Pathogenesis of autoimmune disease Flashcards
What is rheumatoid arthritis?
Chronic joint inflammation in the synovium that can result in joint damage
What are the main autoantibodies of rheumatoid arthritis?
Rheumatoid factor
Anti-cyclin citrullinated peptide (Anti CCP antibodis0
What is ankylosing spondylitis?
Chronic spinal inflammation in the enthesis that can result in spinal fusion and deformity
What is the enthesis?
Where a ligament inserts to the bone
How does ankylosing spondylitis tend to present?
Spontaneously but it’s associated with a strong genetic predisposition
Where are enthuse found in the spine?
Between the vertebrae- in the annulus fibrosis, entheses join it to the bone above and bone below
What is the normal structure of an intervertebral disc?
They have a soft nucleus pulpous and tough fibrous annulus fibrosus around the outside
What can the inflammation between the vertebral bodies lead to if untreated?
Calcified fusion of the vertebrae
What are ankylosing spondylitis cases often referred to as?
Seronegative spondyloarthropathies
Why are they seronegative?
There are no autoantibodies
What is systemic lupous erythematous (SLE)
Chronic tissue inflammation (of sterile tissue- not infected) in the presence of auto-antibodies
How do the autoantibodies lead to inflammation in SLE?
They activate the complement via the classical pathway- inflammatory cells have Fc receptors so if autoantibodies are mobilised on these, you can trigger inflammation
Why do you see widespread inflammation in SLE?
Formation of immune complexes doesn’t immediately indicate that one particular part of the body is inflamed
In lupus you get widespread organ inflammation but which organs are commonly affected?
Skin and kidneys
What autoantibodies is lupus associated with?
Antinuclear antibodies
Antidouble stranded DNA antibodies
What family of diseases does lupus belong to?
Connective tissue diseases
What does Sjogrens syndrome attack?
Exocrine glands
For the aforementioned autoimmune diseases, where are the strongest genetic associations within?
Within the MHC which is encoded by the HLA gene locus
What does MHC class 1 have a genetic association with?
Ankylosing spondylitis
What does MHC class II have a genetic association with?
Rheumatoid arthritis and SLE
What is the MHC molecule responsible for?
Antigen presentation
Which T cells recognise antigens presented by MHC class I?
CD8+ T cells- cell killing
Which T cells recognise antigens presented by MHC class II?
CD4+ T cells- antibody response
Why is MHC so important in antigen recognition?
T cells can only see an antigen when it’s being presented by MHC
What happens in regards to MHC in an autoimmune disease?
You get self antigen binding to the MHC molecule and it’s able to trigger an immune reaction
What HLA is involved in ankylosing spondylitis?
HLA-B27- it allows the binding of some sort of antigen and triggering of class 1 response
When rats were made to express HLA-B27, what happened?
Ankylosing spondylitis type effects
What was thought to be the reason for ankylosing spondylitis type effects in the rats?
Interactions between CD8+ T cells and HLA-B27 molecules
Why was the theory about CD8+ T cells proved wrong?
Experiment was repeated but CD8+ T cells were removed and rats still showed disease so ankylosing spondylitis is independent of CD8+ T cells
What new theory was suggest for the link between HLA-B27 and ankylosing spondylitis?
HLA-B27 has a propensity to misfold which causes cellular stress that triggers IL-23 release and triggers IL-17 production by:
Adaptive immune cells e.g. CD4+ and innate immune cells e.g. CD4- and CD8-
Why don’t you get inflammation everywhere in ankylosing spondylitis?
Chemical stress is more likely to occur in innate immune cells and these innate cells are present in entheses
What are antinuclear antibodies?
Directed against the nucleus
What is the amount of autoantibodies used for?
To give an estimate of the severity of disease
How many nuclear antigens are there that react with anti-nuclear antibodies in lupus and what does this mean?
<100 nuclear antigens of a huge number so lupus ANAs only react with relatively few
How is the presence of autoantibodies detected?
By permeabilising cells on a glass slide to allow entry of autoantibodies
The patient’s serum is then placed over the cells and if there are antinuclear antibodies, they will bind to the nucleus and can be detected by fluorescence
What are the complement levels and serum levels of anti-ds-DNA antibodies like in a lupus patient?
Low complement
High serum levels of anti-ds-DNA antibodies
What does apoptosis normally cause in terms of antigens?
Apoptosis results in translocation of certain nuclear antigens to surface of apoptotic cell so nuclear antigens are accessible to immune response
What happens in lupus in terms of apoptotic cells?
They aren’t cleared normally so this impaired clearance enables abnormal presentation to the immune system and the immune response is amplified through B cells
What is biological therapy?
Manipulation of cytokines and switching them off by using monoclonal antibodies
What cytokines are there and what effect do they have?
y-IFN- activates macrophages
IL-1- activates T cells, fever and pro-inflammatory
IL2- Activates T and B cells
IL-6- Activates B cells, acute phase response
TNF-alpha- Similar to IL-1 but more destructive
Why is anti-TNF treatment so successful and commonly used?
TNF alpha is produced by many cells- mainly macrophages and anti-TNF treatment is so successful because these macrophages that produce TNF-alpha are causing many of the negative effects
What negative effects does TNF alpha that is released by activated macrophages have?
Proinflammatory cytokine release Hepcidin induction PGE2 production Osteoclast activation Chondrocyte activation Angiogenesis Leukocyte accumulation Endothelial cell activation Chemokine release
Apart from TNF alpha blockade what else is available in clinics?
IL-6 and IL-1
What else can be done in addition to cytokine blockade?
We can deplete B cells in rheumatoid arthritis by parenteral administration of an antibody that acts against a B cell surface antigen- this antibody is called rituximab
What effect will blocking RANKL have?
Decreased osteoclast activity
What is RANKL produced by?
T cells and synovial fibroblasts
What upregulates RANKL?
Interleukin-1, TNF-alpha
Interleukin-17
PTH-related peptide
What does RANKL stand for?
Receptor activator of nuclear factor kB ligand
What is denusomab?
Monoclonal antibody against RANKL
What is denusomab used to treat?
Osteoporosis Bone metastases Multiple myeloma Giant cell tumours -Not rheumatoid arthritis
What is B cells hyperactivity a key feature of?
SLE
What biological therapies target B cells in treatment of SLE?
Rituximab- chimeric anti-CD20 antibody that is used to deplete B cells
Belimumab- Monoclonal antibody against a B cell survival factor called BLYS (B-lymphocyte stimulator)
What are prostaglandins?
Lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells
What are prostaglandins synthesised from?
Essential fatty acids: phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes
What are the two pathways that arachidonic acid enters?
Cyclooxygenase pathway- Arachidonic acid -> Prostaglandins
Lipooxygenase pathway- Arachidonic acid -> leukotrienes
What do glucocorticoids inhibit that is involved with prostaglandins?
Phospholipase A2
What do NSAIDs?
COX
What are NSAIDs used to generally deal with?
Pain
