Pathogenesis of Autoimmune Disease Flashcards
Define Rheumatoid Arthritis.
Chronic autoimmune (more than 6 weeks) disease characterised by pain, stiffness and symmetrical synovitis of synovial joints Chronic (more than 6 weeks) joint inflammation that can result in joint damage Site of inflammation is the synovium (synovial membrane) hence called synovitis
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?
synovial membrane 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 (MHC 2)
SLE –HLA-DR3 (MHC 2)
Ankylosing spondylitis – HLA-B27 (MHC 1)
On which chromosome is HLA encoded?
Chromosome 6
HLA-A,B,C,D. Which ones are MHC 1 and 2
HLA ABC = MHC 1
HLA D = MHC 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 cytotoxic CD8+ T cells
Which cells express class II MHC and which cells recognise this class of MHC?
Antigen presenting cells e.g. macrophages, B cells, dendritic cells (they display exogenous antigens)
Recognised by CD4+ T cells
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?
Out of the 2 autoantibodies you need to know for SLE, which one of them correlates with disease activity?
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
What are the features of a sick lupus patient in terms of complement levels and serum levels of anti-dsDNA antibodies?
Low complement levels (used up)
High serum levels of anti-dsDNA antibodies (ie a lot of immune complexes)
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 mediated 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
Which type of Cell can be targeted in the treatment of SLE
B cells. By eg targeting mitogens/survival factors of B cells like BLYS. This leads to 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, osteoblasts and stromal cells (means cells of connective tissue, eg synovial fibroblasts)
It stimulates osteoclast formation
RANKL can be upregulated by eg TNF alpha in RA which leads to osteoclast activation and bone destruction in RA. Hence there are drugs stopping RANKL
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.
denosumab
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
