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Molecular Basis of Disease > SLE > Flashcards

SLE Flashcards

1
Q

What type of condition is SLE?

A

Systemic autoimmune disease

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2
Q

Which population does SLE affect mostly?

A

Women

Between ages of 15-40

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3
Q

Which organs does SLE affect?

A

This is a truly systemic disease

Affects all the organs of the body

CNS 
Blood 
Heart 
Kidney 
Skin 
Foetus
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4
Q

How common is SLE?

A

Affects 1 in 1000 people

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5
Q

What defines the presentation of SLE?

A

The autoantibodies formed

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6
Q

What are the main organs affected by SLE?

A

Skin

Kidneys

Blood

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7
Q

What are the symptoms of SLE that affects the skin?

A

Butterfly rash

Photosensivity

Hair loss

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8
Q

What are the symptoms of SLE that affects the kidney?

A

Kidney failure

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9
Q

What are the symptoms of SLE that affects the blood?

A

Anaemia

Low white blood cells

Low platelets

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10
Q

What causes the presentation of disease in SLE that affects the skin?

A

Deposition of IgG and complement in the skin

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11
Q

What causes the presentation of disease in SLE that affects the kidney?

A

Deposition of immunoglobulins and complement in the glomeruli

Leads to protein leaking into the urine

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12
Q

What causes the presentation of disease in SLE that affects the blood ?

A

Antibodies to blood cells

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13
Q

What are the treatments of SLE affecting the skin?

A

Creams

Mild immunosuppression

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14
Q

What are the treatments of SLE affecting the kidneys?

A

High dose steroids

Immunosuppressants

Death or dialysis if not treated

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15
Q

What are the treatments of SLE affecting the blood?

A

High dose steroids

Immunosuppressants

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16
Q

What is a diagnostic criteria used to differentiate SLE from other autoimmune conditions?

A

Deposition of antibodies in the skin and kidneys

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17
Q

What is the diagnostic feature of lupus in the blood?

A

Depletion of complement in the serum

Due to its recruitment to tissues

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18
Q

How do we know lupus is an autoimmune disease?

A

It is responsive to immunosuppressants

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19
Q

What are the majority of SLE treatments based on?

A

Potent non-specific immunosuppressive agents

Steroids
Cyclophosphamide
Mycophenolate `

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20
Q

What is the disadvantage of current therapies for SLE?

A

Have side-effects like weight gain and diabetes

Not all the patients are responsive

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21
Q

How do we know autoantibodies are essential in SLE?

A

Levels rise and fall according to disease activity

Antibodies are found in inflamed tissues

Some treatments that target the autoantibodies work

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22
Q

Which elements of the immune system play a role in SLE?

A

B cells

T cells

Complement

Cytokines

Phagocytosis

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23
Q

What is the role of B cells in SLE?

A

Produce autoantibodies

Antigen presenting cells

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24
Q

What is the role of T cells in SLE?

A

T cell clones only found in SLE patients respond to histone peptides

Interact with B cells to stimulate the production of high affinity autoantibodies

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25
Q

What is the role of Treg cells in SLE?

A

Regulate or suppress the immune response

Some claim the Treg levels are reduced in SLE patients

Some claim Tregs also become activated by nucleosomes and help suppress the immune reaction

26
Q

What are the markers for Treg cells?

A

Foxp3

CD25

27
Q

What is the role of phagocytosis in SLE?

A

Waste disposal hypothesis

Apoptotic cells produce blebs, presenting their intracellular contents on the surface

There is a problem with phagocytosis of these blebs in SLE

28
Q

What is the role of complement in SLE?

A

C3 and C4 are key in the inflammatory process

However, they also help the clearing of immune complexes through the waste disposal mechanism

So they have dual effect on SLE, helpful at first but worsen the disease progression further along the disease

29
Q

What are the roles of cytokines in SLE?

A

Important in interactions between T cells, B cells and antigen presenting cells

30
Q

How do we know that B cells are involved in SLE?

A

Treatments against B cells are effective

Mouse models with B cell knockout do not get SLE

31
Q

How do we know that T cells are involved in SLE?

A

Some drugs targeting T cells have been effective at treating SLE

32
Q

How do we know that phagocytosis is involved in SLE?

A

Herrman experiment

33
Q

What is the cytokine profile of SLE patients like?

A

There is no one cytokine that has a definitive causative role in the disease pathogenesis

Different manifestations have different cytokine profiles

34
Q

What are important cytokines in SLE?

A

TNF-a

IL-10

IL-17

a-IFN

35
Q

What treatments effectively reduce SLE presentation by targeting B cells?

A

Rituximab

Belimumab

Abetimus

36
Q

How does Rituximab target B cells?

A

Targets CD20

37
Q

How does Belimumab target B cells?

A

BLyS is an important protein that allows B cell survival

Blocking this will deplete the B cell population

38
Q

Example of a drug targeting B cells that was not successful

A

LJP394

Depletes only B cells producing high-affinity anti-dsDNA antibodies

Clinical trials showed this was not successful

39
Q

How does LJP394 kill B cells?

A

Makes a molecule with 4 DNA strands bound to a backbone expressing B cell specific epitopes

No T cells are stimulated therefore

Causes the apoptosis of B cells due to the lack of co-stimulation

40
Q

Why might some clinical trials erroneously conclude a drug is ineffective?

A

The sample size is not big enough

41
Q

Describe the T and B cell interaction

A

T cell presents antigen via TCR to the B cell MHC

Second connection between surface molecule on T and B cells (CD40 and CD40L)

This costimulation leads to B cells making the antibody and T cells making cytokines that activate the B cell further

42
Q

What molecule do T and B cells react to in SLE?

A

Nucleosome

43
Q

Why do T and B cells react to nucleosomes?

A

Contain factors both B and T cells react to

T cells react to histones

B cells react to the dsDNA

44
Q

What two reactions happen upon binding with the nucleosome?

A

Antigen-dependent

Surface receptor dependent

45
Q

Which two drugs drugs target the T-B cell interaction in SLE?

A

anti-CD40 ligand

Abatacept

46
Q

How does Abatacept effectively block the T-B cell interaction?

A

Binds the B7 co-receptors on the APCs with the immunoregulatory CTLA-4 molecule

Causes immunosuppression

47
Q

What does the waste disposal hypothesis describe?

A

The reason the waste disposal mechanism is deficient in SLE patients is because of the phagocytes

48
Q

How was Herrman’s experiment conducted?

A

Apoptotic cells were formed by modifying lymphocytes (from healthy and normal subjects) to become apoptotic

These were put into mixes of phagocytes of the healthy and normal subjects

It was shown that when the SLE apoptotic cells were mixed with healthy phagocytes, normal phagocytosis was observed. Therefore the problem was not with the apoptotic cells

When healthy apoptotic cells were mixed with phagocytes of SLE patients however, phagocytosis was abnormal. This proved that the problem was with the phagocytes

49
Q

What happens when the SLE patients are not able to phagocytose material properly?

A

These materials carrying surface antigens is carried to the germinal centers of the lymph nodes

There it is presented to T cells, leading to the stimulation of both T and B cells

50
Q

Why is SLE so rare?

A

Involves the pathogenesis of both tolerance and waste disposal mechanisms

51
Q

What are the two roles of complement in SLE?

A

Complement helps to clear immune complexes, prevents SLE

When lupus is established, complement deposition in tissue is harmful

52
Q

How was it proven that complement was important in preventing SLE?

A

Icelandic woman lacking C2

Was injected with fresh serum containing C2

Her status improved by improving her waste disposal mechanisms

53
Q

What is the role of cytokines in SLE?

A

No clear role

High variability of symptoms in SLE

54
Q

Why is it hard to investigate cytokines and their roles in SLE?

A

Interact with each other

Measuring the blood levels of one cytokine will not provide the whole picture of the underlying pathologic process

55
Q

Which cytokines have been targeted for SLE therapy?

A

TNF-a

IL-10

IL-17

IFN-a

56
Q

What is the role of TNF-a in SLE?

A

It is believed that this cytokines have dual roles in SLE

Some studies have shown anti-TNF therapy is good, since injection of TNF into a knockout mouse protected against SLE.

Some models have shown that TNF-a deposits in kidneys, and therefore is not protective. Also, human trials of anti-TNF treatment killed 2 patients

57
Q

When do we use anti-TNF treatment?

A

When patient presents with both SLE and RA and RA is the predominant condition

58
Q

What is the role of IL-10 in SLE?

A

Cytokine is raised in patients with SLE

Concentration correlates with disease activity

Definitive involvement in disease progression

anti-IL-10 has shown clinical benefit

59
Q

What is the role of IL-17 in SLE?

A

Stimulates the influx of affected cells into inflamed kidneys

Stimulates B cells

60
Q

What is the role of IFN-a in SLE?

A

Microarray studies have shown the increased expression of interferon-regulated genes in white cells of SLE patients

Expression of these interferon-regulated genes leads to a higher chemokine concentration in the blood

Scientists used the chemokine concentration of the blood to diagnose SLE, a higher chemokine score was related to SLE diagnosis

Molecular Basis of Disease (28 decks)

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