e.g. skin, hair, mucus (enzymes + active peptides)
2nd line = inflammatory response

Question 6

What events follow when one steps on a rusty nail? (5)

Answer 6

1) Pain, swelling, redness = skin damage
2) Underlying cells in the CT respond by releasing chemical inflammatory mediators
3) = promotes inflammation (+ activates complement system)
4) Other cells also recruited to SOI
5) Phagocytes take up and clear bacterial microbes and damaged tissue

Question 7

What are the 5 inflammatory cascades?

Answer 7

1) Complement
2) Coagulation
3) Bradykinin
4) Arachidonic acid
5) Free radicals

Question 8

What does physical trauma lead to?

Answer 8

Activation of inflammatory cascades

1) Blood coagulation - shuts blood flow
2) Inflammation - activating 2 resident cells

Question 9

How and what do invading microorganisms activate?

Answer 9

Innate immune cells through PAMPs - to be processed and presented to B and T cells

Question 10

How is a mast/tissue basophil activated?

Answer 10

1) Pure physical trauma to environment = ruptures to release contents
2) Low O2 tension: cut > blood clotting which cuts off local blood supply to that site –> release of contents from granules
3) Receptors for C3a and C5a: complement components > cascade of enzymes + proteins > promotes inflammation by binding to receptors on mast cells and activating degranulation
4) TLRs: mast cells may directly be activated to a certain degree by microbes ligated to TLRs. Have a limited range of TLRs.
5) Allergic responses e.g. grass pollen-sensitive IgE & high-affinity receptor is ɛIgE for IgE - grass pollen-sensitive IgE binds to receptors

Question 11

Which cytokines and inflammatory mediators do macrophages release?

Answer 11

1) TNFa
2) IL-1b
3) IL-6
4) (IL-8)
5) (IL-12)

Question 12

How do macrophages engulf bacteria?

Answer 12

• Pseudopods: gets ahold of bacteria, engulf, phagocytose then destroy
• Mac have a range of TLRs and PRRs on surface
• Microorganisms ligate its PAMPs to the TLRs

Question 13

Which cytokines do macrophages release?

Answer 13

1) TNFa
2) IL-1
3) IL-6

Question 14

What is the role of IL-8?

Answer 14

Attracts neutrophils to SOI

Question 15

What can IL-6 released from activated macrophages not do?

Answer 15

Increase vascular permeability

Question 16

What are the effects of the cytokines released from activated macrophages?

Answer 16

TNFa and IL-1:

1) Up-regulate vascular adhesion molecules
2) Increase vascular permeability
3) Vasodilation
4) Induce maturation of dendritic cells

IL-6: 1, 3 and 4 only.

Question 17

What is the acute phase response?

Answer 17

A clinical test which measures the amount of systemic inflammation in the body
E.g. release of inflammatory cytokines are local to wound but also flow away through the bloodstream throughout the body (systemic distribution)

Question 18

What causes mast cells to degranulate and release inflammatory mediators?

Answer 18

Wound =

• Tissue damage
• Low O2 tension
• Complement
• Direct contact with organisms

Question 19

What is the effect of histamine?

Answer 19

Vasodilation and increased vascular permeability.

- Tight junctions loosen and allow fluid from blood to get into the SOI = swelling

Question 20

How do neutrophils migrate?

Answer 20

By diapedesis, when it sees an up-regulation of adhesion molecules

Question 21

What is the role of neutrophils?

Answer 21

Remove organisms and dead tissue

Question 22

What are some characteristics of neutrophils?

Answer 22

• Terminally differentiated (cannot mature)
• Make up 60-70% of WBCs but are short-lived because they phagocytose, kill then die at SOI (pus = biggest proportion is dead neutrophils)

Question 23

What does the complement cascade consist of?

Answer 23

3 pathways: C3a and C5a which activate mast cells

Question 24

What does the clotting cascade consist of?

Answer 24

Build up of fibrin. But, as fibrin degrades, peptides are released which are pro-inflammatory (increase vascular permeability and attract neutrophils)

Question 25

What does the kinin cascade consist of?

Answer 25

Receptors are present on nerve endings (for kinin). | Once kinins are produced, this is what causes pain (most potent mediator for pain)

Question 26

What does the arachidonic cascade consist of?

Answer 26

Phospholipid bilayer --> 2 pathways with different products

Question 27

What do leukotrines and prostagladins have in common?

Answer 27

Both are chemoattractants for neutrophils

Question 28

What happens when phagocytic cells take up bacterium?

Answer 28

Secrete enzymes asnd reactive species

Question 29

What is the main feature of rheumatoid arthritis?

Answer 29

Joint inflammation and erosion, leading to deformity and disability. X-rays w/ RA: blurred in joint space bc of erosion of cartilage and underlying bone.

Question 30

What kind of disease is rheumatoid arthritis?

Answer 30

Immune mediated chronic inflammatory diesease. | All 5 pathways occur in the joints.

Question 31

How does rheumatoid arthritis occur?

Answer 31

- B cells produce excess AB > immune complexes e.g. RF > activation of complement - Mac > TNFa: stimulates cells to produce enzymes which destroy cartilage and bone - Neutrophils: produce reactive oxygen species (ROS) and enzymes

Question 32

What is the structure of cartilage?

Answer 32

- On top of bone | - Mainly composed of Type II collagen and proteoglycans (carbohydrates + proteins)

Question 33

What is the role of cartilage?

Answer 33

Carbohydrates in cartilage make cartilage cushiony = shock absorbers at joint

Question 34

What is the normal structure of a joint?

Answer 34

Thin layer of cells which secrete fluid = synovial fluid (like oil)

Question 35

What leads to joints with RA? (2)

Answer 35

1) Pink tissue: synoviocytes (thin layer of cells) secrete fluid = start to invade joints. 2) Inflammatory cells, mediators (cause swelling, pain, redness and heat), enzymes (eat away at the cartilage) and osteoclasts - multi-nucleated (many monocytes fused together) --> cell responsible for eating/dissolving underlying bone)

Question 36

What processes are involved in the development of RA?

Answer 36

1) T cells activated by APC and produce IL-2 (T cell growth factor) = grow and proliferate 2) These cells are pro-inflammatory so produce P-I cytokines e.g. gamma interferon 3) Gamma interferon can activate macrophages which are also in the system, and these macs can then also act as APCs and activate T cells 4) These macs produce inflammatory cytokines like IL-1 and TNF = inflammation in joint 5) Gamma interferon can also interact with fibroblast LS and make it secrete an enzyme which eats away at the cartilage 6) Fibroblast LS can also directly interact with T cells and there's a + feedback loop which activates the fibroblast LS --> produces chemokines which attract more inflammatory cells into joint to promote inflammation 7) T cells can help B cells --> secrete ABs which bind to themselves or to antigens = activate complement cascade 8_ Fibroblast cells also produce survival factors for T cells (positive growth signal to keep inflammation going)