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Medsci 317 > Lecture 16; Brain Immunity 2 > Flashcards

Lecture 16; Brain Immunity 2 Flashcards

1
Q

What is autoimmunity?

A

Autoimmunity occurs when the immune system reacts against own tissue

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2
Q

What is 1/3 possible mechanisms for autoimmunity?

A

• Lymphocytes responding to an infectious agent may coincidentally cross-react with self-tissue (molecular mimicry)

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3
Q

What is 2/3 possible mechanisms for autoimmunity?

A

• 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`

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4
Q

What is 3/3 possible mechanisms for autoimmunity?

A

• the exposure of sequestered self antigens

i.e in the retina

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5
Q

What is molecular mimicry?

A

When a similar self antigen is recognised (in autoimmunity)

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6
Q

Describe the immune response of molecular mimicry;

A
  • 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
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7
Q

What are the normal inhibitors of autoimmunity?

A
  • Subthreshold presentation of antigen
  • Cryptic format of autoantigen
  • No upregulation or costimulatory molecules required for activation
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8
Q

If the autoimmune reaction damages tissues what is it considered to be?

A

An autoimmune disease

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9
Q

What is the set criteria for an autoimmune disease?

I.e what makes it what it is?

A
  1. The presence of antibodies to a defined cell-surface antigen relevant to disease process
  2. Immunoglobulins at target structure
  3. Disease induction with autoantigen
  4. Transmission of the disease to experimental animals by passive transfer with T cells or immunoglobulins
  5. A clinical response to immunomodulatory therapy or plasma exchange
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10
Q

What do autoimmune diseases of the nervous system involve?

A

T cells

Autoantibodies

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11
Q

What may Autoantibody-associated neurological disorders affect?

A 
-  Cortex 
• White matter
• Spinal cord
• Nerve roots
• Neuromuscular junction
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12
Q

What are the possible effector functions of autoantibodies?

A
  • Direct functional block (MG)
  • Antigenic modulation (MG, LEMS)
  • Complement-dependent mechanisms (MG, MS, GBS, RE)
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13
Q

Are all autoimmune reactions severe?

A

No some can just be the removal of antigen without traces of an immune reaction. Right through to complete tissue destruction

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14
Q

What is myasthenia gravis?

A

Severe muscle weakness due to loss of nAcH receptors

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15
Q

What are the clinical symptoms of MG?

A 
Clinical symptoms of MG
•Muscular weakness and fatigability
•Ptosis (drooping of the upper eyelid)
•Diplopia (double vision)
•Bulbar symptoms (difficulty chewing and swallowing)
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16
Q

What is the cause of MG?

A

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)
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17
Q

How does MG work?

A

•Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms:

A.Binding and activation of complement

B.Antigenic modulation

C.Functional AChR block

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18
Q

What is the treatment for MG?

A
  • Anticholinesterase agents
  • Immunosupressive treatment
  • Plasma exchange
  • Thymectomy
  • Future: Specific immunotherapy

Immunotherapy = Corticosteroids mainly

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19
Q

What is the common themes of the MG autoantibodies antigenic target i.e the receptor?

A
  • Abundant in the CNS
  • Highly conserved
  • Important physiological functions
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20
Q

What happens in MG when the autoantigen binds in some instances?

A

Internalisation of the receptor (receptor modulation)

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21
Q

What is a common feature of MG?

A

Muscular weakness of the face (specific groups of muscles are target in this disease)

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22
Q

What can severe MG lead to?

A

Respiratory arrest and death

23
Q

How does MG trigger receptor internalisation?

A

When the autoantibodies become bivalent, cross linking of receptors triggers receptor internalisation

24
Q

What does plasma exchange do?

A

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
25
Q

What is Lambert Eaton Myasthenia Gravis?

A
  • 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

26
Q

How can MG or LEMS be differentially diagnosed?

A

Serum Antibodies against

  • Ca channels
  • nACh receptors
27
Q

What is stiff man syndrome?

A
  • 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)
28
Q

Describe the stiff man pathogenesis;

A

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
29
Q

What is the therapy for stiff man syndrome?

A
  • Diazepam (enhances GABA neurotransmission)

* Immunomodulatory agents (steroids, plasma exchange)

30
Q

What is the most common neurological autoimmune disease?

A

Multiple Sclerosis

31
Q

What is the pathology of MS?

A
  • Pathological hallmark: demyelinated plaque

* Demyelination results in a slowing or blockade of neurotransmission in the CNS resulting in clinical symptoms

32
Q

What is the aetiology of MS?

A

Genetically susceptible people

Women 2x more affected than men

33
Q

What does demyelination lead to?

A

Demyelination leads to increase susceptibility to factors that cause axon lesion

34
Q

How does MS present?

A
  • Unpredictable when itll happen

- Heterogenous CNS areas affected therefore varying symptoms

35
Q

What are the clinical symptoms of MS?

A 
Clinical symptoms:
•Problems with vision and hearing 
•Sensory-motor disturbance
•Coordination and balance problems (Ataxia) •Cognitive deficits 
•Other secondary symptoms
36
Q

What is the clinical course of MS?

A

relapsing-remitting or progressive

i.e can be on/off or progressively worse

37
Q

What is the pathogenesis of MS?

A

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.

38
Q

What can enhance T cell movement into the brain during MS?

A

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.

39
Q

What are the mechanisms of immune mediated injury?

A
  • 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
40
Q

What are the treatments for MS?

A

Corticosteroids
Immunotherapy
Gene therapy

41
Q

Describe immunotherapy for MS;

A

•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

42
Q

What is the gene therapy for MS?

A
  • ‘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
43
Q

What does the inserted gene in the MS gene therapy do?

A

• These genes inhibit the detrimental function of mononuclear cells, but also foster proliferation and differentiation of surviving oligodendrocytes in demyelinating areas

44
Q

What is an experimental model that is similar to MS in humans?

A

Experimental autoimmune encephalomyelitis

45
Q

Describe EAE;

A
  • EAE is an acute or chronic-relapsing, inflammatory and demyelinating disease.
  • Can be induced in: mice, rats
  • Disease process closely resembles MS in humans.
46
Q

How is EAE induced?

A

Generate antibodies against;

  • Myelin Basic Protein (MBP)
  • Proteolipid Protein (PLP)
  • Myelin Oligodendrocyte Glycoprotein (MOG)
47
Q

What is the research benefits of EAE?

A
  • Enables studies of demyelination
  • Allows to study different pathways of inducing EAE
  • Allows to test potential treatments for MS
48
Q

What is GBS?

A

Gullian Barre Syndrome

49
Q

What are AB directed against in GBS?

A

•Antibodies to gangliosides – components of the lipid membrane

Antibodies to gangliosides correlate with GBS pathogenesis

50
Q

Where does GBS occur and what can occur prior to GBS?

A

PNS

Viral or bacterial infection can trigger GBS
- Possible molecular mimicry

51
Q

Where does GBS damage occur?

A

Axonal degeneration occurs as a terminal damage

52
Q

What is the symptoms of GBS?

A
  • Progressive weakness of limbs
  • Areflexia – the absence of reflex
  • High protein levels in the CSF
53
Q

Describe the severity incidence of GBS;

A
  • Acute disease followed by complete recovery (65%)
  • Prolonged suffering – severe axonal damage (27%)
  • Death – severe acute complications (arrhythmia) (8%)
54
Q

What is the treatment for GBS?

A

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.

Medsci 317 (32 decks)

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