Block E Lecture 1 - Rheumatoid Arthritis

Question 1

Why does the body need an inflammatory response?

Answer 1

In order to eliminate the stimulus (such as an infection) and to produce healing and restore tissue to its normal physiological state

(Slide 3)

Question 2

What are 7 examples of inflammatory mediators?

Answer 2

Answers Include:

Complement

Lysosomal Enzymes

Kinins

Histamine

Superoxide

Leukotrienes

Thromboxanes

Prostaglandins

Platelet-activating factor (PAF)

NO

Cytokines (TNFα. interleukins etc..)

(Slide 5)

Question 3

What are the steps of the complement system?

Answer 3

1. C3 is cleaved into C3a and C3b by C3 convertase

2a. C3a triggers histamine release, which leads to inflammation

2b. C3b acts as an opsonin (coats microbes to enhance phagocytosis)

3. C3b also helps cleave C5 into C5a and C5b, with C5b forming part of the C5b-9 complex

4a. C5a is a chemotaxic agent which also releases histamine and activates white blood cells

4b. The C5b-9 complex leads to cell lysis through formation of the membrane attack complex

(Slide 6)

Question 4

What are 3 examples of how lipid mediators, which mediate inflammation are formed? State the enzyme which forms them and at least 1 example of a mediator formed this way.

Answer 4

Answers Include:

Platelet activating factor (PAF) is cleaved from the membrane by phospholipase A2 before acetyltransferase forms the final PAF protein.

Arachidonic acid is the precursor for all of the below;

12-lipooxygenase forms 12-HETE

The COX enzymes form cyclic endoperoxides PGG2 and PGH2 which eventually get turned into PGI2, TXA2, PGD2, PGE2 and PGF2α

5-lipooxygenase forms LTB,C,D and E4

(Slide 7)

Question 5

What are 4 things inflammatory meditators control in order to promote inflammation?

Answer 5

Vascular Permeability

Cell Migration

Vasodilation

Pain sensitivity

Note: pro inflammatory mediators promote 1 or more of these

(Slide 8)

Question 6

What are 2 examples of inflammatory mediators which promote vascular permeability?

Answer 6

Answers Include:

Kinins

Platelet-activating factor (PAF)

Histamine

LTD4

(Slide 8)

Question 7

What are 2 examples of inflammatory mediators which promote cell migration?

Answer 7

Answers Include:

C5a

Platelet-activating factor (PAF)

LTB4

Cytokines

(Slide 8)

Question 8

What are 3 examples of inflammatory mediators which promote vasodilation?

Answer 8

Answers Include:

CGRP

Platelet-Activation factor (PAF)

Histamine

Kinins

Prostaglandins

(Slide 8)

Question 9

What are 2 inflammatory mediators which promote pain sensitisation?

Answer 9

Answers Include

Kinins

PGE2

Platelet-activating factor (PAF)

(Slide 8)

Question 10

How does chronic inflammation occur?

Answer 10

When the acute inflammatory response fails to eliminate the stimulus or if the stimulus is self-perpetuating (ongoing) then the inflammation becomes chronic

(Slide 10)

Question 11

What can a prolonged (chronic) inflammatory response lead to?

Answer 11

Damage to the body, and destruction of healthy cells and tissues

Note: This can be done through chronic auto-immune inflammatory disorders

(Slide 10)

Question 12

What are resolvins?

Answer 12

Mediators which play a crucial role in resolving inflammation via limiting immune cell recruitment and pro-inflammatory cytokine production, and stimulating tissue repair and promoting efferocytosis (clearance of dead cells)

(Slide 11)

Question 13

What happens when something goes wrong during white blood cell maturation?

Answer 13

The white blood cells recognise self antigens (self-proteins) as foreign, and tries to eliminate them, which is how auto-immune diseases occurs.

This then results in a prolonged inflammatory response which results in a perpetual fight to clear the antigens (the body attacks itself)

(Slide 12)

Question 14

What are 3 examples of autoimmune diseases (and what they affect)?

Answer 14

Psoriasis - affecting the skin

Systemic Lupus erythematosus - affects the joints, skin and organs

Multiple sclerosis - affects the brain and spinal cord

Crohns - affects the GI tract (mainly small intestine)

Rheumatoid arthritis - affects the joints but has other extra-articular (outside the joints) manifestations

(Slides 13 and 14)

Question 15

What is the prognosis for rheumatoid arthritis?

Answer 15

It has no cure with treatment involving managing symptoms rather than reversing them.

Symptoms gradually get worse over time

(Slide 15)

Question 16

Is rheumatoid arthritis (as well as most autoimmune disorders) more common in male or female individuals?

Answer 16

Female

(Slide 15)

Question 17

How does rheumatoid arthritis progress?

Answer 17

It may originally start in only a few joints before spreading.

Note: Wrists, hands, elbows, shoulders, knees and ankles are most likely to be attacked

(Slide 16)

Question 18

How does rheumatoid arthritis affect a joint?

Answer 18

Cartilage becomes eroded, joint capsule becomes swollen, loss of bone mass and density, and thickening of the synovium occur

Note: The synovium is the part attacked mistakenly

(Slide 17)

Question 19

What are the 2 factors which can contribute to the immune response mistakenly attacking the immune system in rheumatoid arthritis?

Answer 19

Genetic susceptibility and environmental stimulus

(Slide 18)

Question 20

How can joint destruction occur in rheumatoid arthritis?

Answer 20

Immune response against the synovium leads to joint inflammation.

Joint inflammation leads to formulation of granulation tissue (pannus). This releases a variety of pro-inflammatory mediators and enzymes which degrade the cartilage and bone.

This leads to erosion of the bone and cartilage which then leads to joint destruction

(Slide 18)

Question 21

What is granulation (pannus) tissue?

Answer 21

An abnormal growth of tissue within the joints, specifically an inflamed and thickened synovium, which can contribute to bone and cartilage erosion due to its unexpected behaviour

(Slide 18)

Question 22

Name an example of an antibody which can contribute to rheumatoid arthritis.

Answer 22

Answers Include:

IgG-Fc (Rheumatoid factor) (antibodies targeted against IgG)

Targeting citrullinated proteins

Targeting collagen type II

(Slide 19)

Question 23

What is collagen type II?

Answer 23

It is a major component of cartilage in the joints, especially in the articular cartilage

(Slide 19)

Question 24

What are citrullinated proteins?

Answer 24

Proteins that have undergone a post-translational modification where the amino acid arginine is converted to citrulline

(Slide 19)

Question 25

How can antibody mediated immunity contribute to rheumatoid arthritis?

Answer 25

Anti-bodies targeted against proteins (such as citrullinated proteins or collagen type II) bind to their target protein, forming immune complexes that can deposit in the synovium or the cartilage. These then can activate the complement system and attract inflammatory cells (Slides 19 - 22)

Question 26

What are the steps of immunopathogenesis of rheumatoid arthritis?

Answer 26

1. T helper cells are activated in the presence of IL-6, IL-23 and TGF-β with these cytokines also driving differentiation into TH17 cells which secrete IL-17 and TH1 cells, which secrete TNF-α and IFN-γ 2a. IL-17 activates osteoclasts via RANKL (receptor activator of nuclear factor kappa-b ligand), which break down bone leading to bone erosion and promoting inflammation. 2b. TNF-α and IFN-γ enhance macrophage activation, which leads to more TNF-α as well as IL-1 and other pro-inflammatory cytokines being released, which leads to further inflammation and joint damage. 3. B cells also differentiate into plasma cells, which secrete autoantibodies (such as rheumatoid factor and antibodies targeted against citrullinated proteins), which activate complement, further driving inflammation and tissue damage. B cells can also activate T-cells. 4. The above interactions lead to a positive feedback loop of stimulation of T helper cells, persistent activation of macrophages and fibroblasts, sustained antibody production and constant osteoclast activation, leading to bone destruction. Note: This can start with B cells or T cells. (Slide 23)

Question 27

What are 3 examples of cells or mediators which can be involved in rheumatoid arthritis?

Answer 27

Answers Include: Macrophages Leukocytes Lymphocytes (both B and T cells) Synovial fibroblasts Cytokines (Slide 26)

Question 28

How do macrophages contribute to rheumatoid arthritis?

Answer 28

They engulf and process the antigen. They also produce prostaglandins through COX-2 induction and they secrete pro-inflammatory agents as well as TNFα and IL-1 which stimulates fibroblasts and enhance macrophage activation (Slide 25)

Question 29

How do leukocytes (excluding lymphocytes) contribute to rheumatoid arthritis?

Answer 29

They are directed into the inflamed synovium (Slide 25)

Question 30

What is the production of leukocytes mediated by?

Answer 30

IL-3, GM-CSF, M-CSF and G-CSF (Slide 25)

Question 31

How are lymphocytes involved in rheumatoid arthritis?

Answer 31

B-cells secrete immunoglobulin antibodies which are involved in complement activation and immune complexes. They are also highly effective antigen presenting cells (APCs) IFNγ, IL-2 and IL-4 are secreted by T-cells and stimulate formation of more lymphocytes (Slide 26)

Question 32

How do synovial fibroblasts contribute to rheumatoid arthritis?

Answer 32

Numbers are increased by macrophages. When stimulated, they secrete cartilage destroying enzymes (matrix metalloproteinases (MMPs) and synthesise scar tissues (Slide 26)

Question 33

How do cytokines contribute to rheumatoid arthritis?

Answer 33

Cytokines such as IL-1 and TNFα can stimulate the endothelium to express adhesion molecules and to release prostaglandins into the synovium, further worsening inflammation. These also are secreted by macrophages and activate synovial fibroblasts (Slide 26)