Neuroimmunology Flashcards
What are the stages that occur for the innate and adaptive immunity in the periphery?
- Microorganisms penetrate the epithelial surface of the body for the 1st time
- Phagocytic macrophages possess surface receptors that are able to recognize and bind constituents of bacterial or viral surfaces
- Induction and secretion of inflammatory molecules such as cytokines and chemokines to attract neutrophils and monocytes from the bloodstream = initiation of inflammation
- Local inflammation associated with activation of additional inflammatory molecules (e.g. complement) and recruitment of innate immune cells
- Proteolytic reactions and destruction of microorganisms
Compare the innate response and adaptive responses, what are some downsides to each of the responses?
What is meant by cellular immunity with the innate and adaptive immunity?
Innate immunity associated with macrophages (phagocytosis/ scavenging) and neutrophils.
Adaptive immunity associated with dendritic cells, T and B lymphocytes.
What are dendritic cells? Whats their role?
Dendritic cells are specialized phagocytic cells whose role is to carry pathogen to lymphoid organs and to present to T/B lymphocytes = initiation of the adaptive immunity.
What is a neuron and its role?
Principal functional unit of the nervous system (brain and spinal cord)
Role is to receive, process and transfer the information
What are the three key features of the neuron?
Excitability
Conductibility
Communication
What do neurons use to command the body’s response?
Through a complex neuronal network
The neuron
What are the glial cells in the CNS ans the periphery?
CNS
Astrocytes
Microglia
Oligodendrocytes
Radial glial cells
Ependymal cells
Periphery
Schwann cells
entertic glial cells
Satellite glial cells
What are the important roles of glial cells for the nervous tissue?
Support the neurons
Control the homeostasis of the neuronal environment
Contribute to the transmission of the neuronal signal
Participate to the immune system of the brain
Whats more abundant, glial cells or neurons?
Glial cells (10x more numerous)
Are glial cells excitable?
Whats a property they have?
Glial cells are non-excitable cells with the property to proliferate in the brain
What are the two classifications of glial cells and what does this mean?
Macroglia: oligodendrocytes and astrocytes (derived from the neuroectoderm like the neurons)
Microglia: originate from yolk sac
Tell me about astrocytes?
Trophic support to neurons
Maintenance to local homeostasis
Form the blood-brain barrier
Tell me about oligodendrocytes
Produce myelin sheaths around axons
Increase conductivity between neurons
Tell me about microglia
Brain immune cells
What is the BBB?
Highly selective barrier at the interface between blood and brain, protecting the brain from pathogens.
What is the BBB composed of?
Composed of a monolayer of endothelial cells and astrocytes end-feet stitched together by structure called tight junctions.
What makes the BBB highly restricted?
The presence of tight junctions (lack of intercellular gaps)
What type of molecules can/cannot cross the BBB?
Only small molecules (e.g. oxygen) and liposolubles molecules can cross the barrier. Large molecules (e.g. drugs) need receptors at the surface of the endothelial cell.
The BBB
What is meant by the immune privilege?
Survival of the foreign tumour due to a lack of communication between the brain and periphery
Tell me some more about immune privilege
If a graft is implanted directly into the brain, it survives longer than in other tissues.
Rejection of the brain graft occurs if a graft from a lymphoid organ is also embedded in the brain.
Therefore, T-cell mediated immunity in the brain seems required for the rejection.
This suggests that information of the presence of the tumour graft in the brain does not pass from the brain to the lymphoid organs (lymph nodes, spleen) where T lymphocytes are present.
The immune reactivity of what is similar to that in the periphery?
Immune reactivity of ventricles, choroid plexus, meninges and circumventricular organs similar to periphery
The immune privilege is restricted to what location and what is this due to?
Immune privilege restricted to brain parenchyma (behind the blood-brain barrier) and is due to the absence of dendritic cells in the brain
Specificity of the cerebral immune response
What two cells are important in cerebral immunity?
Microglia
Macrophage-related population in the brain
Tell me about microglia
Resident immune cells of the brain
Originated from yolk-sac derived progenitors (membranous sac attached to the embryo providing nourishment, functions as the developmental circulatory system, before internal circulation)
Reside behind the blood-brain barrier
Tell me about macrophage-related populations in the brain
Perivascular macrophages
Macrophages in leptomeninges and choroid plexus
Tell me about the unique structure of microglia
In a healthy brain: microglia have a unique pattern of gene expression different from the other brain cells and macrophages- “homeostatic signature” driven by the expression of the anti-inflammatory cytokine TGFbeta
106 genes expressed by microglia in healthy condition
Microglial in human brain morphology and functions…
Microglia are motile cells which have dynamic surveillance of what?
The local microenvironment
How often are the brain parenchyma screened by microglia?
Once every few hours
Tell me about sampling of the microglia with the extracellular space?
Extracellular space sampled in a random way and at high turnover rate
What are some roles of the microglia?
Housekeeping function
Effective control of the microenvironment
Clear the parenchyma of accumulated metabolic produces and damaged tissue
What other cells do microglia come into contact with?
Astrocytes
Neurons
Microglia facilitate rapid reactions to what kind of injury?
Brain injury (e.g., disruption to the BBB)
The number of microglia that respond depends on what?
The severity of the injurt
What microglia are activated?
Only microglial cells in the immediate vicinity of the laser injury are activated
What status is returned to once the microglia respond to the stimulus?
They return to the surveying state as the stimulus is resolved
Tell me about the role of microglia with a stroke/ infarct?
Microglia respond to absence of oxygen and tissue damage following stroke
Microglial activation occurs to clear the brain from cell debris
Activation persists for months following the infarct
When do microglia appear in development and whats their involvement?
They colonize the brain very early during brain development
They participate in brain development and maturation by shaping the neuronal network
They represent to 0.5 to 16% of the total cell numbers in human brain
In humans, they adopt different morphologies from ramified cells with fine processes to ameboid cells with spherical shape and lack of processes, based on the environment
In humans, they are the only cells to renew in the healthy brain from the age of 3
A microglial cell lives ~4 years with some cells up to 20 years, remembering brain events
What type of cells are microglia and what do they monitor?
They are dynamic cells, monitoring synaptic activity, surveying the micro-environment, and responding to early pathological events.
What is “inflammaging”?
Predispose per se to inflammation, a concept known as “inflammaging”
What is the ageing concept supported by?
Concept supported in the human brain by altered expression profiles of immune- and inflammation-related genes in middle-aged human and mouse brain during normal ageing
What type of experiment with rats was done and what was it looking at?
Performance of old mice impaired and associated with pro-inflammatory transcriptomic and microglial changes)
Unbalanced proliferation vs apoptosis resulting in increased microglial number
Phenotypic changes such as increased activation status (inflammatory molecules) associated with microglial priming
Tell me about some morphological changes with ageing?
Morphological changes: shorter and less ramified processes, fragmentation of microglial processes observed
What is ageing a risk factor for?
Ageing: strongest risk factor for neurodegenerative disease such as Alzheimer’s disease, Dementia with Lewy bodies, Parkinson’s disease
Different microglial population might coexist within the same brain
Define the following status’ of the primed microglia/ innate memory
- Physiological/ homeostatic
- Primed microglia (one immune stimulus)
- Trained microglia (repetitive immune stimuli)
- Immune memory
Difference between rodent and human microglia with the following…
- Environment
- Life expectancy
- Genetics
- Other variable
- Anatomical distribution
- White matter volume
- Knowledge of distribution, turnover and dynamics
- Recruitment of peripheral monocytes to CNS
- Inflammatory profile
Fill in the gaps…
Microglia are the resident _____ cells of the brain. During embryogenesis, microglia derive from the _____ and participate to the brain _____ and_____. They are identified by a unique _____ signature. The morphology of microglia can be regarded as a _____ from highly _____ to_____ cells. In the healthy brain, microglia are dynamic and motile cells, surveying the brain parenchyma, where they constitute the first line of defence against pathogens or injury.
With ageing, microglia present _____changes characterised by _____ and less ramified processes, and _____ changes with increased inflammatory status that can lead to _____ microglia and the establishment of an_____ memory.
Microglia are the resident immune cells of the brain. During embryogenesis, microglia derive from the yolk sac and participate to the brain development and maturation. They are identified by a unique homeostatic signature. The morphology of microglia can be regarded as a spectrum from highly ramified to amoeboid cells. In the healthy brain, microglia are dynamic and motile cells, surveying the brain parenchyma, where they constitute the first line of defence against pathogens or injury.
With ageing, microglia present morphological changes characterised by shorter and less ramified processes, and phenotypic changes with increased inflammatory status that can lead to primed microglia and the establishment of an immune memory.
What are some characteristics of neurodegenerative disorders?
- Progressive
- fatal
- associated with ageing
- increasing social and economic burden
- degeneration of neurons
Pathology of Alzheimer’s disease
Activation of what cells are the hallmark of Alzheimer’s brain?
Microglia activation
What have epidemiological studies suggested about Alzheimer’s disease?
Epidemiological studies suggest brain inflammation as an important driver of the disease but trials of anti-inflammatory therapies non-conclusive
Brain imaging in live patients with Alzheimer’s disease have shown what?
Brain imaging in live patient’s show both increase of amyloid (PIB-PET) and microglial (PK11195-PET) signals in AD patients, but cognitive decline associated with increased microglial signal
What has a genome wide analysis shown about Alzheimer’s disease?
Genome wide analysis studies have identified variation in genes of the immune system that can influence the development of Alzheimer’s disease- role for microglia in the onset/ progression of the disease
Tell me about the animal models of AD and what is often used as a good model
Based by model chosen e.g., amyloid protein precursor (APP) transgenic mice are very good models of Abeta accumulation but most lack tau or much neurodegeneration- do not fully replicate AD pathology (>200 models)
Differences in innate immunity between mice Vs humans?
Investigate cause and effect relationships
Pilot ideas for therapy
Identification of disease-associated microglia (DAM) profile, with transcriptional analysis at single-cell level has shown what?
- Co-localisation with amyloid plaques, less ramified morphology
- Transcriptional signature includes anti and pro-inflammatory genes, modules for the interferon response, stress response, lysosomal function, and lipid metabolism
- Downregulation of microglial homeostatic markers e.g., CX3CR1, P2RY12
- Conserved transcriptional signatures across mouse models of neurodegenerative diseases
- Associated with apoptosis and phagocytosis via lysosome
Tell me about the Identification of microglial neurodegenerative phenotype (MGnD)- driven by a rise of microglial (APOE/TREM2) and apoptotic markers (e.g, Axl, Clec7a), and the fading of the homeostatic signature (P2RY12, CX3CR1)
Microglia associated with Abeta-plaques exhibit a neurodegenerative phenotype
Phagocytosis of apoptotic neurons suppresses homeostatic microglia
The TREM2-APOE pathway regulates neurodegenerative microglial phenotypic switch
Targeting APOE (amin risk factor for AD) signalling restores homeostatic and immunological tolerance microglia
What is the CFAS?
CFAS: large UK community-based longitudinal multicentre study looking at health and cognitive function in the elderly (n=299)
What is immunolabelling with markers associated with specific function of microglia used for?
In people without dementia, motile microglia associated with Tau deposition
Microglial response to protein deposition may influence the development of dementia
APOE polymorphism may influence the microglia towards a protective or detrimental profile
TREM2 expression in the human brain is a marker of what?
monocyte recruitment
Tell me about TREM2 gene variation
A rare risk factor with a big effect on the development of Alzheimer’s disease
TREM2 is a part of what? and is expressed by what?
TREM2 is part of the immune system and assumed to be expressed by microglia, influencing the balance between phagocytic and pro-inflammatory activity
In 284/299 CFAS cases, what did the TREM2 label?
In 5 cases with acute infarcts, what did the TREM2 identify?
In 284/299 CFAS cases, TREM2 labelled monocytes in the blood vessels, but not microglia or perivascular macrophages
In 5 cases with acute infarcts, TREM2 identified cells in brain parenchyma interpreted as recruited monocytes
? role of systemic immune response
There are several roles for innate immunity in Alzheimer’s disease, tell me about what microglia cells respond to?
Protein deposition which may influence the development of dementia
In people without dementia, what are motile microglia associated with?
The presence of Abeta
In people with dementia, what are phagocytic microglia associated with?
Tau deposition
Genetics are the cause of microglial activation but this is also a consequence of neurodegeneration, tell me some outcomes of this
Increase in harmful “neurotoxic” microglial functions
Reduction in beneficial “homeostatic” microglial functions
Non-disease-specific response to microglia to neuronal damage
What cells are involved in the innate immunity and alzheimer’s?
Microglial
What cells are involved in the adaptive immunity and alzheimers?
CD4+ amd CD8+ T cells
Tell me the roles of the adaptive immunity in Alzheimer’s disease
CD4+ and CD8+ T cell infiltration occurs in human Alzheimer’s brain parenchyma, with CD8+ cells more numerous that CD4+ cells
Level of T cells in Alzheimer’s disease is very low but significant compared to control brains
T cell immunity in Alzheimer’s disease has been mainly related to amyloid pathology
However, what is unclear when it comes tot he adaptive immunities roles in alzheimers disease?
They participate to the disease or an epiphenomenon
Their presence is beneficial or detrimental
This may depend on the relative magnitude and functionality of different types of T cell response
Can we manipulate microglia?
The immune system involves in the onset and progression of the disease
Can we exploit the immune system to prevent or treat AD?
Immunisation with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Tell me about the Abeta immunotherapy in Alzheimer’s disease: Elan pharmaceuticals AN1792 clinical trial
Started in 2000
Active immunisation with AN1792 (full length Abeta42)
Mild to moderate AD (MMSE-15-25)
80 patients with mild to moderate Alzheimer’s disease
-64 patients immunised/ 16 patients with placebo
Safety and immunogenicity study completed
Long term clinical and neuropathological follow up study performed
Quantification of Abeta42 and tau features
Quantification of Abeta42 and tau features
Microglial reaction following Abeta immunisation
Phagocytosis of Abeta by microglia following Abeta immunisation
Immune response following Abeta immunisation
Negative association between the anti-Abeta antibody response and Abeta plaque score indicating the magnitude of the immune response to Abeta influences the degree of Abeta removal from the brain
Microglia after immunisation
Variability in the distribution of microglial markers suggests the presence of different functional states of microglia in the same brain
Overall, downregulation of microglial activation when Abeta has been removed
Immunisation against Abeta does not induce auto-immune disease
In Alzheimer’s disease: inverse correlation between microglia and Abeta
Expression of microglia limits Abeta accumulation?
Or Abeta accumulation down regulates microglia to minimise neuronal damage?
Microglial motility impaired in AD?
Relation of microglia with ptau in Alzheimer’s disease
Hypothesis
Increase harmful functions
Decrease beneficial homeostatic functions
?microglia see plaques as micro-organisms
Non-specific microglial response to neuronal damage (e.g., CD68)
Abeta –> microglia reaction –> Tau (neuritiv plaque) –> Tau (tangles) –>
Clinical follow up (6 years, n=80)
Persistent neuropathological effects 14 years following amyloid-beta immunisation in Alzheimer’s disease
15-year post-mortem neuropathological follow-up
22 brains- 17 brains with Alzheimer’s disease actively immunised against Abeta remain virtually plaque-free for 14 years
Extent of plaque removal is related to the immune response with changes in the microglial function to facilitate Abeta clearance whilst downregulating microglial activation to reduce non-specific bystander damage
Most patients had progressed to severe dementia, notable including the five with very extensive plaque removal, possibly due to conditioned tau propagation
??preventive treatment with aducanumab (Biogen)
What are Th1 cells defined by and what do they promote and why?
Th1 cells defined by IFNgamma and Il2 and tend to promote inflammation, to evoke cell-mediated immunity necessary for combating invading pathognes- whereas Th2 cells produce cytokines (e.g., IL4, IL5, IL10, IL13) and support strong antibody response essential for opsonisation of pathogen s
What did post-mortem examination of immunised patients show with CD3+ T cells?
Post-mortem examination of immunised pateitns showed no different in the CD3+ T cells recruited in the parenchyma
What are some of the possible causes invluded in the recognition of the antigen by?
Abeta-specific T cells
Strong Th1-biased adjuvant
Addition of polysorbate 80 to improve produce solubility and stability
What being developed for adaptive immunity and immunotherapy?
Passive protocols
Systemic infection in the brain…
What are some symptoms?
What does a systemic infection lead to?
Tell me what the hypothesis is for a systemic infection in alzheimers disease
What evidence do the animals models of dementia show for systemic infection
Systemic inflammation exacerbates sickness behaviour
Sickness behaviour is mediated by transient production of pro-inflammatory cytokines by microglia
This pro-inflammatory state of microglia increases neuronal damage
What evidence do clinical studies show in regard to systemic infection?
Microglial activation is associated with cognitive decline
Systemic inflammation is associated with development of sickness behaviour, raised pro-inflammatory cytokines in blood and marked increase in the rate of long-term cognitive decline
Etanercept in Alzheimer’s diseases: a phase 2 clinical trial
etanercept is a TNFalpa inhibitor already used for arthritis
41 participants, well tolerated
“Interesting trends that favour etanercept”
Further trials underway
Systemic infection modifies the neuroinflammatory response in late-stage Alzheimer’s disease
24 controls without infection, 16 controls with infections, 28 AD brains without infection and 40 AD brains with infection
At the end stage of the diseases, systemic infections induce anti-inflammatory brain environment and microglia appear dysfunctions, exhausted and unable to respond
Experimental models suggest that systemic infections drive pro-inflammatory environment with enhanced neuronal loss. However, recent mouse study showed repetitive LPS injections induce microglial immune tolerance
Early treatment to minimise the effected of infection and to support microglia
Tell me the following about SARS-CoV2…
- What is it caused by?
- Symptoms present during the acute phase
- Symptoms present in those in ICU
- Symptoms in patients with the mild/ moderate disease
- What can this disease lead to?
COVID-19: disease caused by sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
During the acute phase, roughly 36% of patients develop neurological symptoms including dizziness, headache, impaired consciousness, seizure
Patients on intensive care unit presented agitation, confusion, and corticospinal tract symptoms (e.g., muscle weakness, abnormal reflexes)
Patients with mild/ moderate disease report olfactory and gustatory dysfunctions (anosmia and dysgeusia)
COVID-19 can lead to inflammation-induced disseminated intravascular coagulation (abnormal blood clotting) which with endothelial dysfunction can cause cerebrovascular complications with ischemic stroke
What are the 4 possible pathogenic mechanisms that may account for the detrimental effect of COVID-19 on the brain?
- Direct viral encephalitis
- Systemic inflammation
- Peripheral organ dysfunction (liver, kidney, lung)
- Cerebrovascular changes
What are COVID-19 survivors at risk to?
COVID-19 survivors are at risk to develop long-term neurological consequences by aggravating a pre-existing neurological condition or by initiating a new disorder (e.g., myalgic encephalomyelitis known as chronic fatigue syndrome)
Summary
- The brain is relatively but not completely isolated from the immune system
- Inflammation is a biological process essential for survival by detrimental in the brain
- Principle brain immune cell are the microglia
- Role of microglia in diseased brain still unclear and immunophenotyping is essential to increase out knowledge
- Manipulation of the immune system (immunisation) has been tried for therapy in alzheimer’s disease prompts removal of amyloid protein by microglia with potentially some benefit in patients early in disease
- There may be crosstalk between peripheral and brain immune system so thay systemic infections can accelerate neurodegeneration in the earliest stage of the disease
