week 4 - inflammation and infection

Question 1

describe autoimmunity

Answer 1

in an autoimmune disease, the immune system attacks itself, targeting the cells, tissues and organs of a persons own body - break in tolerance

Question 2

factors leading to autoimmune disease

Answer 2

genetic factor - susceptibility genes - most conditions are polygenic - causes failure of self tolerance
infection and environmental exposure - smoking
then dysregulation of the immune system leads to autoimmunity

Question 3

describe how there could be immune regulatory failure in autoimmune disease

Answer 3

loss of central tolerance - thymus
loss of peripheral tolerance - lymph nodes, spleen
molecular mimicry - bacterial epitope looks very similar to something we present
inappropriate activation - something happens and sets off a cascade

Question 4

examples of infections or environmental factors that can lead to autoimmunity

Answer 4

smoking
air pollution
drugs
infectious agents such as mycoplasma or EBV
autoimmunity develops after the infection, not directly caused by the infection

Question 5

describe autoantibodies

Answer 5

produced by the immune system and is directed against one or more of the individual’s own proteins
may not be pathogenic

Question 6

autoantibody target in graves disease

Answer 6

TSH receptor

Question 7

autoantibody target in myasthenia gravis

Answer 7

acetyl choline receptor

Question 8

autoantibody target in idiopathic thrombocytopenic purpura

Answer 8

platelets

Question 9

autoantibody target in guillain-barre syndrome

Answer 9

gangliosides

Question 10

pathology of graves disease

Answer 10

(thyroid hormones regulated by thyroid stimulating hormones
TSH binds to receptor and stimulates synthesis of thyroid hormones)
graves disease - results in non-regulated activating autoantibodies that bind to TSH receptor - overstimulation of thyroid hormones
the autoantibodies are called long acting TSHs

Question 11

basic pathology of myasthenia gravis

Answer 11

autoantibody blocks acetyl choline receptors - receptors are internalized and degraded
no Na+ influx
no muscle contraction

Question 12

difference between organ specific and non-organ specific autoimmune disease

Answer 12

organ specific :
autoimmune attack vs self antigens of a given antigen of given organ
results in damage of organ structure and function
systemic:
widespread self-antigens are targets for autoimmune attack
damage affects structures such as blood vessels, cell nuclei etc

Question 13

pathology of guillain-barre syndrome

Answer 13

molecular mimicry sets off immune response
if autoantibodies cross blood nerve barrier they can bind to gangliosides on nerve
sets off cascades
myelin is stripped off
cannot get appropriate muscle contraction

Question 14

phases of rheumatoid arthritis

Answer 14

genotype and environmental factors
pre-articular or lymphoid phase - autoimmunity, rheumatoid factor, collagen specific response, CCP-specific antibody etc
transition phase - neurological events, microvascular dysfunction etc
articular phase - cardiovascular disease, osteoporosis, functional decline (disability)

Question 15

what is tolerance

Answer 15

controlled unresponsiveness to self
maintained by numerous control mechanisms
immune system has regulatory checks

Question 16

symptoms of rheumatoid arthritis

Answer 16

joint pain
stiffness - morning and inactivity
joint swelling
fatigue - inflammation 
systemic: weight loss, fever

Question 17

impact of smoking in RA

Answer 17

increased risk of RA associated with shared epitope in HLA-DRB1 alleles
double shared epitope and smoking gives the biggest risk

Question 18

role of gut microbiome in autoimmunity

Answer 18

where immune system is educated about the environment - allows tolerance

Question 19

pathophysiology of RA

Answer 19

smoking and some infections can induce citrullination of self proteins creating new antigenic epitopes - could be mutation of HLA allele
t cell and antibody response
Th1 and Th17 secrete cytokines which recruit leukocytes into joint and activate synovial cells to produce collagenases
t cells can produce RANK ligand - RANKL binds to RANK on osteoclast precursors and activates them
anti-CCP antibodies and autoantibodies called rheumatoid factor produced by b cells

Question 20

RA treatments

Answer 20

DMARDs - limits disease progression and joint destruction - can use a combination
glucocorticoids, NSAIDs - pain relief while waiting for DMARDs to work
TNF inhibitors such as infliximab
surgery

Question 21

biological agents

Answer 21

drugs such as monoclonal antibodies, receptors or peptides which have been developed rationally by targeting processes important in disease pathogenesis eg. t cells, cytokines, b cells

Question 22

what are biosimilars

Answer 22

cheaper alternatives of drugs

differ in size, manufacturing complexity and the way they interact with cells and other proteins in the body

Question 23

effects of an NSAID drug

Answer 23

analgesic - pain relief
antipyretic - reduce body temp - need higher dose
anti-inflammatory - higher doses

Question 24

function of COX-1 and COX-2 inhibtors, asprin and indomethacin

Answer 24

inhibits cyclooxygenase

prostaglandin and thromboxane synthesis prevented

Question 25

cyclooxygenase

Answer 25

Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes

Question 26

differences between cox-1 and cox-2

Answer 26

1 is constitutive (always switched on) whereas 2 is inducible 1 has housekeeping functions 2 has functions in inflammation and neoplasia - tumor invasion, angiogenesis, cell proliferation

Question 27

effects of paracetamol

Answer 27

no significant anti-inflammatory mild analgesic effect severe hepatotoxicity results at high doses

Question 28

common adverse effects of NSAIDs

Answer 28

platelet dysfunction gastritis and peptic ulceration with bleeding acute renal failure in susceptible sodium+ water retention and edema analgesic nephropathy - injury to kidney prolongation of gestation and inhibition of labour hypersensitivity

Question 29

gastrointestinal problems from NSAIDs

Answer 29

NSAIDs block mucous production, bicarbonate production and prostaglandin production these are all normally involved in protecting the stomach from gastric acid damage can get gastric distress, gastric bleeding, sudden acute hemorrhage

Question 30

advantage of only targeting COX2 rather than COX1 and COX2

Answer 30

COX1 would still produce prostaglandin mucous layer and neutral environment in the stomach would then be produced by prostaglandins avoids gastrointestinal problems

Question 31

NSAID selectivity

Answer 31

``` cox2 selective - increased risk for CV events but decreased risk for GI side effects semiselective NSAIDs - increased affinity for COX2 but still retain affinity for COX1 - use cautiously for patients with increased CV risk nonselective NSAIDs (ibuprofen) - decreased risk for CV events, increased risk for GI side effects irreversible nonselective NSAID (asprin) - cardioprotective at low doses, increased risk for GI side effects ```

Question 32

what are glucocorticoids

Answer 32

produced by the adrenal glands exogenous mineralcorticoids - regulate salt and water metabolism exogenous glucocorticoids have peripheral actions - anti-inflammatory, immunosuppressive effects

Question 33

effects of glucocorticoids

Answer 33

impact protein synthesis can increase protein expression (annexin-1) or decrease protein expression (cytokines, chemokines, inflammatory proteins) increased production of annexin-1 blocks phospholipases and so blocks production of lipid mediators (regulate inflammation)

Question 34

when are glucocorticoids used

Answer 34

``` rheumatoid arthritis acute leukemia asthma psoriasis anaphylaxis crohns disease transplantation ```

Question 35

side effects of glucocorticoids

Answer 35

thinning of skin, easy bruising, poor wound healing, osteoporosis, obesity, increased appetite, increased susceptibility to infection

Question 36

how are biological agents more specific than glucocorticoids

Answer 36

monoclonal antibodies so they only target one antigen - blocking only one pathway more specific to less side effects more specific drugs are successful in fewer people

Question 37

describe checkpoint inhibitor drugs

Answer 37

(checkpoint proteins block t cell activity) these drugs used in cancer treatment CTLA-4 checkpoint protein prevents dendritic cells from priming t cells to recognise tumours - drug would block the inhibitor