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MedSci 317 > Module B - Immunity > Flashcards

Module B - Immunity Flashcards

1
Q

What is neuroimmunology the interaction between?

A

Nervous system and immune system

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2
Q

Why is the brain thought to be immunologically privileged?

A
  1. Existence of BBB (ECs connected with tight junctions and astrocytes and pericytes connected with gap junctions)
  2. Lack of antigen presentation within CNS
  3. Absence of a lymphatic drainage (present in immune organs, but not brain)
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3
Q

Why is the immune privilege theory thought to be incorrect?

A

Cells of the immune system pass through the CNS
Immunoglobulins diffuse in (at low levels)
Microglia and astrocytes may have antigen-presenting role in the brain
Lymphatic drainage does occur (Virchow-Robin spaces)
Immune privilege is rather “immune selectivity”

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4
Q

Describe the afferent limb of the immune response to an antigen (genetic):

A

Recognition of antigen

Generation of effector cells

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5
Q

Describe the efferent limb of the immune response to an antigen (genetic):

A

Passage of activated lymphocytes and antibodies into the tissue
Elimination of antigen by antibodies and effector cells

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6
Q

Describe the completion of the immune response loop:

A

Completed by the movement of activated immune cells across intact BBB membranes and antibody leakage

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7
Q

What do immunogenic signals elicted by an antigen in the CNS result in?

A

Non-inflammatory response (peripherally includes upregulation of antibody response)

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8
Q

What immune molecules are involved in the response:

A

Within the CNS, this includes elevated antibody synthesis, and suppression of hypersensitivty and cytotoxic T-cell response

Intrathecal antibody synthesis presumably involves activated B and T lymphocytes that have crossed intact barrier membranes from the periphery

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9
Q

Describe the types of cells produced from lymphocytes:

A 
B cell (Th2)
T cell (Th1)
(suppressor, cytotoxic, helper, regulatory)
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10
Q

What are the functions of phagocytes (cell eaters)?

A

Scavengers
Antigen-presenting cells
Secretory cells

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11
Q

Describe neuroimmune interactions:

A

The interplay between components of the nervous system with cells and mediators of the immune system

Neuroimmunology was originally concerned with diseases of the nervous system and with a series of animal models of diseases

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12
Q

Describe neuroendocrine immune interactions:

A

Brain and nervous system interacts directly with the immune system, or indirectly through stress and the endocrine system

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13
Q

Describe the neuroendocrine pathway:

A

The immune and neuroendocrine systems share many ligands and receptors that result in constant and important bi-directional communication

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14
Q

Describe the neuroendocrine pathway loop:

A

Cytokines (IL-1, IL-6) from the immune system stimulate the adrenal gland, pituitary, hypothalamus and send neuroendocrine hormones (ACTH, endorphins) back to the immune system

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15
Q

Describe the relationship between the immune system and brain:

A
  • Immune system is sensory organ for stimuli not recognised by the nervous system
  • The brain may send signals and guide the traffic of cells through lymphoid organs
  • Immune recognition of viruses, bacteria, tumour cells or antigens could lead to physiological changes as a result of release of shared peptides acting on receptors common to the immune and neuroendocrine systems
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16
Q

Describe the actions of ACTH:

A

Suppression of antibody synthesis
Suppression of IFN-y synthesis
Suppression of B-cell proliferation
Stimulates NK-cell activity

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17
Q

Describe the actions of endorphin:

A

Enhances the generation of cytotoxic T cells and NK-cell activity
Modulates T-cell proliferation and antibody synthesis

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18
Q

Describe the actions of TSH:

A

Enhances antibody synthesis

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19
Q

Describe the actions of GH:

A

Stimulates the production of superoxide anions by macrophages

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20
Q

Describe the cytokines and effects of the HP-adrenal axis:

A

IL-1, IL-6, TNFa - enhances release of CRH

IL-1, IL-2 - enhances release of ACTH

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21
Q

Describe the cytokines and effects of the HP-thyroid axis:

A

IL-1 - enhances TSH release inhibiting factor (SOM)

TNFa - decreased TRH content

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22
Q

Describe the cytokines of the HP-gonadal axis:

A

IL-1 - inhibits GnRH release

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23
Q

Describe the traits of cytokines:

A

Low molecular weight proteins
Play major role in initiation, propagation, regulation and suppression of immune and inflammatory responses
Secreted and expressed on cell surface
Act locally and initiate action by binding to specific cell surface receptors on target cells
Have redundant functions
Synergistic or antagonistic effects resulting in complex cytokine cascades

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24
Q

List the cytokines implicated in inflammatory and immune responses within the CNS:

A

IL-1 (predominantly produced by activated macrophages)
IL-6
TNF-a
TNF-B
IFN-y
TGF-B (negative regulator, anti-inflammatory)
CSFs

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25
Q

Describe interleukin-1:

A

Major costimulator for helper T cell activation and proliferation
Can enhance growth and diffferentiation of B cells
Inflammatory reactions through induction of other inflammatory molecules (prostaglandins, collagenase, phospholiapse A2)
Promotes leukocyte adhersion and production of other cytokines

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26
Q

What effect does IL-1 have on the HPA axis?

A

Activates HPA axis

Increases plasma ACTH and endophin levels

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27
Q

Which cells in the CNS are the principle sources of cytokines?

A

Activated astrocytes and microglia contribute to propagation of intracerebral immune and inflammatory responses initiated by immune cells

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28
Q

What might changes in cytokine gene expression and function contribute to?

A

Various neurological disorders, such as MS, EAE

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29
Q

Describe the pathway via the autonomic nervous system:

A

Hypothalamus –> Locus coeruleus –> Spinal cord –> Catecholamine release –> lymphoid tissue

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30
Q

Which NTs and NPs alter the immune function and trafficking in primary (thymus, bone marrow) and secondary lymphoid organs (spleen, lymph nodes)?

A

Catecholamines
Acetylcholine
Neuropeptides (VIP, NPY, substance P, CGRP, opiod peptides)

31
Q

Define psychoneuroimmunology:

A

Relationship between stress and immunity (how psychological factors alter the function of the immune system)

Stress can be seen as the most important and complex body reaction to ensure survival

32
Q

Which NPs mediate stress-induced alteration of lymphoid tissues?

A

Glucocorticoids

Catecholamines

33
Q

What effects do corticosteroids (stress hormones) show:

A

Profound lympholytic effect on lymphoid organs
Inhibit lymphocytic function
Ability to suppress immune response
Suppress inflammation

34
Q

Which brain areas in the brain are activated by stress?

A

Several regions in the hypothalamus
Amygdala
Basal ganglia of the thalamus
Brain stem neurons (ventral lateral medulla, nucleus of the solitary tract, locus coeruleus, periaqueductal gray, raphe nuclei)

35
Q

How do we recognise the areas activated by stress:

A

C-Fos positive brain cells in locus coeruleus

36
Q

When does autoimmunity occur?

A

When the immune system acts against its own tissue

37
Q

Describe the three possible mechanisms of autoimmunity:

A
  1. Lymphocytes responding to an infectious agent may coincidentally cross-react with self-tissue (molecular mimicry)
  2. A virus, drug, or genetic mutation may alter the surface of a cell, so that the cell appears to be foreign to the immune system
  3. An antigen which had been hidden from the immune system during embryogenesis so that the tolerance did not occur to the antigen, may serve as an antigenic stimulus if the antigen is exposed to the immune system in adult life
38
Q

List the 5 set criteria for autoimmune diseases:

A
  1. 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 immunoglobuilins
  5. A clinical response to immunomodulatory therapy or plasma exchange
39
Q

Which structures can autoantibody-associated neurological disorders (AAND) can affect each structure of the CNS?

A 
Cortex
White matter
Spinal cord
Nerve roots
Neuromuscular junction
40
Q

What are some target antigens of the CNS:

A

Ion channels, carbohydrate epitopes, transmembrane proteins, intracellular proteins, intracellular enzymes, glycolipids, neurotransmitter receptors

41
Q

What are the three effector functions of autoantibodies?

A 
Direct functional block (MG)
Antigenic modulation (MG, LEMS)
Complement-dependent mechanisms (MG, MS, GBS, RE)
42
Q

Describe the histopathological manifestations of autoimmune disorders:

A

Local reduction of the target antigen without detectable immune response (LEMS, SPS)
–> Severe mononuclear infiltration, deposition of immunoglobulin and complement and macrophage-mediated tissue destruction (MS, GBS)

43
Q 
What do the following conditions affect:
Myasthenia gravis
Lambert-Eaton syndrome
Multiple sclerosis
Stiffman syndrome
Paraneoplastic syndrome
Guillain-Barre syndrome
ALS
Rasmussen's encephalitis
A 
nACh receptor
Ca2+ channel
Myelin proteins
GAD
Neurons
Gangliosides
Ca2+ channel
GluR3
44
Q

What does myasthenia gravis stand for?

A

Muscle weakness severe

45
Q

How does Myasthenia Gravis fulfill the set of 5 criteria for AAND?

A

Autoantibody is present
Autoantibody interacts with the target antigen (nAChR)
Immunisation with the antigen produces a model disease
Passive transfer reproduces disease features
Reduction of antibody levels ameliorates the disease

46
Q

Describe the clinical symptoms of myasthenia gravis:

A

Muscular weakness and fatigability
Ptosis (drooping of the upper eyelid)
Diplopia (double vision)
Bulbar symptoms (difficulty chewing and swallowing)

47
Q

How does Anti-AChR antibodies affect neurotransmuscular transmission in MG?

A

A. Binding and activation of complement (complement-dependent lysis of the postsynaptic membrane)
B. Antigenic modulation (crosslinking/internalisation/degradation of nAChRs)
C. Functional AChR block (direct inhibition)

48
Q

What treatment options are available for myasthenia gravis?

A

Anticholinesterase agents
Immunosuppressive treatment
Plasma exchange
Thymectomy (effective even without tumour)

Future - Specific immunotherapy

49
Q

Describe the animal model (EAMG) for MG:

A

Induced in rabbits, rats, mice by immunisation with
-nAChR from the eels electric organ
-nAChR from other species
-peptide fragments of the nAChR
Immunised animals develop disease which is clinically, electrophysiologically and histologically identical to MG

50
Q

Describe the clinical course of MG in animal models:

A

Acute phase
Chronic phase
Passive transfer of anti-nAChR antibodies from rats with chronic EAMG to normal recipient rats induces signs of acute EAMG

51
Q

Describe Lambert Eaton Myasthenic Syndrome (LEMS):

A

Reduced release of the NT ACh from the nerve terminal into the synaptic cleft
Autoimmune process takes place at presynaptic level (vs. postsynaptic MG)
Characterised by autoantibodies against voltage-gated calcium channel

52
Q

How are MG and LEMS distinguished?

A

Immunocytochemical testing:
Serum antibodies against:
The calcium channel (LEMS)
nACh receptor (MG)

53
Q

Describe Stiffman syndrome:

A

Antibodies against glutamic acid decarboxylase
Antibodies interfere with the synthesis of GABA
Reduction in brain levels of GABA in the motor cortex
High titres of antibodies in most patients

54
Q

Describe the pathogenesis of Stiffman syndrome:

A

Loss of GABAergic inhibitory input into motor neurons via interneurons produces the tonic firing of motor neurons at rest
Leads to excessive excitation in response to sensory stimuli

55
Q

Describe the therapy for Stiffman syndrome:

A 
Diazepam (enhances GABA neurotransmission)
Immunomodulatory agents (steroids, plasma exchange)
56
Q

Describe Multiple Sclerosis incidence:

A

Occurs in genetically susceptible people

Women 2x more frequently affected

57
Q

Describe the pathological hallmark of multiple sclerosis:

A

Demyelinated plaque

Results in slowing or bloackade of neurotransmission in the CNS resulting in clinical symptoms

58
Q

Describe the clinical symptoms and course of multiple sclerosis:

A 
Problems with vision and hearing
Sensory-motor distubance
Coordination and balance problems (ataxia)
Cognitive deficits
Secondary symptoms

Clinical course relapsing-remitting or progressive

59
Q

Describe the pathogenesis of multiple sclerosis:

A

Genetic and environmental factors (viral infection, metabolic stress) may activate pre-existing autoreactive T cells and facilitate their movement from the systemic circulation into the CNS

In the CNS, local factors may further facilitate entry of T cells into the CNS through disruption of the BBB

60
Q

Describe the mechanisms of immune mediated injury in multiple sclerosis:

A

Direct injury to oligodendrocytes by CD4+ and CD8+ T cells
Cytokine-mediated injury of oligodendrocytes and myeline
Digestion of surface myelin antigens by macrophages
Complement-mediated injury

61
Q

Describe the treatment of MS:

A

Corticosteroids (first preference)
Immunotherapy (plasma exchange, cytokines)
-Inteferon-B1a has been shown to reduce axonal injury after demyelination
-Various agents with immune mediating properties are yielding inconclusive results
Gene therapy

62
Q

Describe the MS model of experimental autoimmune encephalomyelitis (EAE):

A

EAE is acute/chronic-relapsing inflammatory and demyelinating disease
Induced in mice, rats, monkeys
Disease process closely resembles MS in humans

63
Q

How is EAE induced (animal models)?

A

Myelin basic protein
Proteolipod protein
Myelin oligodendrocyte glycoprotein

64
Q

What are the benefits of researching EAE?

A

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

65
Q

Describe Guillain Barre syndrome:

A

A disease of the PNS
Antibodies to gangliosides - components of the lipid membrane
Bacterial/viral infections often occur prior to GBS onset
A mechanism of molecular mimicry is hypothesised
Antibodies to gangliosides correlate with GBS pathogenesis
Axonal degradation occurs as a terminal damage

66
Q

Describe the diagnosis of GBS:

A

Progressive weakness of limbs
Areflexia-the absence of reflex
High protein levels in the CSF

67
Q

Describe the course of GBS:

A

Acute disease followed by complete recovery (65%)
Prolonged suffering - severe axonal damage (27%)
Death - severe acute complications (arrhythmia) (8%)

68
Q

How may GBS be treated?

A

Plasma exchange decreases times of acute suffering but does not change prognosis

69
Q

Describe novel therapies of inflammatory demyelinating diseases of the CNS:

A

Gene therapy aimed to deliver therapeutic molecules into the CNS

70
Q

Describe the use of gene therapy and autoimmunity:

A

Protective genes inserted into viral vectors or plasmids and injected into encephalitogenic T cells
Cells uses as Trojan horses to deliver genes coding for anti-inflammatory cytokines and neurotrophic molecules to the CNS of EAE animals
These genes inhibit the detrimetnal function of mononuclear cells, but also foster proliferation and differentiation of surviving oligodendrocytes in demyelinating areas

71
Q

Describe the role of IFN-B in gene therapy:

A

Delivered intracerebrally
Therapeutic
Clinical efficacy

72
Q

Describe the role of IL-1B in gene therapy:

A

Delivered intraveneously
Preventative
Clinical efficacy

73
Q

Describe the role of IL-4 in gene therapy:

A

Delivered via MBP-specific T cells
Therapeutic
Clinical efficacy

74
Q

Describe the role of TGF-B in gene therapy:

A

Delivered via MBP-specific T cells
Therapeutic
Clinical efficacy

MedSci 317 (7 decks)

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