Pathogenesis of Autoimmune Disease Flashcards
Define Rheumatoid Arthritis.
Chronic joint inflammation that can result in joint damage
Characterised by pain, stiffness + 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 (CCP) antibody
Other than at joints, where else is synovium found?
Around tendons (tenosynovium)
Define Ankylosing Spondylitis.
Chronic spinal inflammation that can result in fusion + 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 the family of Seronegative spondyloarthropathies?
Reactive arthritis
Psoriatic arthritis
Enteropathic synovitis
Define Systemic Lupus Erythematosus (SLE).
Chronic tissue inflammation in the presence of antibodies directed at self-antigens
Abnormal production of immune complexes
Lupus causes multi-site inflammation but state some sites that are particularly badly affected.
Joints, Skin + Kidneys
What are the two autoantibodies 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 the family of Connective tissue diseases?
Systemic sclerosis
Polymyositis/ Dermatomyositis
Sjogren’s syndrome
Mixed connective tissue disease
What is Sjogren’s syndrome?
An AI disease that targets 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 (display endogenous antigens)
Recognised by CD8+ T cells (results in cell killing)
Which cells express class II MHC and which cells recognise this class of MHC?
Antigen presenting cells e.g. macrophages, dendritic cells (display exogenous antigens)
Recognised by CD4+ T cells (results in antibody response)
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 + triggers release of IL-23 + IL-17 by adaptive + innate immune cells
Release of chemical mediators leads to inflammation
Cellular stress is most likely to occur in innate immune cells + these are present in the entheses: hence why ankylosing spondylitis causes enthesitis
What is the difference in the specificity of the autoantibodies in SLE?
Anti-nuclear antibodies are found in all cases of SLE but aren’t specific to SLE
Anti-dsDNA antibodies are specific to SLE: serum level correlates with disease activity
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 in SLE?
Apoptosis leads to translocation of nuclear antigens onto membrane surface so are accessible to the immune system
Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to the immune system
Leads to B cell autoimmunity
Tissue damage by antibody effector mechanisms e.g. complement activation + Fc receptor engagement
State 5 important cytokines in rheumatology.
IL-1: from macrophages; activates T cells, fever + pro-inflammatory
TNF-alpha: from macrophages; like IL-1 but more destructive
IL-2: from T cells; activates T + B cells
IL-6: from T cells; activates B cells + acute phase response
Gamma-IFN: from 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? How?
B cell depletion (B cell hyperactivity is a key feature of SLE + RA)
Antibody against CD20 cell surface antigen on B cells
What is RANKL produced by and what does it do?
Produced by T cells+ synovial fibroblasts
Stimulates osteoclast formation
Causes bone destruction in rheumatoid arthritis
What can upregulate RANKL production?
IL-17
IL-1
TNF-alpha
PTH-related peptide
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= 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 (required to generate Arachidonic acid)
What do NSAIDs inhibit?
Cyclooxygenase (required to generate prostaglandins)
What is Rheumatoid factor?
IgM antibody that recognises the Fc portion of IgG as target antigens
In which 4 rheumatological diseases are there no autoantibodies?
Osteoarthritis
Reactive arthritis
Gout
Ankylosing Spondylitis
What are 4 beneficial effects of using NSAIDs in rheumatology?
Analgesia
Anti-Inflammatory
Anti-pyretic
Anti-platelet
