Pathogenesis of Autoimmune Disease Flashcards
What happens in rheumatoid arthiritis?
- Chronic joint inflammation that can result in joint damage
- If untreated -> pain, discomfort and destruction of the joint
- Site of inflammation is the synovium (lining of synovial joints) - chronic sinovitis
Which antibodies are associated with rheumatoid arthritis?
Rheumatoid factor
Anti-cyclic citrullinated peptide (CCP) antibodies
What is an enthesis?
where the tendon inserts into the bone
What happens in ankylosing spondylitis?
- Chronic spinal inflammation that can result in spinal fusion and deformity
- Untreated -> pain and inflammation of the spine, bony fusion of the vertebrae
- Patients have an exaggerated thoracic kyphosis
- Site of inflammation is the enthesis (joints vertebrae together)
- ENTHESITIS -> calcium deposition and BONY FUSION
- No autoantibodies (‘seronegative’)
What are examples of seronegative spondyloarthropathies?
- Ankylosing spondylitis
- Reiters syndrome and reactive arthritis
- Arthritis associated with psoriasis (psoriatic arthritis)
- Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
What happens in systemic lupus erythematosus?
- Chronic tissue inflammation in the presence of antibodies directed against self antigens
- PATHOGENESIS IS DRIVEN BY AUTOANTIBODIES AND IMMUNE COMPLEXES (antibody + antigen)
- antibodies are referred to anti-nuclear antibodies
- Multi-site inflammation but particularly the joints, skin and kidney
- Immune complexes trigger inflammation by activating complement and binding to Fc receptors for antibody (can be inflammatory and anti-inflammatory). Because immune complexes can circulate all over the body and deposit in various places, the problems that occur in SLE are very widespread
What are examples of connective tissue diseases?
- Systemic lupus erythematosus
- Inflammatory muscle disease: polymyositis, dermatomyositis
- Systemic sclerosis
- Sjogren’s syndrome
- A mixture of the above: ‘Overlap syndromes’
What is a HLA?
human leukocyte antigen
encoded in a gene locus called the major histocompatibility complex
They encode surface proteins. There are various serotypes.
What are the types of HLA moleucules?
MHC class I : HLA - A,B.C
MHC class II : HLAA - DR molecule
Which class of MHC are SLE, rheumatoid arthritis and ankylosing spondylitis associated with?
SLE and rheumatoid arthritis - MCH Class II
ankylosing spondylitis - MCH Class II
What is the role of MCH Class I and II molecules?
present antigens to T cells
- Class I HLA molecules are present on ALL nucleated cells, and bind endogenous antigens - they are recognised by CD8+ T-cells
- Class II HLA molecules are present on APCs (dendritic cells, B cells, macrophages etc.) - generally present exogenous molecules, and recognised by CD4 T-cells
What antibodies are associated with SLE?
- Antinuclear antibodies
- Anti-double stranded DNA antibodies
What do antinuclear antibodies react to?
antigen deep in the cell, within the nucleus
What’s the next step if ANA is positive in the lab?
perform further tests to determine which type of ANA it is
- Typically these include screening for: Anti-Ro, Anti-La, Anti-centromere, Anti-Sm, Anti-RNP, Anti-ds-DNA antibodies and Anti-Scl-70
Cytoplasmic antibodies include:
- Anti-tRNA synthetase antibodies
- Anti-ribosomal P antibodies
What does a sick lupus patient commonly have?
- Low complement levels
- High serum levels of anti-ds-DNA antibodies
How are nuclear antigens accessible to the immune response?
Apoptosis results in the translocation of certain nuclear antigens to the surface of the apoptotic cell
Describe the pathogenesis of lupus
In lupus, apoptotic cells are not cleared normally so this impaired clearance enables abnormal presentation to the immune system.
The immune response is amplified through the B cells.
The autoantibodies are normally detectable in patients about 10 year before the symptoms start to appear.
What are the types of CD4+ cells? What do they secrete?
T helper cell subsets include: Th1, Th2 and Th17
Th1 cells secrete IL-2 and γ-IFN and response is important in CD8+ cytotoxicity and macrophage stimulation
Th2 cells secrete IL-4 (IgE responses), IL-5 (eosinophils), IL-6 (B cells to plasma cells) and IL-10 (inhibit macrophage response)
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
What is biological therapy?
cytokines from t helper cells can be manipulated and switched off by monoclonal antibodies
Whats the dominant pro-inflammatory cytokine in rheumatoid arthritis?
TNF alpha (from activated macrophages)
What does TNF-a do?
- Activate osteoclasts -> bone erosion
- Activate synoviocytes -> joint inflammation and swelling (due to increased production of synovial fluid)
- Activate chondrocytes -> cartilage degradation
- PGE2 production
- angiogenesis
- leukocyte accumulation
- endothelial cell activation
- chemokine release
What is rituximab?
antibody against a B cell surface antigen, CD20
In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) - rituximab
What is RANKL?
receptor activator of nuclear factor kB ligand
Produced by T cells and synovial fibroblasts in rheumatoid arthritis
- Acts to stimulate osteoclast formation (osteoclastogenesis) - binds to osteoclast precursor
- Up-regulated by: Interleukin-1, TNF-a, Interleukin-17 and PTH-related peptide
- Interleukin-17 is a potent action on osteoclastogenesis via RANKL-RANK pathway
What antagonises RANKL?
decoy receptor – osteoprotegerin (OPG)
What is denosumab?
a monoclonal antibody against RANKL (isn’t used in rheumatoid arthritis)
-indicated for osteoporosis, bone metastases, multiple myeloma and giant cell tumours treatment
What therapies are used to treat SLE?
Rituximab – a chimeric anti-CD20 antibody used to deplete B cells
- anecdotal therapeutic success rituximab, clinical trials unsuccessful to date
Belimumab – a monoclonal antibody against a B cell survival factor call BLYS
- BELIMUMAB is a recombinant fully human IgG1 monoclonal antibody against BLYS (also termed BAFF)
- inhibits activity of BAFF resulting in impaired B cell survival and reduced B cell numbers
- BAFF = B cell activating factor of the tumour necrosis factor family
- BLYS = B-lymphocyte stimulator
What are prostaglandins?
lipid mediators of inflammation that act on platelets, endothelium, uterine tissue and mast cells.
They are synthesized from essential fatty acids: phospholipase A2 generates arachidonic acid from diacylglycerol in cell membranes.
What are the two pathways for arachadonic acid?
Cyclooxygenase pathway: arachidonic acid prostaglandins
- Prostaglandins mediate e.g. vasodilatation (PGI2/prostacyclin, via receptor called IP), inhibit platelet aggregation (PGI2), bronchodilation (e.g. PGE2 acting via receptor called EP2, PGI2), uterine contraction (PGF2alpha).
Lipooxygenase pathway: arachidonic acid -> leukotrienes
- Leukotrienes mediate leucocyte chemotaxis (LTB4) and smooth muscle contraction, bronchoconstriction and mucus secretion (LTC4, LTD4, LTE4 via CysLT1 receptors)
What are the pros and cons of NSAIDS?
Benefits: analgesia, anti-pyretic, anti-inflammatory and anti-platelet (thromboxane A2)
- generally used to deal with pain
Unwanted effects: e.g. asthma exacerbation, gastro-intestinal ulcers, thrombosis, liver and renal problems
- They are NOT effective at preventing joint damage long term
