Block E Lecture 1 - Rheumatoid Arthritis Flashcards
Why does the body need an inflammatory response?
In order to eliminate the stimulus (such as an infection) and to produce healing and restore tissue to its normal physiological state
(Slide 3)
What are 7 examples of inflammatory mediators?
Answers Include:
Complement
Lysosomal Enzymes
Kinins
Histamine
Superoxide
Leukotrienes
Thromboxanes
Prostaglandins
Platelet-activating factor (PAF)
NO
Cytokines (TNFα. interleukins etc..)
(Slide 5)
What are the steps of the complement?
- C3 is cleaved into C3a and C3b by C3 convertase
2a. C3a triggers histamine release, which leads to inflammation
2b. Acts as an opsonin (coats microbes to enhance phagocytosis)
- C3b helps cleave C5 into C5a and C5b which forms part of the C5b-9 complex
4a. C5a is involved in chemotaxis as well as histamine release and the activation of white blood cells
4b. The C5b-9 complex leads to cell lysis through formation of the membrane attack complex
(Slide 6)
How are prostaglandins which are mediators of inflammation formed?
Arachidonic acid is the precursor for all of these.
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)
What are 4 things inflammatory meditators control in order to promote inflammation?
Vascular Permeability
Cell Migration
Vasodilation
Pain sensitivity
Note: pro inflammatory mediators promote these
(Slide 8)
What are 2 examples of inflammatory mediators which promote vascular permeability?
Answers Include:
Kinins
Platelet-activating factor (PAF)
Histamine
LTD4
(Slide 8)
What are 2 examples of inflammatory mediators which promote cell migration?
Answers Include:
C5a
Platelet-activating factor (PAF)
LTB4
Cytokines
(Slide 8)
What are 3 examples of inflammatory mediators which promote vasodilation?
Answers Include:
CGRP
Platelet-Activation factor (PAF)
Histamine
Kinins
Prostaglandins
(Slide 8)
What are 2 inflammatory mediators which promote pain sensitisation?
Answers Include
Kinits
PGE2
Platelet-activating factor (PAF)
(Slide 8)
How does chronic inflammation occur?
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)
What can a prolonged (chronic) inflammatory response lead to?
Damage to the body, and destruction of healthy cells and tissues
Note: This can be done through chronic auto-immune inflammatory disorders
(Slide 10)
What are resolvins?
Mediators which play a crucial role in solving inflammation via immune cell recruitment, limiting pro-inflammatory cytokine production, and stimulating tissue repair
(Slide 11)
What happens when something goes wrong during white blood cell maturation?
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)
What are 3 examples of autoimmune diseases (and what they affect)?
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)
What is the prognosis for rheumatoid arthritis?
It has no cure with treatment involving managing symptoms rather than reversing them.
Symptoms gradually get worse over time
(Slide 15)
Is rheumatoid arthritis (as well as most autoimmune disorders) more common in male of female individuals?
Female
(Slide 15)
How does rheumatoid arthritis progress?
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)
How does rheumatoid arthritis affect a joint?
Cartilage becomes eroded, joint capsule becomes swollen, loss of bone mass and density, and thickening of the synovium
Note: The synovium is the part attacked mistakenly
(Slide 17)
What are the 2 factors which can contribute to the immune response mistakenly attacking the immune system in rheumatoid arthritis?
Genetic susceptibility and environmental stimulus
(Slide 18)
How can joint destruction occur in rheumatoid arthritis?
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)
What is granulation (pannus) tissue?
An abnormal growth of tissue within the joints, specifically an inflamed and thickened synovium, which can contribute to bone and cartilage bone due to its unexpected behaviour
(Slide 18)
Name an example of how antibodies can contribute to rheumatoid arthritis.
IgG-Fc (Rheumatoid factor)
Targeting citrullinated proteins
Targeting collagen type II
(Slide 19)
What is collagen type II?
It is a major component of cartilage in the joints, especially in the articular cartilage
(Slide 19)
How can antibody mediated immunity contribute to rheumatoid arthritis?
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)
What are 3 examples of cells which can be involved in rheumatoid arthritis?
Answers Include:
Macrophages
Leukocytes
Lymphocytes (both B and T cells)
Synovial fibroblasts
Cytokines
(Slide 26)
How do macrophages contribute to rheumatoid arthritis?
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
(Slide 25)
How do leukocytes contribute to rheumatoid arthritis?
They are directed into the inflamed synovium
(Slide 25)
What is the production of leukocytes mediated by?
IL-3, GM-CSF, M-CSF and G-CSF
(Slide 25)
How are lymphocytes involved in rheumatoid arthritis?
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)
How do synovial fibroblasts contribute to rheumatoid arthritis?
Numbers are increased by macrophages.
When stimulated, they secrete cartilage destroying enzymes (matrix metalloproteinases (MMPs) and synthesise scar tissues
(Slide 26)
How do cytokines contribute to rheumatoid arthritis?
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)
