C Edmead Lec 1 & 2Chronic Inflam Flashcards
What is the main purpose of inflammation?
- To bring cells from blood to site of infection
Chronic inflammation is an abnormal response to prolonged stim leading to further tissue damage and scarring.
What can be a cause of the tissue damage?
- Release reactive O2 species - free radicals
Rheumatoid arthritis often becomes BETTER or WORSE in pregnancy?
BETTER
Before RA patients often experience a period of prolonged ___-____ symptoms 21 months previous to the onset of RA
Flu-like
NSAIDs can be ineffective at reducing pain and swelling in RA. Why?
Because in progressive RA inflammation is not driven by PG’s and NSAIDs act on COX enzymes that prevent the production of PGs
RA is an inflammatory disease of small joints of extremities and larger joints characterised by inflam of the _____.
Synovium
RA involves the production of autoantibodies. What are these?
- Antibodies against own body
List some characteristics of a joint affected by RA… (5)
1) Bone loss/erosion
2) Cartilage loss
3) Generalised bone loss
4) Inflamed synovium
5) Swollen joint capsule (red, hot, swollen)
There is an increase/decrease of incidence of RA in females?
- INCREASE
There is a __% risk of RA in identical twins
16% (Genetic link?)
RA is associated with particular ___ alleles (HLA-_ _ 4)
MHC (proteins on T cells that presents antigen to immune)
HLA-DR4 (presents elements of cartilage to immune system really well)
RA can often follow an infection. Especially by…
- M________ infection
- S________ infections
As elements of cartilage look similar to these bacteria which can activate the immune system which attacks cartilage that looks similar to these antigens
Mycobacterium
Streptococcal
An infection can lead to RA due to exposure of ____ ____ ______ after inflammation and tissue damage uncovers new tissues that the body hasn’t seen before
Novel self antigens
C___ T cells initiate and sustain RA through recognition of autoantigens (collagen and other cartilage components)
CD4+
CD4+ T cells recognise auto antigens and become activated Th1 cells that can stimulate macrophages to release __-_ and ___-_. This can lead to release of the inflammatory _______ and chemokines causing an influx of inflam cells that lead to _____ of cartilage and bone and joint damage.
Activated Th1 cells can also stimulate the release of __________ (collagenase) from ________ and fibroblasts. This also leads to the erosion of cartilage and bone JOINT DAMAGE
1) IL-1 and TNF-alpha
2) Cytokines
3) Erosion
4) Metalloproteinases
5) Osteoclasts
Chronic inflammation is mediated largely by _____
Cytokines (small proteins secreted by cells of the immune system)
When do cells produce cytokines?
- Cells are activated to produce cytokines on exposure to antigens
Prolonged activation of the immune system due to failure to eradicate antigen can lead to ____ ________
Chronic inflammation
Why cant you switch of inflammation altogether?
- Because we still need inflammation to help fight infections. We just want to dampen down the inflammatory response instead
Cytokines can be autocrine, paracrine and endocrine
What are these?
Autocrine: Released by cells and act on that same cell
Paracrine: Released by local cells and act on other cells
Endocrine: Between distant cells by hormones
The level of cytokine receptors present is usually low but increases on ____ exposure.
This enhances ______
Antigen
Specificity
Cytokines…
1) induce _ and _ cell _____.
2) cause activation of ______.
3) cause cellular migration through release of _____.
4) cause apoptosis by TNF and ___ _
T and B cell differentiation
Macrophages
Chemokine
FasL
Cytokines are produced mainly by ______ ______ in response to infectious agents (LPS, dsRNA, ag stim T cells)
Mononuclear phagocytes
___ and __-_ increase leukocyte adhesion to endothelium
TNF and IL-1
- This leads to increased transmigration and chemotaxis.
Chemokines enhance _______
extravasation of leukocytes into tissues from capillaries
Th1 cells secrete ___ _ to simulate macrophages and cytotoxic T cells (express FasL to cause apoptosis) causing tissue damage
IFN-gamma
The presentation and response to antigens is dependent upon ___ alleles (genetic susceptibility)
MCH alleles (genetic link in RA) due to HLA-DR4 allele?
Th2 cells release anti inflammatory cytokines __-_
IL-4
So we need to dampen down Th1 cells that secrete IFN-gamma and promote Th2 cells that secrete IL-4
Complete the gaps:
1) Bacterial LPS stimulates monocytes/macrophages
2) This causes release of _____ and ___
3) This ultimately leads to increased leukocyte ______
4) This leads to an adaptive immune response involving release of ___ cells , __ and ___ cells
5) The first of these leads to secretion of IFN gamma, the second leads to secretion of FasL and the third causes release of IL-4
Chemokines and TNF
Extravasation
Th1 cells, Tc and Th2 cells
Secretion of TNF can stimulate macrophages and cause ______
Apoptosis
Cytokines should be synthesised as required or activated by ______ cleavage.
Proteolytic
Cytokines can ____, _____ or _______ another
Trigger, synergise or antagonise another
The balance of pro-inflammatory and anti-inflammatory cytokines keeps systems in check
Inflammatory ones include ___, __-_ (macrophages)
Anti-inflammatory ones include __-_, __-__ (Th2, macrophages)
TNF, IL-1
IL-4 and IL-10
Innate immune systems includes activation of macrophages that secrete _____ and neutrophils that release _____
Cytokines
Reactive oxygen species
Activation of innate leads on to activation of adaptive immune system such as T and B ______.
lymphocytes
Have RF (____ ____) and anticitronallated protein antibodies present in RA - means activation of B cells is involved
Rheumatoid factor
During activation of immune system. WBC’s become activated and release proteases (MMPs) and reactive O2 species which can lead to ____ _____.
This can increase the inflammatory response and inflammatory cells try to inject and clean up the cell debris.
Cell death
It is thought that exposure of self antigens present on ____ and ____ lead to the continued immune system activation
Cartilage and collagen
DMARDs are anti-rheumatic NOT ____-_______
anti-inflammatory
DMARDs do NOT reduce disease _______.
Progression - just masking the symptom and decreasing apparent disease activity.
Most DMARDs pose a risk of severe ______.
TOXICITY
Monitoring needs to take place, especially for changes in bone marrow, kidney function and skin.
DMARDs have many issues.
1) Take a long time to have effect e.g - weeks.
2) Need patient ____ due to long time taken to see benefit.
3) Recommended use ____ in disease process
4) Usually stated on ___therapy but often switched to ____therapy
1) 3-4 weeks (can cause depression due to pain and impact)
2) Counseling
3) Early
4) Monotherapy to Combination therapy BUT combination approach disappointing results (lack of synergy)
After year 1 on a DMARD: \_\_% in remission \_\_% some response \_\_% no response (worse) \_\_% toxicity so drug withdrawal
10%
30%
30%
30%
After year 2 on a DMARD: less than ____% remain on the drug.
Less than 50%
Methotrexate: Most commonly used DMARD (anti-cancer)
Is a ____ antagonist.
Blocks ___ synthesis.
Prevents cell _____.
Folate
DNA
Proliferation
Prevention of cell proliferation means less inflammation as less proliferation of fibroblasts and less proliferation of T and B cells etc…
Fewer cells = fewer cytokines = dampen down inflammation
Methotrexate used at ____ doses than in cancer treatment.
Lower doses (7.5-15mg/wk im/sc)
Methotrexate targets an enzyme so changes to enzyme can lead to ______ to get round blockage to enzyme
Resistance
Many patients show high _____ to Methotrexate
Toxicity
Methotrexate can lead to depression of ____ _____ and __ ____ damage
Bone marrow
GI tract damage
Methotrexate mechanism of action:
- May block proliferation of epithelial cells leading to _______
- Suppress IL-1 induced __-_ (cytokine that has pro/anti inflammatory actions - more pro inflam)
- __-_ drives synovial cell proliferation and production of ___.
1) angiogenesis
2) IL-6
3) IL-6
4) ROS (reactive oxygen species)
Sulphasalazine has _____ actions as well as anti-rheumatic actions.
May work as possibly underlying _____ that can lead to inflammation.
Might effect _____ biochemistry and activation.
Antibiotic actions.
Infection.
Macrophage - leading to higher IL-10 production (anti-inflammatory)
Penicillamine:
- Appears to decrease IGG circulating antibody __.
- Appears to decrease joint swelling.
- Appears to decrease conc of acute phase proteins
- Prevents maturation of newly synthesised _____ thus reducing antigenicity (as mature form of collagen may be producing the antigen that causes RA inflam).
RF (rheumatoid factor)
Collagen
Penicillamine may lead to side effects such as _______ (decrease in platelets) and promote further auto-immune diseases (thyroiditis and Myasthenia Gravis).
Thrombocytopenia - need monitoring
HydroxyChloroquine: Used mainly to treat Malaria.
- Reduce joint swelling and __ (but levels of RF may be due to B cell activation producing these antibodies)
- Stabilises ______ (reduce release of ROS)
- Inhibs PLA2 so reduce acute inflam mediators
- Reduce cytokine _______.
Focus more on mediators rather than cells (e.g Methotrexate)
1) RF
2) Lysosomes
3) Transcription
Leflunomide:
- Inhibits enzyme (orotate dehydrogenase) involved in DNA synth so reduces cellular _____.
- May target _ cells and reduce RF production
Proliferation
B cells
DMARDs…
inhibit _____ activation.
inhibit cell ______.
decrease release of ________ cytokines and ROS.
Macrophage
Proliferation
Anti-inflammatory cytokines
Treatment regime:
1) NSAID
2) NSAID + _____
3) 2nd ______ (maybe in combination)
NSAID (target acute inflam mediators) + Methotrexate
2nd DMARD added or used as mono therapy
Steroids are endogenous reagents that enter nucleus, effect gene transcription and block _______ cytokine production.
Pro-inflammatory
Endogenous steroids (corticoids) are released from _____ cortex (just above kidneys)
Adrenal cortex
Endogenous steroids include…
1)
2)
1) Mineralocorticoids e.g aldosterone - affect water and electrolyte balance DONT INTERFERE WITH THIS
2) Glucocorticoids e.g hydrocortisone - affect carb and protein metab DONT INTERFERE WITH THIS but INTERFERE WITH anti inflam and suppressive effects
THIS IS AN ISSUE as give exogenous steroids that want to focus on just one area.
Deficiency of steroids can lead to _____ disease.
Addisons
Too much glucocorticoids can lead to ______ syndrome.
Too much mineralocorticoids can lead to ____ syndrome.
Cushings
Conns
If the body has high levels of _____ steroids (cortisol) this can can have a _____ effect on endogenous system and switch off endogenous steroid release. Body becomes reliant on exogenous steroids. Leaves patient with no steroid control if patient stops taking steroids suddenly.
This is why short course, low dose steroid regimes are preferred if possible.
1) exogenous
2) suppressive
