39. Immunopathology 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
What diseases come under the category of ‘connective tissue disease’?
SLE Systemic sclerosis Dermatomyositis/polymyositis Sjogren’s syndrome Mixed connective tissue disease
Which gender does SLE more commonly affect?
Females 9:1
Describe the presentation of SLE including some specific features.
Malaise, fatigue, weight loss, fever, lymphadenopathy Specific features: Butterfly rash Alopecia Arthralgia Long history of Raynaud’s phenomenon
Describe the characteristics of the rash seen in SLE.
It tends to go across the nose It may look a bit like acne It is not painful or itchy Some rashes become depigmented when the inflammation spreads to the dermis (depigmentation and scarring is irreversible)
Describe the pathogenesis of SLE.
SLE patients have a defect in apoptosis Apoptotic cells are not cleared properly so they persist and expose their nuclear antigens and autoantibodies are generated against these nuclear antigens The defect in apoptosis is combined with B cell hyperactivity The overactive B cells are exposed to the nuclear antigens and the plasma cells begin to produce autoantibodies that circulate and form immune complexes The immune complexes deposit in tissues and activate complement leading to inflammation
What is the first investigation performed in the diagnosis of SLE?
Check for anti-nuclear antibodies (this is not specific for SLE though)
The pattern with which the antinuclear antibodies bind to the nuclear antigens is important in reaching a diagnosis. List some different patterns and the antigens they are associated with.
Homogenous – DNA Speckled – antibodies to Ro, La, Sm and RNP Nucleolar – topoisomerase – scleroderma Centromere – limited cutaneous scleroderma
What conditions are associated with the presence of anti-Ro and anti-La antibodies?
Neonatal lupus syndrome Subacute cutaneous lupus erythematosus
What are some other tests that can be done for SLE?
Measuring complement levels Anti-cardiolipin antibodies Lupus anticoagulant Beta 1 glycoprotein
Describe the haematological features of SLE.
SLE is generally associated with low blood counts Thrombocytopenia Lymphopenia Normocytic anaemia Autoimmune haemolytic anaemia
What renal changes might occur in SLE?
Proteinuria Haematuria Active urinary sediment
List some clinical features that could help pre-empt severe attacks in SLE.
Malaise, weight loss, alopecia, rash
List some laboratory markers that could help pre-empt severe attacks in SLE.
Raised ESR Raised anti-dsDNA antibodies Reduced complement levels
Describe the differences between mild, moderate and severe disease in SLE.
Mild – skin and joint involvement Moderate – inflammation of other organs (e.g. pleuritis, pericarditis) Severe – severe inflammation of vital organs
Describe the treatment of mild disease.
Paracetamol and NSAIDs Hydroxychloroquine (good for arthropathy and cutaneous manifestations) Topical corticosteroids
Describe the treatment of moderate disease.
ORAL GLUCORTICOIDS Start with a HIGH dose and titre downwards
Describe the treatment of severe disease.
Azathioprine – useful steroid-sparing drug Has a risk of neutropenia/bone marrow suppression so needs regular blood monitoring Cyclophosphamide – one used if there is severe organ involvement Problem – infertility
Name and explain the mechanism of action of two new treatments for severe disease.
Mycophenolate mofetil Reversible inhibitor of inosine monophosphate dehydrogenase This is the rate limiting step in de novo purine synthesis Lymphocytes rely heavily on de novopurine synthesisRituximab Anti-CD20 antibody Causes depletion of B cells Useful in lupus nephritis
SLE has and early peak and a late peak in mortality. What are the usual causes of the two peaks?
Early – renal failure, CNS disease, infection Late – MI and stroke
What can usually be seen on the blood film of a patient with SLE?
Schistocytes (evidence of microangiopathic haemolytic anaemia) Teardrop cells Spherocytes Few leukocytes Few platelets
Describe the appearance of a renal biopsy in a patient with SLE
Hypercellular Mesangial proliferation Crescent development
Which gender does SLE more commonly affect?
Females 9:1
Describe the presentation of SLE including some specific features.
Malaise, fatigue, weight loss, fever, lymphadenopathy Specific features: Butterfly rash Alopecia Arthralgia Long history of Raynaud’s phenomenon
Describe the characteristics of the rash seen in SLE.
It tends to go across the nose It may look a bit like acne It is not painful or itchy Some rashes become depigmented when the inflammation spreads to the dermis (depigmentation and scarring is irreversible)
Describe the pathogenesis of SLE.
SLE patients have a defect in apoptosis Apoptotic cells are not cleared properly so they persist and expose their nuclear antigens and autoantibodies are generated against these nuclear antigens The defect in apoptosis is combined with B cell hyperactivity The overactive B cells are exposed to the nuclear antigens and the plasma cells begin to produce autoantibodies that circulate and form immune complexes The immune complexes deposit in tissues and activate complement leading to inflammation
Describe the appearance of a renal biopsy in a patient with SLE
Hypercellular Mesangial proliferation Crescent development
What can usually be seen on the blood film of a patient with SLE?
Schistocytes (evidence of microangiopathic haemolytic anaemia) Teardrop cells Spherocytes Few leukocytes Few platelets
SLE has and early peak and a late peak in mortality. What are the usual causes of the two peaks?
Early – renal failure, CNS disease, infection Late – MI and stroke
Name and explain the mechanism of action of two new treatments for severe disease.
Mycophenolate mofetil Reversible inhibitor of inosine monophosphate dehydrogenase This is the rate limiting step in de novo purine synthesis Lymphocytes rely heavily on de novopurine synthesisRituximab Anti-CD20 antibody Causes depletion of B cells Useful in lupus nephritis