Autoimmune Disorders Flashcards
What are some genetic factors that can cause autoimmune disorders?
FOXP3 gene mutation = no T reg cells
MHC/HLA gene polymorphisms = highly polymorphic, different variants bind to different peptides
Sex hormone gene polymorphisms
What are some environmental factors that lead to autoimmune disorders?
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
What are some examples of MSK autoimmune conditions?
Rheumatoid arthritis, myasthenia gravis, scleroderma, polymyositis, dermatomyositis, lupus, Sjogren’s syndrome, relapsing polychondritis, eosinophilic fasciitis, vasculitis
What is myasthenia gravis (MG)?
Autoimmune neuromuscular disorder characterised by severe muscular weakness and progressive fatigue
What antibodies are involved in MG?
Auto-IgG = bind with acetylcholine receptors on muscle cells
What other conditions is MG associated with?
SLE, rheumatoid arthritis, thyrotoxicosis
What is the epidemiology of MG?
Any age group or gender, 90% of cases are of unknown cause, 10% of cases caused by thymic tumour, has HLA genetic associations
When may MG first appear?
During pregnancy, postpartum or with the administration of certain anaesthetics
What are the first muscles to be affected by MG?
Eyes, face, mouth, throat and neck
What muscles are not commonly involved in MG?
Shoulder girdle and hip flexors
What occurs in advanced MG?
All muscles are weak, causing life threatening impairment of respiration
What is early onset MG with AChR antibodies associated with?
Increased adaptive immune response in thymus (thymic follicular hyperplasia with lymphoid follicles and germinal centres)
What activates CD4+ cells in MG?
Unfolded AChR subunits expressed by thymic epithelial cells
What do effector TH cells do in MG?
Stimulate auto-reactive B cells, resulting in the production of anti-AChR IgG antibodies
What do anti-AChR IgG antibodies attack in MG?
Thymic myoid cells, which release AChR-IgG immune complexes
What do AChR-IgG immune complexes do in MG?
Activate other antigen presenting cells, perpetuating the response
What do AChR antibodies block in MG?
Binding of endogenous ACh ligands to ACh receptors, leading to defects in the nerve impulse transmission at the skeletal muscle NMJ
What is the end result of the autoimmune response in MG?
Eventually AChRs are destroyed:
Antibody-bound receptors are internalised and degraded
AChR antibodies bind Complement, leading to destruction of the muscle endplate
What kind of hypersensitivity response is shown in MG?
Type II
How is MG diagnosed?
Laboratory tests = presence of anti-AChR IgG in serum
Repetitive nerve stimulation = gradually reducing responses indicates NMJ dysfunction
What are the basic treatments for MG?
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
How should acute MG be treated?
Respiratory support, plasmapheresis, IV immunoglobin, high dose corticosteroids
What are some examples of specialised drugs used to treat MG?
Eculizumab = terminal pathway Complement activator Rituximab = B cell destruction
