SLE Flashcards
What type of condition is SLE?
Systemic autoimmune disease
Which population does SLE affect mostly?
Women
Between ages of 15-40
Which organs does SLE affect?
This is a truly systemic disease
Affects all the organs of the body
CNS Blood Heart Kidney Skin Foetus
How common is SLE?
Affects 1 in 1000 people
What defines the presentation of SLE?
The autoantibodies formed
What are the main organs affected by SLE?
Skin
Kidneys
Blood
What are the symptoms of SLE that affects the skin?
Butterfly rash
Photosensivity
Hair loss
What are the symptoms of SLE that affects the kidney?
Kidney failure
What are the symptoms of SLE that affects the blood?
Anaemia
Low white blood cells
Low platelets
What causes the presentation of disease in SLE that affects the skin?
Deposition of IgG and complement in the skin
What causes the presentation of disease in SLE that affects the kidney?
Deposition of immunoglobulins and complement in the glomeruli
Leads to protein leaking into the urine
What causes the presentation of disease in SLE that affects the blood ?
Antibodies to blood cells
What are the treatments of SLE affecting the skin?
Creams
Mild immunosuppression
What are the treatments of SLE affecting the kidneys?
High dose steroids
Immunosuppressants
Death or dialysis if not treated
What are the treatments of SLE affecting the blood?
High dose steroids
Immunosuppressants
What is a diagnostic criteria used to differentiate SLE from other autoimmune conditions?
Deposition of antibodies in the skin and kidneys
What is the diagnostic feature of lupus in the blood?
Depletion of complement in the serum
Due to its recruitment to tissues
How do we know lupus is an autoimmune disease?
It is responsive to immunosuppressants
What are the majority of SLE treatments based on?
Potent non-specific immunosuppressive agents
Steroids
Cyclophosphamide
Mycophenolate `
What is the disadvantage of current therapies for SLE?
Have side-effects like weight gain and diabetes
Not all the patients are responsive
How do we know autoantibodies are essential in SLE?
Levels rise and fall according to disease activity
Antibodies are found in inflamed tissues
Some treatments that target the autoantibodies work
Which elements of the immune system play a role in SLE?
B cells
T cells
Complement
Cytokines
Phagocytosis
What is the role of B cells in SLE?
Produce autoantibodies
Antigen presenting cells
What is the role of T cells in SLE?
T cell clones only found in SLE patients respond to histone peptides
Interact with B cells to stimulate the production of high affinity autoantibodies
What is the role of Treg cells in SLE?
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
What are the markers for Treg cells?
Foxp3
CD25
What is the role of phagocytosis in SLE?
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
What is the role of complement in SLE?
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
What are the roles of cytokines in SLE?
Important in interactions between T cells, B cells and antigen presenting cells
How do we know that B cells are involved in SLE?
Treatments against B cells are effective
Mouse models with B cell knockout do not get SLE
How do we know that T cells are involved in SLE?
Some drugs targeting T cells have been effective at treating SLE
How do we know that phagocytosis is involved in SLE?
Herrman experiment
What is the cytokine profile of SLE patients like?
There is no one cytokine that has a definitive causative role in the disease pathogenesis
Different manifestations have different cytokine profiles
What are important cytokines in SLE?
TNF-a
IL-10
IL-17
a-IFN
What treatments effectively reduce SLE presentation by targeting B cells?
Rituximab
Belimumab
Abetimus
How does Rituximab target B cells?
Targets CD20
How does Belimumab target B cells?
BLyS is an important protein that allows B cell survival
Blocking this will deplete the B cell population
Example of a drug targeting B cells that was not successful
LJP394
Depletes only B cells producing high-affinity anti-dsDNA antibodies
Clinical trials showed this was not successful
How does LJP394 kill B cells?
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
Why might some clinical trials erroneously conclude a drug is ineffective?
The sample size is not big enough
Describe the T and B cell interaction
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
What molecule do T and B cells react to in SLE?
Nucleosome
Why do T and B cells react to nucleosomes?
Contain factors both B and T cells react to
T cells react to histones
B cells react to the dsDNA
What two reactions happen upon binding with the nucleosome?
Antigen-dependent
Surface receptor dependent
Which two drugs drugs target the T-B cell interaction in SLE?
anti-CD40 ligand
Abatacept
How does Abatacept effectively block the T-B cell interaction?
Binds the B7 co-receptors on the APCs with the immunoregulatory CTLA-4 molecule
Causes immunosuppression
What does the waste disposal hypothesis describe?
The reason the waste disposal mechanism is deficient in SLE patients is because of the phagocytes
How was Herrman’s experiment conducted?
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
What happens when the SLE patients are not able to phagocytose material properly?
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
Why is SLE so rare?
Involves the pathogenesis of both tolerance and waste disposal mechanisms
What are the two roles of complement in SLE?
Complement helps to clear immune complexes, prevents SLE
When lupus is established, complement deposition in tissue is harmful
How was it proven that complement was important in preventing SLE?
Icelandic woman lacking C2
Was injected with fresh serum containing C2
Her status improved by improving her waste disposal mechanisms
What is the role of cytokines in SLE?
No clear role
High variability of symptoms in SLE
Why is it hard to investigate cytokines and their roles in SLE?
Interact with each other
Measuring the blood levels of one cytokine will not provide the whole picture of the underlying pathologic process
Which cytokines have been targeted for SLE therapy?
TNF-a
IL-10
IL-17
IFN-a
What is the role of TNF-a in SLE?
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
When do we use anti-TNF treatment?
When patient presents with both SLE and RA and RA is the predominant condition
What is the role of IL-10 in SLE?
Cytokine is raised in patients with SLE
Concentration correlates with disease activity
Definitive involvement in disease progression
anti-IL-10 has shown clinical benefit
What is the role of IL-17 in SLE?
Stimulates the influx of affected cells into inflamed kidneys
Stimulates B cells
What is the role of IFN-a in SLE?
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
