rheumatoid and immune disorders

Question 1

what is RA

Answer 1

autoimmune disease in which the synovial lining of joints is degraded

Question 2

what is RA symptoms

Answer 2

chronic inflammation but manifest in the joints

rheumatic nodules can be seen on patient joints = joint deformation

Question 3

what are some risk factors for RA

Answer 3

smoking, alcohol, obesity
genetic = HLA DR4 postive immune = RF and anti-ccp positive

> combo of risk factors lead to disease

Why hla4???

Question 4

how is RA diagnosed

Answer 4

physical examination to see how many joints involved

serology to see if patient is postitive for acute phase reactants and inflammatory markers

Question 5

what is Rheumatoid factor?

Answer 5

family of antibodies that are produced against crystal fragment of IgG

Question 6

why is having higher levels of RF associated with poorer prognosis?

Answer 6

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

Question 7

what is anti-cyclic citrulinated peptide?

Answer 7

IgG antibodies against synovial membrane proteins

Question 8

why does anti-ccp get produced?

Answer 8

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

Question 9

what happens to synovial peptides for them to be recognised as foreign?

Answer 9

the arginine residues are converted into citrulline by peptidyl arginine deaminase

Question 10

when the immune system is activated in RA what happens?

Answer 10

inflammation leads to destruction of synovium

and then thickening of it

Question 11

how do anti-ccp antibodies get produced?

Answer 11

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

Question 12

what are acute phase reactants?

Answer 12

proteins produced by liver that show changes in serum concentration response to inflammation

so are inflammatory markers

Question 13

name some acute phase reactants

Answer 13

ESR, CRP
serum amyloid A
albumin, transferrin

Question 14

which acute phase reactants become upregulated during inflamation?
A serum amyloid A
B albumin
C CRP
D C3 complement

Answer 14

all apart from albumin become upregulated during inflammatory response

Question 15

which acute phase reactants become downregulated during inflamation?
A serum amyloid A
B albumin
C transferrin
D C3 complement

Answer 15

B and C

they become downregulated

Question 16

what is a pannus tissue?

Answer 16

its the result of synovium expansion
an extra layer of tissue seen in inflammatory diseases

Question 17

how does the pannus tissue change over RA?

Answer 17

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)

Question 18

how are osteoclasts implicated in RA?

Answer 18

they do bone reabsorption and they are highly active

so responsible for a lot of bone destruction

Question 19

what do current RA therapies focus on?

Answer 19

no cure or reverse damage

so instead manage the pain

Question 20

what happens to synoviocyte in RA (phenotype)?

Answer 20

they become hypertrophic and hyperplastic

Question 21

what are hallmarks of RA

Answer 21

rheumatic nodules - swelling of synovial membrane

elevation of specific acute phase reactants - c3, c4 complement, esr, crp, serumAA

Question 22

what do DMARDs focus on targeting?

Answer 22

target specific immune components like il-6, tnf alpha

Question 23

what is the last resort option in current RA therapy?

Answer 23

synovoectomy - surgical removal of the inflammed syonovial tissue

but underlying inflammation persists so this is
temporary alleviaiton

Question 24

why should we rotate the usage of biologics?

Answer 24

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

Question 25

as well as activating b-lymph to produce RF and anti-ccp, what do the T-cell cytokines also produce?

Answer 25

tnf-alpha and il-17 produced by t-help cell activate synoviocytes leading to RANKL peptide release

Question 26

what is RANKL?

Answer 26

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

Question 27

what are CD4+ and CD8+ cells?

Answer 27

t-helper cells

t-cytotoxic cells

Question 28

what happens to monocytes when acted upon by RANKL?

Answer 28

monocytes in blood migrate into tissue and become type 1 pro-i macrophage

they then differentiate into osteoclast

Question 29

what is frustrative phagocytosis?

Answer 29

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

Question 30

what molecule extends survival of macrophage?

Answer 30

MCL-1 a prosurvival molecule part of the BCL2 family

Question 31

what are some emerging DMARDs?

Answer 31

target the immune system mediators like CD4 and their cytokines that are released

target metabolism like reduce glycolysis, target lactate

Question 32

what is the aim of DMARDs?

Answer 32

reduce inflammation, stop the joint destruction and overall prevent disease progresssion

Question 33

what does the novel therapy schlerostin do?

Answer 33

inhibitor of wnt signalling so will enable osteoblast formation

Question 34

how is metabolism related to RA?

Answer 34

immune cells undergo metabolic shift from ox phos to glycolysis

because the synovium is highly hypoxic

Question 35

what is purpose of complement system?

Answer 35

30 different zymogens which act to amplify pro-i response

Question 36

how does the complement system destroy pathogens?

Answer 36

through the membrane attack complex which is a pore

multiple MAC disrupt the osmotic pressure of pathogen causing it to lyse

Question 37

how do the different complement system pathways differ?

Answer 37

stimulus is different

antibody, lectin, foreign surface

Question 38

why is c3 the most important complement molecule?

Answer 38

where the most activation and amplification occurs

Question 39

what is advantage of lectin pathway over classical complement pathway?

Answer 39

antibodies take time to produce so lectin pathway a quicker response to pathogen is initiated

Question 40

what is the main issue with complement system
(brief)

Answer 40

if not regulated can lead to chronic inflammation

And many other diseases

Question 41

how can complement system be regulated?

Answer 41

Intrinsically many of the complement are labile so have short half lifes

also regulatory proteins can help to enhance the breakdown process

Question 42

which of these is not a complement - regulatory protein?
A C4 - BP
B Factor H
C CD46
D CD8

Answer 42

option D

C4-BP enhances decay of c3 convertase in classic+ leptin

Factor H breaks fluid c3 convertase

CD46 inhibits c3b and c4b

Question 43

how can dysregulated complement system lead to bacterial infection?

Answer 43

if MAC doesn’t form there is less lysis of pathogen

and less opsonisation and recruitment of neurophils

so more likely to develop infection

Question 44

what diseases are complement system deficency associate with?

Answer 44

cancer
AMD
aHUS (anaemic)

Question 45

what is unique about cancer stemming from complement system dysregulation

Answer 45

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