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
