Pathogenesis of Autoimmune Disease Flashcards
Define Rheumatoid Arthritis.
Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis of synovial joints
What is the site of inflammation in rheumatoid arthritis?
Synovium
What are the two main autoantibodies that are associated with rheumatoid arthritis?
Rheumatoid factor
Anti-cyclic citrullinated peptide antibody
Other than at joints, where else is synovium found?
Around tendons (tenosynovium)
Define Ankylosing Spondylitis.
Chronic spinal inflammation that can result in fusion and deformity
What is the site of inflammation in ankylosing spondylitis?
Entheses – where a ligament or a tendon inserts into bone
What family of diseases is ankylosing spondylitis a part of?
Seronegative spondyloarthropathies
Which other diseases fall into this family of diseases?
Reiter’s syndrome and reactive arthritis
Psoriatic arthritis
Enteropathic synovitis
Define Systemic Lupus Erythematosus (SLE).
Chronic tissue inflammation in the presence of antibodies directed at self-antigens
NOTE: it is inflammation of sterile tissue
Lupus causes multi-site inflammation but state some sites that are particularly badly affected.
Joints, Skin and Kidneys
What are the two autoantibodies that are associated with lupus?
Anti-nuclear antibodies
Anti-double stranded DNA antibodies
What family of diseases is lupus a part of?
Connective tissue diseases
What other diseases are part of this family?
Systemic sclerosis (diffuse and localised)
Polymyositis/Dermatomyositis
Sjogren’s syndrome
Mixed connective tissue disease
What is Sjogren’s syndrome?
An autoimmune disease that targets the exocrine glands (e.g. lacrimal glands)
What are the MHC associations of rheumatoid arthritis, ankylosing spondylitis and SLE?
Rheumatoid arthritis – HLA-DR4
SLE –HLA-DR3
Ankylosing spondylitis – HLA-B27
On which chromosome is HLA encoded?
Chromosome 6
A change in which class of MHC is associated with rheumatoid arthritis, ankylosing spondylitis and SLE?
Ankylosing spondylitis = Class 1
Rheumatoid Arthritis + SLE = Class 2
Which cells express class I MHC and which cells recognise this class of MHC?
All nucleated cells (they display endogenous antigens)
They are recognised by CD8+ T cells
Which cells express class II MHC and which cells recognise this class of MHC?
Antigen presenting cells e.g. macrophages, dendritic cells (they display exogenous antigens)
Recognised by CD4+ T cells
How does HLA-B27 cause ankylosing spondylitis?
Ankylosing spondylitis is independent of CD8+ T cells
HLA-B27 has a propensity to misfold, which causes cellular stress and triggers the release of IL-23 and IL-17 by adaptive immune cells and innate immune cells
The release of chemical mediators leads to inflammation
The cellular stress is most likely to occur in innate immune cells and these are present in the entheses – hence why ankylosing spondylitis causes enthesitis
What is the key autoantibody in:
a. Diffuse systemic sclerosis
b. Limited systemic sclerosis
c. Dermatomyositis/Polymyositis
d. Mixed connective tissue damage
a. Diffuse systemic sclerosis Anti-Scl-70 antibody b. Limited systemic sclerosis Anti-centromere antibody c. Dermatomyositis/Polymyositis Anti-tRNA transferase antibody d. Mixed connective tissue disease Anti-U1-RNP antibody
What is the difference in the specificity of the autoantibodies in SLE?
Anti-nuclear antibodies are found in all cases of SLE but isn’t specific to SLE
Anti-dsDNA antibodies are specific to SLE – serum level of this antibody correlates with disease activity
How is the presence of anti-nuclear antibodies detected?
Some cells are permeabilised so the antibodies can enter the cell andthen the patient’s serum is washed over the cells
If there are anti-nuclear antibodies, they will bind to the nuclearantigens
What are the features of a sick lupus patient in terms of complement levels and serum levels of anti-dsDNA antibodies?
Low complement levels
High serum levels of anti-dsDNA antibodies
How do antinuclear antibodies react with nuclear antigens, which are found within the nucleus?
Apoptosis leads to the translocation of nuclear antigens onto the surface of the cell so that they are accessible to the immune system
In lupus, apoptotic cells are not cleared normally
This impaired clearance enables abnormal presentation to the immune system
The immune response is amplified through B cells
State some important cytokines in rheumatology.
IL-1 – produced by macrophages and activates T cells, fever + pro-inflammatory
IL-2 – produced by T cells – activates T + B cells
IL-6 – produced by T cells – activates B cells + acute phase response
TNF-alpha – produced by macrophages – similar to IL-1 but more destructive
Gamma-IFN – produced by T cells – activates macrophages
Blockage of which cytokine with biological therapy has proven to be very effective in reducing some of the negative effects of rheumatoid arthritis?
TNF-alpha
Other than cytokine blockade, what else can be targeted to improve symptoms in rheumatoid arthritis?
B cell depletion (B cell hyperactivity is a key feature of SLE)
What is RANKL produced by and what does it do?
RANKL is produced by T cells and synovial fibroblasts
It stimulates osteoclast formation
What can upregulate RANKL production?
IL-17
IL-1
TNF-alpha
PTH-related peptide
What decoy receptor antagonises the action of RANKL?
Osteoprotegrin
Name a monoclonal antibody that targets RANKL.
Denusomab
State two drugs that deplete B cells and specify what they target.
Rituximab – anti-CD20 monoclonal antibody
Belimumab – anti-BLYS monoclonal antibody (BLYS is a B cell survival factor)
What are the effects of prostaglandins produced by COX?
Vasodilation, inhibit platelet aggregation, bronchodilation, uterine contraction
What are the effects of leukotrienes produced by lipooxygenase?
Leukocyte chemotaxis, smooth muscle contraction, bronchoconstriction, mucous secretion
What do glucocorticoids inhibit?
Phospholipase A2
