Inflammation Flashcards
What cells initiate the inflammatory response and where are they found?
- Tissue-resident mast cells (same as basophils)
- Tissue-resident macrophages (monocytes are precursors)
Found in body tissues e.g. CT
What is the role of cells which initiate the IR?
They detect damage and insult - first to respond
What does inflammation trigger?
An immune response (innate and adaptive).
This triggers maturation of APCs to activate T cells.
What stimuli give rise to inflammation?
- Physical (cut or burn)
- Chemical (acid, alkali)
- Immunological (hypersensitivity)
- Bacterial (pathogenic microbes)
Describe the 2 lines of defence of the human body, against invading microbes
1st line = physical barriers e.g. skin, hair, mucus (enzymes + active peptides)
2nd line = inflammatory response
What events follow when one steps on a rusty nail? (5)
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
What are the 5 inflammatory cascades?
1) Complement
2) Coagulation
3) Bradykinin
4) Arachidonic acid
5) Free radicals
What does physical trauma lead to?
Activation of inflammatory cascades
1) Blood coagulation - shuts blood flow
2) Inflammation - activating 2 resident cells
How and what do invading microorganisms activate?
Innate immune cells through PAMPs - to be processed and presented to B and T cells
How is a mast/tissue basophil activated?
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
Which cytokines and inflammatory mediators do macrophages release?
1) TNFa
2) IL-1b
3) IL-6
4) (IL-8)
5) (IL-12)
How do macrophages engulf bacteria?
- 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
Which cytokines do macrophages release?
1) TNFa
2) IL-1
3) IL-6
What is the role of IL-8?
Attracts neutrophils to SOI
What can IL-6 released from activated macrophages not do?
Increase vascular permeability
What are the effects of the cytokines released from activated macrophages?
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.
What is the acute phase response?
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)
What causes mast cells to degranulate and release inflammatory mediators?
Wound =
- Tissue damage
- Low O2 tension
- Complement
- Direct contact with organisms
What is the effect of histamine?
Vasodilation and increased vascular permeability.
- Tight junctions loosen and allow fluid from blood to get into the SOI = swelling
How do neutrophils migrate?
By diapedesis, when it sees an up-regulation of adhesion molecules
What is the role of neutrophils?
Remove organisms and dead tissue
What are some characteristics of neutrophils?
- 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)
What does the complement cascade consist of?
3 pathways: C3a and C5a which activate mast cells
What does the clotting cascade consist of?
Build up of fibrin. But, as fibrin degrades, peptides are released which are pro-inflammatory (increase vascular permeability and attract neutrophils)
What does the kinin cascade consist of?
Receptors are present on nerve endings (for kinin).
Once kinins are produced, this is what causes pain (most potent mediator for pain)
What does the arachidonic cascade consist of?
Phospholipid bilayer –> 2 pathways with different products
What do leukotrines and prostagladins have in common?
Both are chemoattractants for neutrophils
What happens when phagocytic cells take up bacterium?
Secrete enzymes asnd reactive species
What is the main feature of rheumatoid arthritis?
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.
What kind of disease is rheumatoid arthritis?
Immune mediated chronic inflammatory diesease.
All 5 pathways occur in the joints.
How does rheumatoid arthritis occur?
- 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
What is the structure of cartilage?
- On top of bone
- Mainly composed of Type II collagen and proteoglycans (carbohydrates + proteins)
What is the role of cartilage?
Carbohydrates in cartilage make cartilage cushiony = shock absorbers at joint
What is the normal structure of a joint?
Thin layer of cells which secrete fluid = synovial fluid (like oil)
What leads to joints with RA? (2)
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)
What processes are involved in the development of RA?
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)
