Systemic inflammation - RA pathophysiol COPY

Question 1

WHAT IS RA?

i) what type of disease is it? how is that defined?
ii) name two acute actions of cytokines? name one chronic action of cytokines
iii) how does inflammation change over time in a person with RA? what is the goal of treatment

Answer 1

i) autoimmune disease - immune response to self antigens where there is a breakdown of immune tolerance

ii) acute action of cytokines > removal of pathogen/tissue repair
chronic action of cytokines > tissue destruction

iii) there is fluctuation over time in a person with chronic inflam disease but this is always high/above threshold
- goal of treatment is to restore natural fluctuations below threshold

Question 2

CHARACTERISTICS OF RA

i) which area of the body is inflamed?
ii) does it affect men or women more? how many x?
iii) name three problems associated with RA
iv) name a co-morbidity assoc with liver, bv, brain, muscle and bone

Answer 2

i) inflammation of synovial joints
ii) affects 3x more women than men
iii) reduced QOL, disability and decreased life expectancy
iv) liver - CRP raised, bv - atherogenesis, brain - low stress tolerance, bone - low bone mineral density and fractures, muscles - insulin resistance

Question 3

CLINICAL MARKERS OF RA

i) which two markers will be raised in the blood?
ii) which two auto antibodies will be present?

Answer 3

i) raised ESR and CRP
ii) presence of rheumatoid factor and cyclic citrullinated peptide (anti-CCP) antibodies

Question 4

RHEUMATOID FACTOR

i) what portion of another antibody are these antibodies directed against? what does this lead to?
ii) what % of patients with RA are they present in
iii) are they specific for RA? is it possible for a patient to have RA and not have RF? (seronegative)
iv) do levels correlate with disease activity? do RF positive patients have more severe disease?

Answer 4

i) antibodies directed against the Fc portion of another antibody > leads to immune complex formation
ii) present in 60-70% of patients with RA

iii) not specific for RA as present in other AI diseases
- some RA patients are seronegative

iv) levels dont correlate with disease activity but RF+ patients have more severe disease

Question 5

ANTI CYCLIC CITRULINATED PEPTIDE ANTIBODY

i) whats it aka?
ii) what % of patients with RA is anti CCP found in?
iii) how specific is the test? is this antibody commonly found in healthy people?
iv) when may it be detectable in blood in relation to disease onset?
v) is anti CCP+ RA more aggressive?

Answer 5

i) aka ACPA
ii) 60-70% RA patients have anti CCP
iii) high specificity > rarely found in healthy people
iv) can be detected in blood many years before disease onset
v) anti CCP RA has a more aggresive clinical course

Question 6

CITRULLINATION

i) what is it?
ii) does it normally occur in the body? when may it be abnormal?
iii) what do anti CCP antibodies form in response to? give two examples?

Answer 6

i) process of replacing protein argenine residues with citrulline residues
ii) does normally occur but if it occurs on an unusual part of the protein then it can be recognised as foreign > antibody response
iii) anti CCP forms in response to self proteins that have been citrullinated eg keratin and fibrinogen

Question 7

ANTI CCP AND PATHOGENESIS OF RA

i) can it induce arthritis alone?
ii) what effect does it have on a mouse that already has mild synovitis?
iii) give three possible mechanisms that anti CCPs mediated RA

Answer 7

i) cant induce arthritis alone
ii) enhances development and severity of inflammation in mice when a mild synovitis is already present
iii) poss mechanisms - activation of inflam cells by anti CCP immune complexes

anti CCP mediated neutrophil cell death producing NETs

direct binding of anti CCPs to drive osteoclastogenesis

Question 8

EPIDEMIOLOGY OF RA

i) which three things contribute to AI disease?
ii) where in the world is incidence the highest?
iii) what is the concordance in monozygotic twins?

Answer 8

i) immune dysfunction, genes and environment
ii) USA
iii) 12-15% concordance

Question 9

GENETICS OF RA

i) what level of penetrance fo most genes show?
ii) is there a single gene that is necessary or sufficient?
iii) what is suscep and severity determined by?
iv) what do many of the genes involved regulate? what may this be in response to?

Answer 9

i) most genes have low penetrance
ii) no individual gene necessary or sufficient
iii) suscep and severity is det by a combination of genes
iv) genes identified may regulate the immune system - possible in response to environmental agents

Question 10

GENES ASSOCIATED WITH RA

i) what acounts for 30-50% of overall genetic risk?
ii) what is a negative regulator of antigen receptor signalling in T and B cells?
iii) how is CTLA4 implicated in RA?
iv) what two factors does A20 inhibit? how is this implicated in RA?

Answer 10

i) HLA
ii) PTPN22
iii) CTLA4 is downregulated in RA

iv) A20 inhibits NFkB and TNFa mediated apoptosis
- downregulated in RA

Question 11

HORMONES

i) what testosterone levels may be seen in men with RA?
ii) during what time can RA patients experience remission?
iii) what has early menopause been associated with?
iv) what effect do oral contraceptives have on anti CCP+ RA?

Answer 11

i) low testosterone levels
ii) RA patients may experience remission in pregnancy
iii) early menopause can be associated with increased risk of RA and RF positivity
iv) oral contraceptives can decrease risk of anti CCP+ RA

Question 12

SMOKING

i) heavy smoking can increase the risk of RA in people with which allele?
ii) what have twin studies demonstrated about gene environment interaction?
iii) what does smoking and HLA-DRB1 allele increase the risk of?

Answer 12

i) increased suscep with people who have HLA-DR4 allele
ii) twin studies show gene enviro interaction by showing effect of smoking is greater in genetically suscep indivs espec HLA DRB1 +
iii) smoking and HLA-DRB1 alleles increase risk of being anti CCP positive

Question 13

INFECTIOUS TRIGGERS OF RA

i) which two types of infection have been suggested to trigger autoimmunity?
ii) why is it hard to find evidence to prove this?
iii) what has been identified in joint tissue from RA patients? is this also found in healthy joints?
iv) is there seasonal influence on incidence of AI disease?

Answer 13

i) bacterial and viral
ii) hard to find evidence as the infection may no longer be present when disease has been established
iii) bacterial components have been ident in RA joints but also in healthy joints
iv) there is no seasonal influemce on incidence of AI disease

Question 14

OSTEOCLAST BONE EROSION

i) name five cytokines that promote osteoclast differentiation and activation
ii) what develops in the bone that becomes filled with inflammatory tissue?
iii) name two sites this is worse
iv) why is there little repair?
v) what % of patients does it affect 1 year after diagnosis

Answer 14

i) IL-17, RANKL, TNFa, IL-1 and IL-6 promote Oclast differen
ii) deep bone resorption pits develop and fill with inflam tissue
iii) worse at vulnerable sites eg 2nd and 3rd metacarpal
iv) little repair as Cks inhibit differentiation of osteoblasts
v) affects 80% of RA patients within one year of diagnosis

Question 15

what is indicated by the arrows?

Answer 15

osteoclast bone erosion

Question 16

CARTILAGE EROSION

i) which cells undergo apoptosis?
ii) which cells adhere to and invade the cartilage?
iii) which cells make MMPs? what do MMPs do? what does this lead to?

Answer 16

i) chrondrocytes undergo apoptosis
ii) fibroblasts adhere to and invade the cartilage
iii) fibroblasts make MMps > break down collagen network in the cartilage

Question 17

T CELLS IN RA

i) involvement of which antigen suggests a T cell role?
ii) name the two type of T cells that predominate in the RA synovium
iii) which T cells have been suggested to be majorly pathogenic? which IL does it release and name two things it does
iv) are Tregs found in the RA joint? are they normal?

Answer 17

i) HLA associations suggets a T cell role
ii) Th1 and Th17 predominate

iii) Th17 = pathogenic
- release IL-17 which is known to actival synovial fibroblasts and osteoclasts and favour cartilage resorption

iv) Tregs are enriched in RA joints but have a defect that can be reversed by blocking TNF

Question 18

B CELLS

i) what two types of B cell infiltrates are seen in the RA synovium?
ii) which monoclonal antibody treatment can is effective?
iii) what do B cells produce? what is this involved in?

Answer 18

i) see follicular or diffuse infiltrates in RA synovium
ii) B cell depletion using monoclonal anti CD20 is an effective treatment
iii) B cells produce cytokines that are important for antigen presentation

Question 19

NEUTROPHILS

i) what type of cell death do activated neutrophils undergo? what do they release?
ii) where are neutrophils found in relation to RA?
iii) what behaviour of neutrophils correlates with presence of anti CCP antibodies?
iv) what proteins can also be released by this process?

Answer 19

i) undergo NETosis > release nuclear chromatin
ii) neutrophils infiltrate synovial fluid
iii) enhanced NETosis correlates with prescence of anti CCP antibodies
iv) NETs release citrulinated proteins

Question 20

INNATE IMMUNE CELLS

i) name three cells that infiltrate the synovium
ii) name three key things that macrophages do in RA
iii) what are most therapies targeted towards?
iv) what does decreased macrophage infiltreation correlate with strongly?

Answer 20

i) macrophages, mast cells and NK cells
ii) MPs phagocytose, antigen present and relaase cytokines such asn TNFa, IL1/6
iii) most therapies are targeted towards MP cytokine production
iv) decrease MP infiltreation strongly correlates with degree of clinical improvement to therapy