Module B - Immunity Flashcards
What is neuroimmunology the interaction between?
Nervous system and immune system
Why is the brain thought to be immunologically privileged?
- Existence of BBB (ECs connected with tight junctions and astrocytes and pericytes connected with gap junctions)
- Lack of antigen presentation within CNS
- Absence of a lymphatic drainage (present in immune organs, but not brain)
Why is the immune privilege theory thought to be incorrect?
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”
Describe the afferent limb of the immune response to an antigen (genetic):
Recognition of antigen
Generation of effector cells
Describe the efferent limb of the immune response to an antigen (genetic):
Passage of activated lymphocytes and antibodies into the tissue
Elimination of antigen by antibodies and effector cells
Describe the completion of the immune response loop:
Completed by the movement of activated immune cells across intact BBB membranes and antibody leakage
What do immunogenic signals elicted by an antigen in the CNS result in?
Non-inflammatory response (peripherally includes upregulation of antibody response)
What immune molecules are involved in the response:
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
Describe the types of cells produced from lymphocytes:
B cell (Th2) T cell (Th1) (suppressor, cytotoxic, helper, regulatory)
What are the functions of phagocytes (cell eaters)?
Scavengers
Antigen-presenting cells
Secretory cells
Describe neuroimmune interactions:
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
Describe neuroendocrine immune interactions:
Brain and nervous system interacts directly with the immune system, or indirectly through stress and the endocrine system
Describe the neuroendocrine pathway:
The immune and neuroendocrine systems share many ligands and receptors that result in constant and important bi-directional communication
Describe the neuroendocrine pathway loop:
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
Describe the relationship between the immune system and brain:
- 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
Describe the actions of ACTH:
Suppression of antibody synthesis
Suppression of IFN-y synthesis
Suppression of B-cell proliferation
Stimulates NK-cell activity
Describe the actions of endorphin:
Enhances the generation of cytotoxic T cells and NK-cell activity
Modulates T-cell proliferation and antibody synthesis
Describe the actions of TSH:
Enhances antibody synthesis
Describe the actions of GH:
Stimulates the production of superoxide anions by macrophages
Describe the cytokines and effects of the HP-adrenal axis:
IL-1, IL-6, TNFa - enhances release of CRH
IL-1, IL-2 - enhances release of ACTH
Describe the cytokines and effects of the HP-thyroid axis:
IL-1 - enhances TSH release inhibiting factor (SOM)
TNFa - decreased TRH content
Describe the cytokines of the HP-gonadal axis:
IL-1 - inhibits GnRH release
Describe the traits of cytokines:
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
List the cytokines implicated in inflammatory and immune responses within the CNS:
IL-1 (predominantly produced by activated macrophages)
IL-6
TNF-a
TNF-B
IFN-y
TGF-B (negative regulator, anti-inflammatory)
CSFs
Describe interleukin-1:
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
What effect does IL-1 have on the HPA axis?
Activates HPA axis
Increases plasma ACTH and endophin levels
Which cells in the CNS are the principle sources of cytokines?
Activated astrocytes and microglia contribute to propagation of intracerebral immune and inflammatory responses initiated by immune cells
What might changes in cytokine gene expression and function contribute to?
Various neurological disorders, such as MS, EAE
Describe the pathway via the autonomic nervous system:
Hypothalamus –> Locus coeruleus –> Spinal cord –> Catecholamine release –> lymphoid tissue
Which NTs and NPs alter the immune function and trafficking in primary (thymus, bone marrow) and secondary lymphoid organs (spleen, lymph nodes)?
Catecholamines
Acetylcholine
Neuropeptides (VIP, NPY, substance P, CGRP, opiod peptides)
Define psychoneuroimmunology:
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
Which NPs mediate stress-induced alteration of lymphoid tissues?
Glucocorticoids
Catecholamines
What effects do corticosteroids (stress hormones) show:
Profound lympholytic effect on lymphoid organs
Inhibit lymphocytic function
Ability to suppress immune response
Suppress inflammation
Which brain areas in the brain are activated by stress?
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)
How do we recognise the areas activated by stress:
C-Fos positive brain cells in locus coeruleus
When does autoimmunity occur?
When the immune system acts against its own tissue
Describe the three possible mechanisms of autoimmunity:
- Lymphocytes responding to an infectious agent may coincidentally cross-react with self-tissue (molecular mimicry)
- 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
- 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
List the 5 set criteria for autoimmune diseases:
- 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 immunoglobuilins
- A clinical response to immunomodulatory therapy or plasma exchange
Which structures can autoantibody-associated neurological disorders (AAND) can affect each structure of the CNS?
Cortex White matter Spinal cord Nerve roots Neuromuscular junction
What are some target antigens of the CNS:
Ion channels, carbohydrate epitopes, transmembrane proteins, intracellular proteins, intracellular enzymes, glycolipids, neurotransmitter receptors
What are the three effector functions of autoantibodies?
Direct functional block (MG) Antigenic modulation (MG, LEMS) Complement-dependent mechanisms (MG, MS, GBS, RE)
Describe the histopathological manifestations of autoimmune disorders:
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)
What do the following conditions affect: Myasthenia gravis Lambert-Eaton syndrome Multiple sclerosis Stiffman syndrome Paraneoplastic syndrome Guillain-Barre syndrome ALS Rasmussen's encephalitis
nACh receptor Ca2+ channel Myelin proteins GAD Neurons Gangliosides Ca2+ channel GluR3
What does myasthenia gravis stand for?
Muscle weakness severe
How does Myasthenia Gravis fulfill the set of 5 criteria for AAND?
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
Describe the clinical symptoms of myasthenia gravis:
Muscular weakness and fatigability
Ptosis (drooping of the upper eyelid)
Diplopia (double vision)
Bulbar symptoms (difficulty chewing and swallowing)
How does Anti-AChR antibodies affect neurotransmuscular transmission in MG?
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)
What treatment options are available for myasthenia gravis?
Anticholinesterase agents
Immunosuppressive treatment
Plasma exchange
Thymectomy (effective even without tumour)
Future - Specific immunotherapy
Describe the animal model (EAMG) for MG:
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
Describe the clinical course of MG in animal models:
Acute phase
Chronic phase
Passive transfer of anti-nAChR antibodies from rats with chronic EAMG to normal recipient rats induces signs of acute EAMG
Describe Lambert Eaton Myasthenic Syndrome (LEMS):
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
How are MG and LEMS distinguished?
Immunocytochemical testing:
Serum antibodies against:
The calcium channel (LEMS)
nACh receptor (MG)
Describe Stiffman syndrome:
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
Describe the pathogenesis of Stiffman syndrome:
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
Describe the therapy for Stiffman syndrome:
Diazepam (enhances GABA neurotransmission) Immunomodulatory agents (steroids, plasma exchange)
Describe Multiple Sclerosis incidence:
Occurs in genetically susceptible people
Women 2x more frequently affected
Describe the pathological hallmark of multiple sclerosis:
Demyelinated plaque
Results in slowing or bloackade of neurotransmission in the CNS resulting in clinical symptoms
Describe the clinical symptoms and course of multiple sclerosis:
Problems with vision and hearing Sensory-motor distubance Coordination and balance problems (ataxia) Cognitive deficits Secondary symptoms
Clinical course relapsing-remitting or progressive
Describe the pathogenesis of multiple sclerosis:
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
Describe the mechanisms of immune mediated injury in multiple sclerosis:
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
Describe the treatment of MS:
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
Describe the MS model of experimental autoimmune encephalomyelitis (EAE):
EAE is acute/chronic-relapsing inflammatory and demyelinating disease
Induced in mice, rats, monkeys
Disease process closely resembles MS in humans
How is EAE induced (animal models)?
Myelin basic protein
Proteolipod protein
Myelin oligodendrocyte glycoprotein
What are the benefits of researching EAE?
Enables studies of demyelination
Allows to study different pathways of inducing EAE
Allows to test potential treatments for MS
Describe Guillain Barre syndrome:
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
Describe the diagnosis of GBS:
Progressive weakness of limbs
Areflexia-the absence of reflex
High protein levels in the CSF
Describe the course of GBS:
Acute disease followed by complete recovery (65%)
Prolonged suffering - severe axonal damage (27%)
Death - severe acute complications (arrhythmia) (8%)
How may GBS be treated?
Plasma exchange decreases times of acute suffering but does not change prognosis
Describe novel therapies of inflammatory demyelinating diseases of the CNS:
Gene therapy aimed to deliver therapeutic molecules into the CNS
Describe the use of gene therapy and autoimmunity:
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
Describe the role of IFN-B in gene therapy:
Delivered intracerebrally
Therapeutic
Clinical efficacy
Describe the role of IL-1B in gene therapy:
Delivered intraveneously
Preventative
Clinical efficacy
Describe the role of IL-4 in gene therapy:
Delivered via MBP-specific T cells
Therapeutic
Clinical efficacy
Describe the role of TGF-B in gene therapy:
Delivered via MBP-specific T cells
Therapeutic
Clinical efficacy
