Pathogenesis of autoimmune disease Flashcards
What is rheumatoid arthritis?
Chronic joint inflammation that can result in joint damage - site of inflammation is the synovium: chronic synovitis
What is rheumatoid arthritis associated to?
Autoantibodies
- Rheumatoid factor
- Anti-cyclic citrullinated peptide (CCP) antibodies
What is ankylosing spondylitis?
Chronic spinal inflammation that can result in spinal fusion and deformity - site of inflammation is the enthesis (anulus fibrosus)
Spinal deformities include increased thoracic kyphosis and loss of the normal lumbar lordosis
List some seronegative spondyloarthropathies?
Seronegative - No autoantibodies
- Ankylosing spondylitis
- Reiters syndrome and REACTIVE ARTHRITIS
- Arthritis associated with psoriasis (psoriatic arthritis)
- Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
What is systemic lupus erythematosus (SLE)?
Chronic tissue inflammation in the presence of antibodies directed against self antigens - multi site inflammation but particularly the joints, skin and kidney
Immune complexes
What is SLE associated to?
Autoantibodies:
- antinuclear antibodies
- anti-double stranded DNA antibodies
( - Anti-cardiolipin antibodies
also termed anti-phospholipid antibodies and associated with risk of arterial and venous thrombosis in SLE; may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome’)
What MHCs are associated with RA, SLE and AS?
RA = HLA-DR4 SLE = HLA-DR3 AS = HLA-B27
The genes within the MHC class I (B) and class II (DR) regions encode cell surface proteins These were first recognised on human white cells – hence termed human leucocyte antigens (‘HLA’)
What is the function of MHC class I & II molecules?
They present antigens to T cells.
Draw table
E.g. antigen and HLA-B27 triggers CD8 +ve T cell response in Ankylosing Spondylitis
E.g. antigen and HLA-DR4 triggers CD4 +ve T cell response in Rheumatoid Arthritis
The antigen is peptide that can be exogenous or self.
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Which diseases have autoantibodies?
Rheumatoid arthritis - RF, anti CCP antibody
Systemic Lupus - ANA, anti-dsDNA antibodies
What are the autoantibodies in SLE?
ANA - Seen in all SLE cases, not specific for SLE
Anti-dsDNA - Specific for SLE. Serum level of antibody correlates with disease activity.
anti-cardiolipin antibodies - associated with risk of arterial and venous thrombosis in SLE.
What does a sick lupus patient commonly have?
Low complement levels - because they have been used to cause inflammation.
High serum levels of anti-ds-DNA antibodies
What is the current understanding of the pathogenesis of systemic lupus erythematosus?
Main point = causes apoptosis
1) Apoptosis leads to translocation of nuclear antigens to membrane surface
2) Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
3) B cell autoimmunity
4) Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
What are the different cytokines in rheumatology?
See slides
- CD4 +ve T helper cell subsets include: Th1, Th2 and Th17
1) Th1 cells secrete IL-2 and γ-IFN and response is important in CD8 +ve cytotoxicity and macrophage stimulation
2) Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response)
3) Th17 cells develop in response to IL-23 and secrete IL-17, a potent cytokine which triggers IL-6, IL-8, TNFα, matrix metalloproteinases and RANKL in target cells. Important in mucosal immunity but also in disease including arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis
What is TNF-alpha?
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental. Therefore it is a target for treatment
Describe the function of RANKL?
It is important in bone destruction in rheumatoid arthritis. It is produced by T cells and synovial fibroblasts in rheumatoid arthritis. Acts to stimulate osteoclast formation (osteoclastogenesis)
It binds to ligand on osteoclast precursors (RANK)
What is RANKL upregulated by?
- Interleukin-1, TNF-alpha
- Interleukin-17 - potent action on osteoclastogenesis via RANKL-RANK pathway
- PTH-related peptide
What antagonizes the action of RANKL?
Decoy receptor - osteoprotegerin (OPG)
What drug is used against RANKL?
Denosumab - Monoclonal antibodies against RANKL: indicated for treatment of osteoporosis, bone metastases, multiple myeloma and Giant cell tumours
What can be used to treat SLE?
B cell hyper-reactivity is a key feature of SLE
Rituximab – a chimeric anti-CD20 antibody used to deplete B cells
Belimumab - a monoclonal antibody against a B cell survival factor call BLYS
Describe belimumab?
Recombinant fully human IgG1 monoclonal antibody against BLYS (also termed BAFF)
BAFF = B cell activating factor of the tumour necrosis factor family BLYS = B-lymphocyte stimulator
Inhibits activity of BAFF resulting in impaired B cell survival and reduced B cell numbers
(you don’t really need to know it)
What are prostaglandins?
Lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells. They are synthesised from essential fatty acids
Phospholipase A2 –> Generates arachidonic acid from diacylglycerol in cell membranes. Arachidonic acid can enter two pathways.
1) Cyclooxygenase pathway: Prostaglandins
2) Lipooxygenase pathway: Leukotrienes
See slides
What drugs are used to counteract the effects of prostaglandins?
1) Glucocorticoids inhibit phospholipase A2
2) Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (‘COX inhibition’)
- Benefits: analgesia, anti-pyretic, anti-inflammatory and anti-platelet (thromboxane A2)
- Unwanted effects: e.g. asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems
They don’t help with bone damage
Don’t focus too much on management
