Autoinflammatory and autoimmune 2 Flashcards
- Describe the pathophysiology of Graves’ disease.
Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor
- Which antibodies is Hashimoto’s thyroiditis associated with?
Anti-TPO antibodies
Anti-thyroglobulin antibodies
- What histological feature has been observed in the pancreas of non-obese diabetic mice?
CD8+ T cell infiltration of the pancreas
The CD8+ T cells bind to peptides presented by MHC Class I
- List some autoantibodies that are found in type I diabetes mellitus.
Anti-GAD
Anti-IA2
Anti-islet cell
Anti-insulin
- Outline the pathophysiology of pernicious anaemia.
Patients develop antibodies against intrinsic factor which leads to failure of absorption of vitamin B12
- What is a major complication of vitamin B12 deficiency?
Subacute degeneration of the spinal cord (involved the posterior and lateral columns)
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
Myasthenia gravis is characterised by fluctuating weakness
- Which investigations may be used in the diagnosis of myasthenia gravis?
EMG studies are usually abnormal
Tensilon test – administer very short-acting acetylcholinesterase (e.g. edrophonium bromide) which causes a rapid improvement in symptoms
- 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 PAD in the pathogenesis of rheumatoid arthritis.
Peptidylarginine deaminases (2 and 4) are involved in the deamination 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 is associated with rheumatoid arthritis as it expresses PAD, thereby promoting 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
Rheumatoid factor – IgM antibody directed against Fc region of human IgG
- Describe B cell involvement in the pathophysiology of rheumatoid arthritis.
Type II – antibodies bind to citrullinated peptides leading to activation of macrophages, NK cells and complement
Type III – immune complexes form and get deposited leading to complement activation
- Outline the roles of T cells in the pathophysiology of rheumatoid arthritis.
APCs present peptides to CD4+ T cells which then produce IFN-gamma and IL17
These cytokines act on fibroblasts and macrophages
This leads to the production of MMPs, IL1 and TNF-alpha
- What happens to joints affected by rheumatoid arthritis?
The synovium becomes inflamed forming a pannus
This invades 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
Tested by staining Hep-2 (human epidermoid cancer line) cells
- List some genetic defects that may predispose to the development of SLE.
Abnormalities in clearing apoptotic cells (polymorphisms in complement, MBL and CRP)
Abnormalities in cellular activation (polymorphisms in genes encoding cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules)
B cell hyperactivity and loss of tolerance
Antibodies directed against particular intracellular proteins (could bind to nuclear or cytoplasmic antigens)
- What are the two types of ANA and how can they be distinguished?
Anti-dsDNA – homogenous staining pattern, they are highly specific for SLE and high titres are associated with severe disease (useful for disease monitoring)
Anti-ENA4 (extractable nuclear antigens such as ribonucleoproteins (e.g. Ro, La, Sm))
- Which disease are anti-Ro and anti-La antibodies characteristically found in?
Sjogren’s syndrome
- List some other autoantibodies that are implicated in autoimmune disease.
Scl70, RNA polymerase, fibrillarin – diffuse cutaneous systemic sclerosis
Mi2, SRP – idiopathic inflammatory myopathies
- Other than dsDNA, which other quantifiable component can be measured as a surrogate marker for disease activity in SLE?
C3 and C4 – C4 will decrease before C3
NOTE: we measure unactivated complement proteins
- What triad defines antiphospholipid syndrome?
Recurrent venous or arterial thrombosis
Recurrent miscarriage
Thrombocytopaenia
