Immuno: Autoinflammatory and Autoimmune diseases 2 Flashcards
Describe the pathophysiology of Graves’ disease
Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor
NOTE: negative feedback does not override the antibody stimulation, it is a type II hypersensitivity
Which antibodies is Hashimoto’s thyroiditis associated with?
Anti-thyroid peroxidase (TPO) antibodies
Anti-thyroglobulin antibodies
NOTE: there can be present in normal people
Which Gel and Coombs class is T1DM
Type IV hypersensitivity - CD8 T cell mediated destruction of pancreatic islet cells
List some autoantibodies that are found in type I diabetes mellitus.
- Anti-glutamic acid dehydrogenase (GAD)
- Anti-islet antigen (IA2)
- Anti-islet cell
- Anti-insulin
NOTE: the detection of these antibodies does not currently play a part in diagnosis of diabetes mellitus
Outline the pathophysiology of pernicious anaemia.
Autoimmune destruction of gastric parietal cells leading to vitamin B12 deficiency
What is a major complication of vitamin B12 deficiency?
- Subacute degeneration of the spinal cord (involving the posterior and lateral columns)
- Megaloblastic anaemia
NOTE: other neurological features include peripheral neuropathy and optic neuropathy
Which antibodies are useful in the diagnosis of pernicious anaemia?
Anti-parietal cell antibodies
Anti-intrinsic factor antibodies
Outline the pathophysiology of myasthenia gravis.
Patients develop antibodies against nicotinic acetylcholine receptors leading to failure of depolarisation of the motor endplate
What are some characteristic symptoms of myasthenia gravis?
Progessive muscle weakness following repetitive activity
- Drooping eyelids, double vision
- Dysarthria, dysphasia
- Proximal muscle weakness
Symptoms worse at the end of the day
Which investigations may be used in the diagnosis of myasthenia gravis?
- Anti-nAchR antibodies in blood
- EMG studies are usually abnormal
- Tensilon test- administer very short-acting acetylcholinesterase inhibitor which causes a rapid improvement in symptoms (rarely used)
Outline the pathophysiology of Goodpasture’s syndrome.
Caused by anti-glomerular basement membrane antibodies (specifically binding to collagen type IV)
Leads to lung and kidney damage
What are typical symptoms of Goodpasture disease
- Lungs - SoB, haemotypsis, widespread crackes
- Kidneys - haematuria, oedema, reduced urine output, hypertension
List some genetic polymorphisms that predispose to rheumatoid arthritis.
- HLA DR1
- HLA DR4
- PTPN22
- PAD 2 and PAD 4 polymorphisms
- Polymorphisms affecting TNF, IL1, IL6 and IL10
What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?
They share a sequence at position 70-74 of the HLA DR-beta chain (shared epitope)
This enables binding of HLA to arthritogenic peptides (particularly citrullinated peptides)
Describe the role of peptidylarginine deiminases (PAD) in the pathogenesis of rheumatoid arthritis.
Peptidylarginine deiminases (2 and 4) are involved in the deimination of arginine to form citrulline
Polymorphisms that are associated with increased citrullination leads to a high load of citrullinated peptides
List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis
- Smoking is associated with the development of erosive disease (due to increased citrullination)
- Gum infection by Porphyromonas gingivalis - expresses PAD thus increasing citrullination
Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.
-
Anti-cyclic citrullinated peptide antibodies
- Bind to peptides where arginine has been converted to citrulline
- 95% specific, 60-70% sensitive
- Best diagnostic test
- Rheumatoid factor - IgM antibody directed against Fc region of human IgG
NOTE: there are IgA and IgG variants of RF
What happens to joints affected by rheumatoid arthritis?
- The synovium becomes inflamed forming a pannus
- This invades the articular cartilage and adjacent bone
- There is also an increased synovial fluid volume
What are antinuclear antibodies and how are they tested?
Group of antibodies against nuclear proteins - they characterise the connective tissue autoimmune diseases
NOTE: these are very common and are often present in healthy individuals
List some genetic defects that may predispose to the development of SLE.
- Abnormalities in clearing apoptotic cells (polymorphisms in complement, MBL and CRP)
- Leads to antigen persistance
- Abnormalities in cellular activation (polymorphisms in genes encoding cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules)
- Leads to B cell hyperactivity and loss of tolerance
Both of the above promote the creation of antibodies directed against particular intracellular proteins (could bind to nuclear or cytoplasmic antigens)
Which type of hypersensitivity reaction is SLE?
Type III hypersensitivity - antibodies bind to antigens forming immune complexes which deposit in tissues (e.g. skin, joints, kidneys) and activate complement via the classical pathway
These antibodies can also stimulate cells that express Fc receptors
What is antibody titre?
The titre value represents the highest dilution of the patient’s serum at which the antibodies can still be detected. For example, if a person has an antibody titer of 1:320, it means that their blood can be diluted 320 times and still show a measurable level of antibodies.
minimal dilution at which the antibody can be detected
What are the two types of ANA and how can they be distinguished?
- Anti-dsDNA - highly specific for SLE (used diagnostically and for disease monitoring)
- Anti-ENA (extractable nuclear antigens) - ribonucleoproteins (e.g. Ro, La, Sm), Scl-70, centromere
Other than anti-dsDNA titre, which other quantifiable component can be measure as a surrogate marker for disease activity in SLE?
- Complement proteins C3 and C4 (will be low)
- ESR, CRP
Describe the difference in immunofluorescence patterns between dsDNA and ENA antigens
- anti-dsDNA creates homogenous
- anti-ENA creates speckled patterns
What are some clincial features of anti-phospholipid syndrome
Triad
- recurrent arterial or venous thrombosis
- recurrent miscarriages
- thrombocytopenia
Livedo reticularis on skin
Can occur alone or secondary to SLE
Which antibodies are tested for in antiphospholipid syndrome?
- Anti-cardiolipin - immunoglobulins directed against phospholipids (also positive in syphilis)
- Anti-beta2 glycoprotein-1 - antibody specific for glycoprotein found associated with negatively charged phospholipids
- Lupus anticoagulant - prolongation of phospholipid-dependent coagulation tests (in vitro phenomenon)
NOTE: lupus anticoagulant cannot be assessed if the patient is on anticoagulant therapy
NOTE: all three tests should be performed as 40% of patients have disconcordant antibodies
What is the pathophysiology of Sjorgren’s syndrome?
Autoimmune destruction of exocrine glands
What autoantibodies are positive in Sjogren’s?
Anti-Ro and Anti-La
Which malignancy are patients with Sjogrens at risk of developing
Mucosa Associated Lymphoid Tissue Lymphoma
Outline the pathophysiology of systemic sclerosis.
Cytokines released by Th2 and Th17 leads to activation of fibroblasts and the development of fibrosis
NOTE: polymorphisms in type I collagen alpha 2 chains, fibrillin 1 and TGF-beta may be implicated
Cytokines can also activate endothelial cells and contribute to microvascular disease
What are the main features of limited cutaneous systemic sclerosis?
Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasia
NOTE: also pulmonary hypertension
What are the main features of diffuse cutaneous systemic sclerosis?
- Skin involvement extends beyond the forearms
- CREST features
- More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Renal cysts / failure
Which antibodies are seen in limited and diffuse cutaneous systemic sclerosis?
Limited - anti-centromere
Diffuse - anti-topoisomerase (aka anti-Scl70)
Describe the differences between the histology of dermatomyositis and polymyositis.
- Dermatomyositis - perivascular CD4+ T cell and B cells are seen, this can cause an immune complex-mediated vasculitis (type III response)
- Polymyositis - CD8+ T cells surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)
What are some cutaneous features of dermatomyositis
- Heliotrope rash
- Gottron papules
- Photosensitivity
What are some diagnostic investigations in inflammatory myopathies
- Bloods
- Raised CK
- ANA
- EMG
- Muscle biopsy (gold standard)
What key symptoms differentiates inflammatory myopathies from PMR
Muscle weakness only present in inflammatory myopathies not PMR
Which antibodies are seen in dermatomyositis and polymyositis?
- ANA positive (in some patients) - ask for extended myositis panel
- Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2
- Polymyositis: anti-aminoacyl tRNA synthetase antibody is cytoplasmic
If ANA is positive, which ANA subtypes indicate which type of disease
Which classification system is used for systemic vasculitides?
Chapel Hill
What does ANCA stand for
Anti-neutrophil cytoplasmic antibodies
Which small vessel vasculitides are associated with ANCA?
- Microscopic polyangiitis (pANCA)
- Eosinophililc Granulomatosis with polyangiitis (pANCA)
aka Churg-Strauss syndrome - Granulomatosis with polyangiitis (cANCA)
Outline the pathophysiology of ANCA.
- These antibodies are specific to antigens located within the cytoplasm of neutrophils
- Inflammation may lead to expression of these antigens on the surface of neutrophils
- Antibody engagement with these antigens may lead to neutrophil activation (type II hypersensitivity)
NOTE: these are different from anti-nuclear antibodies
Describe the key difference between cANCA and pANCA.
cANCA
- Cytoplasmic fluorescence
- Associated with antibodies against proteinase 3
Occurs in >90% of GPA patients with renal involvement (wegeners)
pANCA
- Perinuclear staining pattern
- Associated with antibodies to myeloperoxidase
- Associated with MPA and EGPA (Churg-Strauss syndrome)
- Less sensitive and specific than cANCA
