Immuno: Autoinflammatory and Autoimmune diseases Pt.3

Question 1

Describe the pathophysiology of Graves’ disease

Answer 1

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

Question 2

Which antibodies is Hashimoto’s thyroiditis associated with?

Answer 2

Anti-thyroid peroxidase (TPO) antibodies

Anti-thyroglobulin antibodies

NOTE: there can be present in normal people

Question 3

Which Gel and Coombs class is T1DM

Answer 3

Type IV hypersensitivity - CD8 T cell mediated destruction of pancreatic islet cells

Question 4

List some autoantibodies that are found in type I diabetes mellitus.

Answer 4

• 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

Question 5

Outline the pathophysiology of pernicious anaemia.

Answer 5

Autoimmune destruction of gastric parietal cells leading to vitamin B12 deficiency

Question 6

What is a major complication of vitamin B12 deficiency?

Answer 6

• Subacute degeneration of the spinal cord (involving the posterior and lateral columns)
• Megaloblastic anaemia

NOTE: other neurological features include peripheral neuropathy and optic neuropathy

Question 7

Which antibodies are useful in the diagnosis of pernicious anaemia?

Answer 7

Anti-parietal cell antibodies

Anti-intrinsic factor antibodies

Question 8

Outline the pathophysiology of myasthenia gravis.

Answer 8

Patients develop antibodies against nicotinic acetylcholine receptors leading to failure of depolarisation of the motor endplate

Question 9

What are some characteristic symptoms of myasthenia gravis?

Answer 9

Progessive muscle weakness following repetitive activity

• Drooping eyelids, double vision
• Dysarthria, dysphasia
• Proximal muscle weakness

Symptoms worse at the end of the day

Question 10

Which investigations may be used in the diagnosis of myasthenia gravis?

Answer 10

• 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)

Question 11

Outline the pathophysiology of Goodpasture’s syndrome.

Answer 11

Caused by anti-glomerular basement membrane antibodies (specifically binding to collagen type IV)

Leads to lung and kidney damage

Question 12

What are typical symptoms of Goodpasture disease

Answer 12

• Lungs - SoB, haemotypsis, widespread crackes
• Kidneys - haematuria, oedema, reduced urine output, hypertension

Question 13

List some genetic polymorphisms that predispose to rheumatoid arthritis.

Answer 13

• HLA DR1
• HLA DR4
• PTPN22
• PAD 2 and PAD 4 polymorphisms
• Polymorphisms affecting TNF, IL1, IL6 and IL10

Question 14

What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?

Answer 14

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)

Question 15

Describe the role of peptidylarginine deiminases (PAD) in the pathogenesis of rheumatoid arthritis.

Answer 15

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

Question 16

List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis

Answer 16

• Smoking is associated with the development of erosive disease (due to increased citrullination)
• Gum infection by Porphyromonas gingivalis - expresses PAD thus increasing citrullination

Question 17

Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.

Answer 17

• 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

Question 18

What happens to joints affected by rheumatoid arthritis?

Answer 18

• The synovium becomes inflamed forming a pannus
• This invades the articular cartilage and adjacent bone
• There is also an increased synovial fluid volume

Question 19

What are antinuclear antibodies and how are they tested?

Answer 19

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

Question 20

List some genetic defects that may predispose to the development of SLE.

Answer 20

• 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)

Question 21

Which type of hypersensitivity reaction is SLE?

Answer 21

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

Question 22

What is antibody titre?

Answer 22

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

Question 23

What are the two types of ANA and how can they be distinguished?

Answer 23

• 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

Question 24

Other than anti-dsDNA titre, which other quantifiable component can be measure as a surrogate marker for disease activity in SLE?

Answer 24

• Complement proteins C3 and C4 (will be low)
• ESR, CRP

Question 25

Describe the difference in immunofluorescence patterns between dsDNA and ENA antigens

Answer 25

• anti-dsDNA creates homogenous
• anti-ENA creates speckled patterns