Block E - IP lecture one

Question 1

why do we need an inflammatory response ?

Answer 1

To eliminate the stimulus such as infection with bacteria, virus or wound which elicits inflammation.

• To produce healing and restore tissue to normal physiological state

Question 2

what 3 things are stimuli for inflammation ?

Answer 2

3 things are stimulating factors

Infection

Chemical damage

Mechanical damage

These all trigger the immune response leading to inflammation.

Question 3

what mediators are most important in chronic infalmmation cases ?

Answer 3

cytokines

Question 4

what are the 3 complement pathways and where do they all converge ?

Answer 4

There are 3 complement pathways: classical, complement and lectin and all 3 pathways converge at C3 molecule.

Question 5

all 3 contain opsonisation , what is this ?

Answer 5

All 3 pathways involve opsonisation, this is a process which coats the pathogen using opsonin’s which tags the foreign pathogen for elimination by phagocytes which are white blood cells that engulf pathogens.

Question 6

C5a >

Answer 6

C5a is produced by the complement pathways and attracts macrophages, neutrophils and activates mast cells. It is also involved in chemotaxis, the migration of WBC, release of histamine and activating other WBC’s in the body.

Question 7

C5b-9 ?

Answer 7

C5b-9 is involved in complement mediated cell lysis.

Question 8

alternative pathway ?

Answer 8

The alternative complement pathway is activated by C3b molecule binding to a microbe or infectious agent. It also contains an amplification loop for the other pathways. The process of C3 cleaving into C3a and C3b underpins the whole process of complement.

Question 9

when are prostaglandins produced

Answer 9

Prostaglandins are produced in cells due to phospholipase A2 cleaving phospholipase in position 2 (hence the name) to produce arachidonic acid, a precursor to prostaglandins.

Question 10

PGI2 found ?

Answer 10

in blood vessels

Question 11

thromboxane A2 (TXA2) found ?

Answer 11

Thromboxane A2 (TXA2) is found in platelets.

Question 12

what occurs ion normal inflammation with PGE2 ?

Answer 12

For normal inflammation it is PGE2 that is involved, it is a strong mediator of pain and vascular leakage. PGE2 is produced using the COX enzyme, in arthritis there are large amounts of PGE2 produced due to activity of COX2.

Question 13

what are lekotrienes ( LTB4 + LTE4 ?

Answer 13

Leukotrienes ( LTB4 + LTE4) are chemotaxes, this means attracting immune cells to the site of inflammation/injury. It is made from 5-lipoxygenase.

Question 14

effect of histmaine ?

Answer 14

Histamine causes increased vascular permeability and vasodilation.

Question 15

target of kinins such as bradykinin ?

Answer 15

Kinins such as bradykinin are short and fast acting mediators targeting phospholipase A2 whereas cytokines are slower acting and last longer.

Question 16

what do nerves release ?

Answer 16

Nerves release substance P and CGRP which contribute to inflammation in a short term called neurogenic inflammation

Question 17

lysosomal granule release is triggered by what ?

Answer 17

C5a ( cytokine) and PAF are involved in lysosomal granule release

Question 18

leukotrienes endothelial cells ?

Answer 18

Leukotrienes are involved in chemoattractant and make endothelial cells sticky so that immune cells can roll along them.

Question 19

what does nerurogenic inflammation involve ?

Answer 19

Neurogenic inflammation involves substance P from nerve endings and kinins causing a rapid inflammatory response.

Question 20

time span of PGE2 release ?

Answer 20

PGE2 is released over a longer period and they require a lot of upstream effects before being released.

Question 21

when does chroonic inflammation occur and why is this an issue ?

Answer 21

If the acute inflammatory response fails to eliminate the stimulus or if the stimulus is self-perpetuating ( cannot be cleared) then inflammation becomes chronic.

THIS IS THE MAJOR PROBLEM FOR US ALL

A prolonged inflammatory response can lead to damage to the body, destruction of healthy cells and tissues. Examples are chronic auto-immune inflammatory disorders.

Question 22

how does chronic inflammation occur ?

Answer 22

This is the process for chronic inflammation, normally the stimulus is eliminated after a few days or week and the body clears the infection and inflammation is resolved.

If the stimulus is not eliminated this leads to a continuous stream of mediators such as lipoxins, resolvins and IL-10, therefore the inflammation is not resolved and chronic inflammation occurs.

Question 23

autoimmune disease and chronic inflammation ?

Answer 23

What happens when the immune system fails all its checkpoints and tight regulations during WBC maturation?

Recognition of self antigens (proteins) as self. In auto-immune disorders the immune system recognizes normal proteins within the body as foreign and tries to eliminate them, A prolonged inflammatory response ensues with a perpetual ‘fight’ to clear the antigens (i.e. the body attacks itself).

Question 24

examples of inflammation ?

Answer 24

Examples of auto-immune disorders (over 80 known);

Psoriasis (a disease affecting the skin),

Systemic Lupus erythematosus – SLE (affects joints, skin and organs),

Multiple sclerosis (affects the brain and spinal cord)

Crohn’s (affects GI tract, mainly small intestine)

Rheumatoid arthritis (affects the joints primarily)

All slightly different but involve inflammation and immune dysfunction have the same key principals.

Question 25

what disease is rheumatoid arthritis ?

Answer 25

Chronic, auto-immune inflammatory disease primarily affecting the joints but with other, extra-articular manifestations such as rheumatoid vasculitis.

Question 26

is there a cure ?

Answer 26

no , treatment manages symptoms

Question 27

C reactive proteins RA ?

Answer 27

Also higher levels of C reactive protein in patients with RA compared to healthy patients.

Question 28

RA symetrical joints ?

Answer 28

RA affects joints symmetrically if it is in right wrist, it will also occur in the left wrist.

Question 29

why do inflammed joints occur ?

Answer 29

Inflamed joint has an influx of immune cells and inflammatory mediators which promote joint swelling , cartridge erosion , bone loss and the synovial fluid becomes filled with these mediators

Question 30

genetic succeptibility ?

Answer 30

There is a genetic susceptibility leading to the generation of autoreactive B and T cells and environmental stimulus such as smoking or infection. These two events lead to immune response occurring against autoantigens (self) and joint inflammation. This in turn leads to formation of granulation tissue ( panus) , erosion of bone and cartridge causing joint destruction.

Family history of RA leads to a 3-5 x more likelihood of developing RA.

Question 31

Antibodies in RA ?

Answer 31

IgG-Fc (rheumatoid factor) - these are pentameric and bind to the Fc region on IgG

citrullinated proteins - antibodies against citrullinated proteins bind to collagen type II.

collagen type II

and others!

Occur due to autoreactive of B cells

Question 32

Ab mediated immunity ?

Answer 32

APC can be dendritic cells , macrophages and they present antigen to T lymphocytes.

Antibody immunity is driven by CD4 cells and Th2 subset , these alongside Il-4 and B cells produce antibodies after proliferation. It is the Plasma cells (P) that store and produce these antibodies. A subset of B cells are memory cells, (MB) which elicit a response to the same antigen quicker and with a bigger reaction.

Question 33

chain of events after APC presents to CD4 cells ?

Answer 33

APC present to CD4 cells, these are differentiated into T0 cells, then with the presence of IL-2 and type of antigen this will dictate if they develop into Th1 or Th2 cells.

Question 34

Th1 ?

Answer 34

TH1 cells produce potent pro inflammatory cytokines such as TNF-a and IFN-g , these activate macrophages to go on and engulf pathogenic particles leading to inflammation.

Question 35

APC and CD8+ cells ?

Answer 35

APC will interact with CD8 cells, they expand in population to produce cytotoxic T cells and can directly kill virally infected cells.

Question 36

Th17 subset ?

Answer 36

CD4 cells and APC can produce Th17 subset, these release IL-17 which is a pro inflammatory cytokine to lead to neutrophil production and recruitment.

Question 37

what does RA contribute by cell or antibody mediated immuniy ?

Answer 37

both

Question 38

immune complexes activate ?

Answer 38

Immune complexes activate complement - coats foreign particles to attract and infiltrate immune cells.

Question 39

T cells involved ?

Answer 39

T-cells involved through activation of macrophages and other cells – activated T cells move to the synovium and locally interact with resident macrophages.

Question 40

B cells ?

Answer 40

B-cells play an important role both in antibody production and in activating T-cells through antigen-presentation.

Question 41

Th1 secrete ?

Answer 41

Th1 cells secrete IL-1 , TNF-a and IFN-g which potently provide help to other immune cells resulting in activation of macrophages and B cells. This initiate and maintains inflammation in the synovium.

Question 42

Th17 activated by ?

Answer 42

Th17 are activated by IL-6,IL-1 , IL-23 and TGF-B and found in synovial fluid , they recruit neutrophils and B cells and promote osteoclast genesis.

Question 43

what occurs when Th1 and Th17 pathways come together ?

Answer 43

When the Th1 and Th17 pathways come together there is a continual expansion of B cells, T helper cells. There is also APC presenting our own antigens , this leads to a continual perpetual loop of secretion, stimulation, activation, expansion, migration and destruction leading to RA.

Question 44

cellular events in chornic inflammation ?

Answer 44

Influx of immune cells to the site of injury/infection,

Key cell types involved include;

Macrophages are recruited – produce potent vasoactive mediators,

Other leukocytes – produce lipid mediators and cytokines,

Lymphocytes (B and T cells) – release antibodies and cytokines

Resident cells such as synovial fibroblasts – release proteases and inflammatory cytokines.

Question 45

how does recruitment of T cells and monocytes occur from blood vessels ?

Answer 45

Recruitment of T cells and monocytes from blood vessels squeeze through the endothelium lining of the vessel due to chemo adhesion molecules and chemoattracts.

Question 46

cellular events in RA - macrophages ?

Answer 46

Cellular events in RA – macrophages

Engulf and process antigen.

Synthesise pro-inflammatory agents;

Release prostaglandins due to COX-2 induction.

They release TNFα and IL-1 to stimulate fibroblasts

Il-1 activates T cells

Question 47

luekocytes such as dendritic cells ?

Answer 47

Cellular events in RA – Leukocytes such as dendritic cells

Production mediated by increased levels of IL-3, GM-CSF, M-CSF and G-CSF.

Leukocytes are directed into inflamed joint synovium

Question 48

lymphocytes ?

Answer 48

Cellular events in RA – Lymphocytes

B-cells secrete immunoglobulin involved in complement activation, and immune complexes.

Secrete INFγ, IL-2 and IL-4 which stimulate formation of more lymphocytes

Question 49

synovial fibroblasts ?

Answer 49

Cellular events in RA – Synovial fibroblasts

Mitosis triggered by macrophages (IL-1 & TNFα) causing a vast increase in numbers.

Stimulated to secrete cartilage destroying enzymes (MMPs) and synthesize scar tissues.

Question 50

cytokines ?

Answer 50

Cellular events in RA – Cytokines

Such as IL-1 and TNFα stimulate the endothelium to express adhesion molecules and to release prostaglandins into the synovium

Secreted by macrophages.

Question 51

is RA a systemic disease ?

Answer 51

Remember also that RA is a systemic disease, it doesn’t just affect the joints!