Autoimmune Disorders

Question 1

What are some genetic factors that can cause autoimmune disorders?

Answer 1

FOXP3 gene mutation = no T reg cells
MHC/HLA gene polymorphisms = highly polymorphic, different variants bind to different peptides
Sex hormone gene polymorphisms

Question 2

What are some environmental factors that lead to autoimmune disorders?

Answer 2

Molecular mimicry = cross-reactivity between foreign antigens and self antigens
Intercurrent infections = immune responses can potentiate ongoing autoimmune reactions
Tissue damage = release of previously hidden self antigens
Superantigens = bacterial superantigens can activate T cells non-specifically

Question 3

What are some examples of MSK autoimmune conditions?

Answer 3

Rheumatoid arthritis, myasthenia gravis, scleroderma, polymyositis, dermatomyositis, lupus, Sjogren’s syndrome, relapsing polychondritis, eosinophilic fasciitis, vasculitis

Question 4

What is myasthenia gravis (MG)?

Answer 4

Autoimmune neuromuscular disorder characterised by severe muscular weakness and progressive fatigue

Question 5

What antibodies are involved in MG?

Answer 5

Auto-IgG = bind with acetylcholine receptors on muscle cells

Question 6

What other conditions is MG associated with?

Answer 6

SLE, rheumatoid arthritis, thyrotoxicosis

Question 7

What is the epidemiology of MG?

Answer 7

Any age group or gender, 90% of cases are of unknown cause, 10% of cases caused by thymic tumour, has HLA genetic associations

Question 8

When may MG first appear?

Answer 8

During pregnancy, postpartum or with the administration of certain anaesthetics

Question 9

What are the first muscles to be affected by MG?

Answer 9

Eyes, face, mouth, throat and neck

Question 10

What muscles are not commonly involved in MG?

Answer 10

Shoulder girdle and hip flexors

Question 11

What occurs in advanced MG?

Answer 11

All muscles are weak, causing life threatening impairment of respiration

Question 12

What is early onset MG with AChR antibodies associated with?

Answer 12

Increased adaptive immune response in thymus (thymic follicular hyperplasia with lymphoid follicles and germinal centres)

Question 13

What activates CD4+ cells in MG?

Answer 13

Unfolded AChR subunits expressed by thymic epithelial cells

Question 14

What do effector TH cells do in MG?

Answer 14

Stimulate auto-reactive B cells, resulting in the production of anti-AChR IgG antibodies

Question 15

What do anti-AChR IgG antibodies attack in MG?

Answer 15

Thymic myoid cells, which release AChR-IgG immune complexes

Question 16

What do AChR-IgG immune complexes do in MG?

Answer 16

Activate other antigen presenting cells, perpetuating the response

Question 17

What do AChR antibodies block in MG?

Answer 17

Binding of endogenous ACh ligands to ACh receptors, leading to defects in the nerve impulse transmission at the skeletal muscle NMJ

Question 18

What is the end result of the autoimmune response in MG?

Answer 18

Eventually AChRs are destroyed:
Antibody-bound receptors are internalised and degraded
AChR antibodies bind Complement, leading to destruction of the muscle endplate

Question 19

What kind of hypersensitivity response is shown in MG?

Answer 19

Type II

Question 20

How is MG diagnosed?

Answer 20

Laboratory tests = presence of anti-AChR IgG in serum

Repetitive nerve stimulation = gradually reducing responses indicates NMJ dysfunction

Question 21

What are the basic treatments for MG?

Answer 21

Increase neurotransmission = first line treatment to improve symptoms, anti-cholinesterase agents (e.g pyridostigine)
Surgery = thymectomy (first line if thymic tumour)
Reduce autoimmune reaction = second line, immunosuppressive drugs, cortiosteroids

Question 22

How should acute MG be treated?

Answer 22

Respiratory support, plasmapheresis, IV immunoglobin, high dose corticosteroids

Question 23

What are some examples of specialised drugs used to treat MG?

Answer 23

Eculizumab = terminal pathway Complement activator
Rituximab = B cell destruction