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Module 3 > Introduction to SLE > Flashcards

Introduction to SLE Flashcards

1
Q

What is the gender ratio in SLE?

A

F:M 8:1

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2
Q

What are the key questions in differentiated SLE from other diseases that cause fatigue; joint pains etc?

A

Photosensitivity; Raynauds; malar rash; oral ulceration

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3
Q

What drug can cause SLE?

A

hydralazine

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4
Q

What does frothy urine indicate?

A

high protein content

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5
Q

What is classically seen in SLE with CRP and ESR?

A

normal CRP but high ESR

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6
Q

What is seen on FBC with SLE?

A

lots of paenias- low Hb; WBC; platelts

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7
Q

What antibodies are found in SLE?

A

ANA; extractable nuclear antigen; dsDNA; antiphospholipid antibodies

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8
Q

what are the antiphospholipid antibodies?

A

lupus anticoagulant; anticardiolipin; anti-glycoprotein b2

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9
Q

What is the sensitivity/specifiity of ANA?

A

high sensitivity but low specificity (if don’t have ANA don’t have lupus, but ANA doesn’t mean you have)

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10
Q

What are the cuntaeous manifestations of lupus?

A

alopecia; malar rash; oral/nasal ulcers

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11
Q

Give exanmples of extractable nuclear antigens?

A

anti-Ro; anti-La; anti-Smith

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12
Q

What proportion of lupus patients will develop lupus nephritis?

A

upto 2/3rds

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13
Q

What is the pathogenesis of lupus nephritis?

A

circulating IC deposited, complement activation, pro-inflam cytokines, infiltration of lymphocytes nad macrophages

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14
Q

How is lupus nephritis diagnosed?

A

kidney biopsy- LM; IF; EM; clinical features; serological features

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15
Q

Why may some patietns with lupus go into long term remission?

A

immune exhaustion

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16
Q

Why is vitamin D important in lupus?

A

tolerogenic for Dcs

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17
Q

How is hydroxychloroquine thought to work in SLE?

A

by affecting TLRs and TNFa which is key to DC activation

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18
Q

What is complete response in lupus nephritis?

A

proteinuria <50mg/mmol and goood renal function

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19
Q

What may be the problem with rituximab in treating SLE?

A

reduces B cells which increases BAFF levels, then when B cells come back its to a very activating envionrmnet

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20
Q

What is seen in B cells in lupus patients?

A

not increased numbers but increased proliferation and increased spontaneously secreted IgG

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21
Q

What can maybe fix the problem with rituximab in SLE?

A

giving rituximab followed by belimumab (anti-BAFF)

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22
Q

Which patients receiving rituximab get a complete reposnse?

A

those with complete peripheral B cell depletion

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23
Q

What is SLE characterised by immunlogically?

A

global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury

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24
Q

What showed that DCs are key in the pathogenesis of SLE?

A

in mouse model of lupus, DC-deficient mice exhibited less severe disease than DC-intact models

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25
Q

How do activated neutrophils die?

A

NETosis

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26
Q

What is the feed forward loop of neutrophils and NETs?

A

IFNa in SLE activate neutrophils who release NETs which then are available for TLR-directed pDC activation and IFN release which then prime further neutrophils and aid cDC maturation with autreactive T cell activation

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27
Q

How do steroids work in SLE?

A

inhibit NFkB with subsequent pDC death and reduced IFN production

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28
Q

Why may SLE patietns require higher than usual doses of steroids?

A

engagement of TLR7 and TLR9 after endosomal uptake of nucleic acid containing immune complexes promotes pDC survival and IFN production via activation of NFkB, overcoming IFN production

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29
Q

How is B cell tolerance defective in SLE?

A

at several levels both in central and peripheral selection responsible for removal of self-reactive immature B cells

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30
Q

What ultimately promotes activation and surviial of autoreactive B cells?

A

aberrant tolerance; enhanced BCR; TLR and BAFF receptor receptor signalling in lupus

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31
Q

What suggests taht the pathogenic autoantibodies are products of the gereminal centre?

A

they are high affinity; somatically mutated; Ig-switched

32
Q

How have Tfh been linked to SLE?

A

in mouse models, dysregulation of Tfh cells that promote B cell differentation in GCs is associated with SLE development

33
Q

How is BAFF realted to SLE?

A

there are increased levels of BAFF in SLE patietns and indeed correlate with disease activity

34
Q

What suggets that TLR4 and TLR2 are important in the pathogenesis of SLE?

A

expression levels in PBMCs is much higher, TLR4 deficiency downregulated the production of autoantibodies and attenuates renal injury in mouse lupus ; TLR4 upregulation is a potent trigger to induce lupu-like autoimmune disease

35
Q

How may TLR4 and TLR2 be involved in pathogenesis?

A

by binding HMGB1 which binds with DNA and thereby stimulating pathogenic anti-DNA autoantibodes

36
Q

What is the effect of TLR engagaement on B cells?

A

increases BCR signalling and antibody production

37
Q

What is the effect of IFNa on DCs?

A

increase BAFF secretion and activation

38
Q

What is SLE?

A

an autoimmune disease that can affect many organs including hte skin, joints CNS and kidneys typically affecting women of child-bearing age

39
Q

What are the potential environmental factors that predispose to SLE?

A

UV light exposure; EBV infection; endogenous retroviral sequences; drugs and hormonal factors—result in immune dysregulation of cytokines; T cells; B cells and macrophages

40
Q

What is the only drug to be approved for SLE in the past 60 years?

A

belimumab

41
Q

What makes drug trials in SLE difficult?

A

the heterogeneity of SLE–due to defects in many partso the immune cascade?

42
Q

What is the concordance rate for SLE in MZ twins?

A

25%

43
Q

Give an example of a other mutations aart from in complement which GWAS studies have implicated in SLE?

A

interferon regulatory factor 5- increased levels of type I IFN

44
Q

What suggests a role for hormones in SLE?

A

female preponderance; when patients with SLE are given HRT, risk of flare increases

45
Q

What ethnicity have higher rates of SLE?

A

afro-caribbeans

46
Q

What is one of the strongest predicotrs of increased mortality risk with SLE?

A

lupus nephritis

47
Q

What are the main causes of mortality in SLE patietns?

A

infection; CVD (esp. later in disease course)

48
Q

What suggests that the development of an inappropriate immune response is not the only mechanism in developing SLE?

A

production of antibodes against nucliec acid containing cellular particles is common in the general population

49
Q

What are the determinants of progression to SLE ?

A

genetic susceptibility factors that shape immune function; sex and stochastic factors that affect responses to exogenous or endogenous triggers

50
Q

What type of infection do the immune alterations observed in SLE show similarity to?

A

chronic immune response assocaited with models of viral infection

51
Q

What immune alterations seen in SLE are similar to chronic virus infection?

A

sustained expression of type I IFNs; increased and sustained production of pro-inflam mediatorsl; altered expression of PDL1; TRAIL; shift in T cell differentation towards Tfh cell

52
Q

What is the result of the immune alterations seen in SLE that are similar to chronic viral infection?

A

sustained and poorly regulated macrophage activation; impaired T cell function and regulation of cell death; excessive B cell differentiation; production of autoantibodies and immune complexes and widespread tissue and organ inflam and damage

53
Q

Apart from its role in clearance of apoptotic cell debris, what other protective role may C1q play in SLE?

A

directing stimulatory ICs to monocytes rather than IFNa-producing plasamcytoid DCs

54
Q

What suggests taht an X-chromosome gene-dose effect is an important contributor in SLE susceptibility?

A

Klinefelter syndrome is increased 14-fold amon men with SLE compared with men without SLE (47XXY)

55
Q

What may be the relationship between EBV and SLE?

A

T cell repsonse may be defective- increased EBV infected mononuclear cells nad increased EBV DNA; contribute to innate immune system activation and B cell differentiaion

56
Q

What led to the suggest that a viral infection may trigger SLE?

A

clinical manifestations present at diagnosis- joint pains and fatigue

57
Q

What do antibodies specific for EBNA1 corssreact with?

A

dsDNA- EBV can induce an autoimmune repsonse (common conformational epitopes)

58
Q

Why do UV and drugs contribute to the pathogenesis of SLE?

A

UV induces DNA breaks that may alter gene expression; generate nucleic acid fragments or lead to apoptotic or necrotic cell death; hydralazine results in altered DNA methylation

59
Q

How do nucleic acid containing immune complexes contribute to innate immune system activation?

A

activate nucleic acid -repsonsive endosomal TLRs leading to type I IFN procuction

60
Q

What confirms the role of immune complexes in type I IFN procuction?

A

increased expression of type I IFN0induible genes in PBMCs; autoantibodes with specific for DNA-binding proteins are strongly associated with high IFN signature

61
Q

What is the effect of IFNa on driving disease?

A

activated DCs and promotes their capacity to present antigens to T cells

62
Q

What dysfunctions in T cells have been documented in SLE patients?

A

deficiencies or alterations in T cell signalling, in the production of cytokines, in proliferation and regulatory functions - express CD40L after activation and maintain this expression longer than normal- extra help for activation and differentiation of B cells

63
Q

What type of T cell is increased in SLE?

A

Tfh cells-rpomote differentation of autoantibody-producing B cells

64
Q

What is seen in populations of Treg and Th17 in SLE?

A

reduced Tregs; increased Th17 and increased IL-17–functional consequences aren’t clear

65
Q

Why might there be reduced Tregs in SLE?

A

decreased production of IL-2 is characteristic of T cells

66
Q

What B cell factors are increased in SLE?

A

IL-21 and BAFF

67
Q

Give examples of some difference in B cells in SLE compared with normal?

A

decreased expression of inhibitory Fc receptor; altered cytokine production when engaged by nucleic-acid containing immune complexes

68
Q

Why are the anti-Sm and anti-Ro antibodies refractory to therapy?

A

produced by long-lived plasma cells which are maintained by chemokines and stromal cell products in protective bone marrow niches

69
Q

What is a protective role of antibodies in SLE?

A

natural IgM react with apoptotic cells and inihbit their activation through TLRs

70
Q

What may contribute to the increased CVS risk in SLE?

A

icnreased IFNs may contribute to impaired endotehlial repair after vascular damage; increased adgesion molecules

71
Q

Which patients is belimumab more effective in?

A

patients with higer disease activity, anti-dsDNA positivity and low complement levels

72
Q

What suggests taht low dose glucocorticoid regimes should be used, eve in renal SLE?

A

reduce steroid comorbidities and patietns treated with lower-dose steroids do not have worse sytmpoms

73
Q

Why is ritixumab an enigma?

A

several case reports have suggested benefit in resistant lupus nephritis but RCT have showed no benefit- the way the trial was done?

74
Q

What are some future strategies in SLE?

A

early detection of damage- new biomarkers eg urinary VCAM1 which correlates with renal damage and activity; or TWEAK which reflects renal flares

75
Q

What is the lipid paradox in SLE?

A

CVD risk can be higher in those with lower total and LDL cholesterol- uncertainty about which parameters are best to modify

76
Q

Give examples of agents in clinical development for SLE?

A

anti-CD22; IFN atagonists; IL-6 and blockers

Module 3 (33 decks)

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