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 (CCP)
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- inflammation in enthesis
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- no autoantibodies
Which other diseases fall into this family of diseases?
Seronegative spondyloarthropathies
Reiter’s syndrome and reactive arthritis
Psoriatic arthritis
Enteropathic synovitis - arthritis associated with GI inflammation
Define Systemic Lupus Erythematosus (SLE).
Chronic tissue inflammation in the presence of antibodies directed at self-antigens
NOTE: it is inflammation of sterile tissue
caused by immune complexes
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?
Connective tissue diseases
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)- dry eyes, dry mouth
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 (both class 1 &2)
A change in which class of MHC is associated with rheumatoid arthritis, ankylosing spondylitis and SLE?
Ankylosing spondylitis = Class 1 (A,B,C)
Rheumatoid Arthritis + SLE = Class 2 (DP, DQ, DR)
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 (anti topoisomerase 1)
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 and then the patient’s serum is washed over the cells
If there are anti-nuclear antibodies, they will bind to the nuclear antigens- detected by immunofluorescence
What are the features of a sick lupus patient in terms of complement levels and serum levels of anti-dsDNA antibodies?
Low complement levels - as its used up
High serum levels of anti-dsDNA antibodies
How do antinuclear antibodies (ANAs) 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
Tissue damage by antibody effector mechanisms eg compliment activation
State some important cytokines in rheumatology.
IL-1 – produced by macrophages –> 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 (monoclonal Ab’s) has proven to be very effective in reducing some of the negative effects of rheumatoid arthritis?
TNF-alpha– as its the dominant pro inflammatory cytokine in the rheumatoid synovium
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)- rituximab (anti CD20 Ab)
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 (PTHrp)
What decoy receptor antagonises the action of RANKL?
Osteoprotegrin (OPG)
Name a monoclonal antibody that targets RANKL.
Denusomab (also treats osteoporosis)
State two drugs that deplete B cells and specify what they target.
Rituximab – anti-CD20 chimeric monoclonal antibody
Belimumab – anti-BLYS human 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–> (which therefore inhibits AA production)
