Lecture 16; Brain Immunity 2 Flashcards
What is autoimmunity?
Autoimmunity occurs when the immune system reacts against own tissue
What is 1/3 possible mechanisms for autoimmunity?
• Lymphocytes responding to an infectious agent may coincidentally cross-react with self-tissue (molecular mimicry)
What is 2/3 possible mechanisms for autoimmunity?
• A virus, drug, or a genetic mutation may alter the surface of a cell, so that the cell appears to be foreign to the immune system`
What is 3/3 possible mechanisms for autoimmunity?
• the exposure of sequestered self antigens
i.e in the retina
What is molecular mimicry?
When a similar self antigen is recognised (in autoimmunity)
Describe the immune response of molecular mimicry;
- Memory cells are created
- Primary response not too bad as some autoimmunity inhibition molecules
- Secondary Response: Swifter and more severe. Compliment factors may be activated and membrane pores may be created
What are the normal inhibitors of autoimmunity?
- Subthreshold presentation of antigen
- Cryptic format of autoantigen
- No upregulation or costimulatory molecules required for activation
If the autoimmune reaction damages tissues what is it considered to be?
An autoimmune disease
What is the set criteria for an autoimmune disease?
I.e what makes it what it is?
- The presence of antibodies to a defined cell-surface antigen relevant to disease process
- Immunoglobulins at target structure
- Disease induction with autoantigen
- Transmission of the disease to experimental animals by passive transfer with T cells or immunoglobulins
- A clinical response to immunomodulatory therapy or plasma exchange
What do autoimmune diseases of the nervous system involve?
T cells
Autoantibodies
What may Autoantibody-associated neurological disorders affect?
- Cortex • White matter • Spinal cord • Nerve roots • Neuromuscular junction
What are the possible effector functions of autoantibodies?
- Direct functional block (MG)
- Antigenic modulation (MG, LEMS)
- Complement-dependent mechanisms (MG, MS, GBS, RE)
Are all autoimmune reactions severe?
No some can just be the removal of antigen without traces of an immune reaction. Right through to complete tissue destruction
What is myasthenia gravis?
Severe muscle weakness due to loss of nAcH receptors
What are the clinical symptoms of MG?
Clinical symptoms of MG •Muscular weakness and fatigability •Ptosis (drooping of the upper eyelid) •Diplopia (double vision) •Bulbar symptoms (difficulty chewing and swallowing)
What is the cause of MG?
Autoantibodies bind to Ach receptors (functional block)
= loss Ach transmission = muscle weakness
There is also
- decreased nAch receptors
- Decrease synaptic folds (compliment proteins decrease SA)
How does MG work?
•Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms:
A.Binding and activation of complement
B.Antigenic modulation
C.Functional AChR block
What is the treatment for MG?
- Anticholinesterase agents
- Immunosupressive treatment
- Plasma exchange
- Thymectomy
- Future: Specific immunotherapy
Immunotherapy = Corticosteroids mainly
What is the common themes of the MG autoantibodies antigenic target i.e the receptor?
- Abundant in the CNS
- Highly conserved
- Important physiological functions
What happens in MG when the autoantigen binds in some instances?
Internalisation of the receptor (receptor modulation)
What is a common feature of MG?
Muscular weakness of the face (specific groups of muscles are target in this disease)
What can severe MG lead to?
Respiratory arrest and death
How does MG trigger receptor internalisation?
When the autoantibodies become bivalent, cross linking of receptors triggers receptor internalisation
What does plasma exchange do?
Plasma exchange removes AB
Future;
- Feeding nAchR to limit autoimmune systemic response
- Typically in MG thyroid tumors are removed as they develop during the disease
What is Lambert Eaton Myasthenia Gravis?
- Reduced release of the neurotransmitter acetylcholine from the nerve terminal into the synaptic cleft.
- The autoimmune process takes place at the presynaptic level.
- This disorder is caused by autoantibodies against the voltage-gated calcium channel.
Prevents Ca flux and neurotransmitter release
How can MG or LEMS be differentially diagnosed?
Serum Antibodies against
- Ca channels
- nACh receptors
What is stiff man syndrome?
- Antibodies against glutamic acid decarboxylase
- Antibodies interfere with the synthesis of GABA (decrease inhibitory transmission)
- Reduction in brain levels of GABA in the motor cortex
- High titers of antibodies in most patients (which is proportionally to the severity of the disease)
Describe the stiff man pathogenesis;
The loss of GABAergic inhibitory input into motor neurones via interneurones produces the tonic firing of motor neurones at rest and leads to excessive excitation in response to sensory stimuli.
- Painful
- Takes years to diagnose
What is the therapy for stiff man syndrome?
- Diazepam (enhances GABA neurotransmission)
* Immunomodulatory agents (steroids, plasma exchange)
What is the most common neurological autoimmune disease?
Multiple Sclerosis
What is the pathology of MS?
- Pathological hallmark: demyelinated plaque
* Demyelination results in a slowing or blockade of neurotransmission in the CNS resulting in clinical symptoms
What is the aetiology of MS?
Genetically susceptible people
Women 2x more affected than men
What does demyelination lead to?
Demyelination leads to increase susceptibility to factors that cause axon lesion
How does MS present?
- Unpredictable when itll happen
- Heterogenous CNS areas affected therefore varying symptoms
What are the clinical symptoms of MS?
Clinical symptoms: •Problems with vision and hearing •Sensory-motor disturbance •Coordination and balance problems (Ataxia) •Cognitive deficits •Other secondary symptoms
What is the clinical course of MS?
relapsing-remitting or progressive
i.e can be on/off or progressively worse
What is the pathogenesis of MS?
Genetic and environmental factors(viral infection - E B V, bacterial lipopolysaccharides, superantigens, reactive metabolites, metabolic stress) may activate pre-existing autoreactive T cells and facilitate their movement from the systemic circulation into the CNS.
What can enhance T cell movement into the brain during MS?
In the CNS, local factors (viral infection, metabolic stress) may further facilitate the entry of T cells into the CNS through disruption of the BBB.
What are the mechanisms of immune mediated injury?
- Direct injury to oligodendrocytes by CD4+ and CD8+ T cells
- Cytokine-mediated injury of oligodendrocytes and myelin
- Digestion of surface myelin antigens by macrophages
- Complement-mediated injury
What are the treatments for MS?
Corticosteroids
Immunotherapy
Gene therapy
Describe immunotherapy for MS;
•Immunotherapy (plasma exchange, cytokines):
–Interferon-β1a has been shown to reduce axonal injury after demyelination
–Various agents with immune mediating properties (Glatiramer acetate, Dimethyl fumarate, Fingolimod)are yielding inconclusive results
What is the gene therapy for MS?
- ‘Protective’ genes inserted into viral vectors or plasmids and injected into ‘encephalitogenic’ T cells
- These cells used as ‘Trojan horses’ to deliver genes coding for anti-inflammatory cytokines and neurotrophic molecules to the CNS of EAE animals
What does the inserted gene in the MS gene therapy do?
• These genes inhibit the detrimental function of mononuclear cells, but also foster proliferation and differentiation of surviving oligodendrocytes in demyelinating areas
What is an experimental model that is similar to MS in humans?
Experimental autoimmune encephalomyelitis
Describe EAE;
- EAE is an acute or chronic-relapsing, inflammatory and demyelinating disease.
- Can be induced in: mice, rats
- Disease process closely resembles MS in humans.
How is EAE induced?
Generate antibodies against;
- Myelin Basic Protein (MBP)
- Proteolipid Protein (PLP)
- Myelin Oligodendrocyte Glycoprotein (MOG)
What is the research benefits of EAE?
- Enables studies of demyelination
- Allows to study different pathways of inducing EAE
- Allows to test potential treatments for MS
What is GBS?
Gullian Barre Syndrome
What are AB directed against in GBS?
•Antibodies to gangliosides – components of the lipid membrane
Antibodies to gangliosides correlate with GBS pathogenesis
Where does GBS occur and what can occur prior to GBS?
PNS
Viral or bacterial infection can trigger GBS
- Possible molecular mimicry
Where does GBS damage occur?
Axonal degeneration occurs as a terminal damage
What is the symptoms of GBS?
- Progressive weakness of limbs
- Areflexia – the absence of reflex
- High protein levels in the CSF
Describe the severity incidence of GBS;
- Acute disease followed by complete recovery (65%)
- Prolonged suffering – severe axonal damage (27%)
- Death – severe acute complications (arrhythmia) (8%)
What is the treatment for GBS?
Plasma exchange decreases time of acute suffering
Immunoglobulin therapy: High doses of immunoglobulins from a healthy donor can block the damaging antibodies that may contribute to GBS.
