rheumatoid and immune disorders Flashcards
what is RA
autoimmune disease in which the synovial lining of joints is degraded
what is RA symptoms
chronic inflammation but manifest in the joints
rheumatic nodules can be seen on patient joints = joint deformation
what are some risk factors for RA
smoking, alcohol, obesity
genetic = HLA DR4 postive immune = RF and anti-ccp positive
> combo of risk factors lead to disease
Why hla4???
how is RA diagnosed
physical examination to see how many joints involved
serology to see if patient is postitive for acute phase reactants and inflammatory markers
what is Rheumatoid factor?
family of antibodies that are produced against crystal fragment of IgG
why is having higher levels of RF associated with poorer prognosis?
RF can be made against any of the Ig- family
so IgM and IgG are main activators of the complement system so more likely to be blocked by RF
contributes to inflammation
what is anti-cyclic citrulinated peptide?
IgG antibodies against synovial membrane proteins
why does anti-ccp get produced?
usually the synovial membrane protein is not exposed
but due to joint damage they get exposed and body recognise body as foreign object so anti-ccp is created
what happens to synovial peptides for them to be recognised as foreign?
the arginine residues are converted into citrulline by peptidyl arginine deaminase
when the immune system is activated in RA what happens?
inflammation leads to destruction of synovium
and then thickening of it
how do anti-ccp antibodies get produced?
granulocytes release granules containing PAD
enzyme acts on the synovial peptide and citrillunated protein is taken up by DENDRITIC cell
antigen is presented as DR4 to t-cell -> b-cell -> plasma cell = antibody produced
what are acute phase reactants?
proteins produced by liver that show changes in serum concentration response to inflammation
so are inflammatory markers
name some acute phase reactants
ESR, CRP
serum amyloid A
albumin, transferrin
which acute phase reactants become upregulated during inflamation?
A serum amyloid A
B albumin
C CRP
D C3 complement
all apart from albumin become upregulated during inflammatory response
which acute phase reactants become downregulated during inflamation?
A serum amyloid A
B albumin
C transferrin
D C3 complement
B and C
they become downregulated
what is a pannus tissue?
its the result of synovium expansion
an extra layer of tissue seen in inflammatory diseases
how does the pannus tissue change over RA?
it can become vascularised leading to more immune cell recruitment (adaptive + innate cells)
it can become overgrown and lead to bone erosion and SF is pushed out to joint junction (effusion)
how are osteoclasts implicated in RA?
they do bone reabsorption and they are highly active
so responsible for a lot of bone destruction
what do current RA therapies focus on?
no cure or reverse damage
so instead manage the pain
what happens to synoviocyte in RA (phenotype)?
they become hypertrophic and hyperplastic
what are hallmarks of RA
rheumatic nodules - swelling of synovial membrane
elevation of specific acute phase reactants - c3, c4 complement, esr, crp, serumAA
what do DMARDs focus on targeting?
target specific immune components like il-6, tnf alpha
what is the last resort option in current RA therapy?
synovoectomy - surgical removal of the inflammed syonovial tissue
but underlying inflammation persists so this is
temporary alleviaiton
why should we rotate the usage of biologics?
they are targetinng different immune system components so rotate to see which one works best for pain relievement
also prevents any furthur compromise to immune system
as well as activating b-lymph to produce RF and anti-ccp, what do the T-cell cytokines also produce?
tnf-alpha and il-17 produced by t-help cell activate synoviocytes leading to RANKL peptide release
what is RANKL?
immune mediator in RA
it drives differentiation of synoviocytes and macrophages into osteoclasts leading to eventual bone destruction and erosion
RANKL can also be produced by b-lymph
what are CD4+ and CD8+ cells?
t-helper cells
t-cytotoxic cells
what happens to monocytes when acted upon by RANKL?
monocytes in blood migrate into tissue and become type 1 pro-i macrophage
they then differentiate into osteoclast
what is frustrative phagocytosis?
neutrophils are recruited to synovium when it becomes vascularised and survive for longer so there is delayed apoptosis
they release more pro-i cytokines and more cells are recruited
what molecule extends survival of macrophage?
MCL-1 a prosurvival molecule part of the BCL2 family
what are some emerging DMARDs?
target the immune system mediators like CD4 and their cytokines that are released
target metabolism like reduce glycolysis, target lactate
what is the aim of DMARDs?
reduce inflammation, stop the joint destruction and overall prevent disease progresssion
what does the novel therapy schlerostin do?
inhibitor of wnt signalling so will enable osteoblast formation
how is metabolism related to RA?
immune cells undergo metabolic shift from ox phos to glycolysis
because the synovium is highly hypoxic
what is purpose of complement system?
30 different zymogens which act to amplify pro-i response
how does the complement system destroy pathogens?
through the membrane attack complex which is a pore
multiple MAC disrupt the osmotic pressure of pathogen causing it to lyse
how do the different complement system pathways differ?
stimulus is different
antibody, lectin, foreign surface
why is c3 the most important complement molecule?
where the most activation and amplification occurs
what is advantage of lectin pathway over classical complement pathway?
antibodies take time to produce so lectin pathway a quicker response to pathogen is initiated
what is the main issue with complement system
(brief)
if not regulated can lead to chronic inflammation
And many other diseases
how can complement system be regulated?
Intrinsically many of the complement are labile so have short half lifes
also regulatory proteins can help to enhance the breakdown process
which of these is not a complement - regulatory protein?
A C4 - BP
B Factor H
C CD46
D CD8
option D
C4-BP enhances decay of c3 convertase in classic+ leptin
Factor H breaks fluid c3 convertase
CD46 inhibits c3b and c4b
how can dysregulated complement system lead to bacterial infection?
if MAC doesn’t form there is less lysis of pathogen
and less opsonisation and recruitment of neurophils
so more likely to develop infection
what diseases are complement system deficency associate with?
cancer
AMD
aHUS (anaemic)
what is unique about cancer stemming from complement system dysregulation
instead of complement system deficiency of the regulatory BP
there is high conc. of these RegBP so less MAC/pore is created so tumour cells evade issue
