week 4 - inflammation and infection Flashcards
describe autoimmunity
in an autoimmune disease, the immune system attacks itself, targeting the cells, tissues and organs of a persons own body - break in tolerance
factors leading to autoimmune disease
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
describe how there could be immune regulatory failure in autoimmune disease
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
examples of infections or environmental factors that can lead to autoimmunity
smoking
air pollution
drugs
infectious agents such as mycoplasma or EBV
autoimmunity develops after the infection, not directly caused by the infection
describe autoantibodies
produced by the immune system and is directed against one or more of the individual’s own proteins
may not be pathogenic
autoantibody target in graves disease
TSH receptor
autoantibody target in myasthenia gravis
acetyl choline receptor
autoantibody target in idiopathic thrombocytopenic purpura
platelets
autoantibody target in guillain-barre syndrome
gangliosides
pathology of graves disease
(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
basic pathology of myasthenia gravis
autoantibody blocks acetyl choline receptors - receptors are internalized and degraded
no Na+ influx
no muscle contraction
difference between organ specific and non-organ specific autoimmune disease
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
pathology of guillain-barre syndrome
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
phases of rheumatoid arthritis
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)
what is tolerance
controlled unresponsiveness to self
maintained by numerous control mechanisms
immune system has regulatory checks
symptoms of rheumatoid arthritis
joint pain stiffness - morning and inactivity joint swelling fatigue - inflammation systemic: weight loss, fever
impact of smoking in RA
increased risk of RA associated with shared epitope in HLA-DRB1 alleles
double shared epitope and smoking gives the biggest risk
role of gut microbiome in autoimmunity
where immune system is educated about the environment - allows tolerance
pathophysiology of RA
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
RA treatments
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
biological agents
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
what are biosimilars
cheaper alternatives of drugs
differ in size, manufacturing complexity and the way they interact with cells and other proteins in the body
effects of an NSAID drug
analgesic - pain relief
antipyretic - reduce body temp - need higher dose
anti-inflammatory - higher doses
function of COX-1 and COX-2 inhibtors, asprin and indomethacin
inhibits cyclooxygenase
prostaglandin and thromboxane synthesis prevented
cyclooxygenase
Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes
differences between cox-1 and cox-2
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
effects of paracetamol
no significant anti-inflammatory
mild analgesic effect
severe hepatotoxicity results at high doses
common adverse effects of NSAIDs
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
gastrointestinal problems from NSAIDs
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
advantage of only targeting COX2 rather than COX1 and COX2
COX1 would still produce prostaglandin
mucous layer and neutral environment in the stomach would then be produced by prostaglandins
avoids gastrointestinal problems
NSAID selectivity
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
what are glucocorticoids
produced by the adrenal glands
exogenous mineralcorticoids - regulate salt and water metabolism
exogenous glucocorticoids have peripheral actions - anti-inflammatory, immunosuppressive effects
effects of glucocorticoids
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)
when are glucocorticoids used
rheumatoid arthritis acute leukemia asthma psoriasis anaphylaxis crohns disease transplantation
side effects of glucocorticoids
thinning of skin, easy bruising, poor wound healing, osteoporosis, obesity, increased appetite, increased susceptibility to infection
how are biological agents more specific than glucocorticoids
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
describe checkpoint inhibitor drugs
(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
