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
