Midterm Flashcards
(248 cards)
1
Q
Immune cells
A
Dynamic set of specialized cells that search for, deal with and eliminate danger
2
Q
Pathogens
A
Things that our immune system defends against. Can include viruses, bacteria, fungi, etc.
3
Q
Immune system
A
A network of blood derived cellular operations that orchestrates protection against the microbial world.
4
Q
Innate immune system
A
A nonspecific response that includes the first and second line of defence.
5
Q
Leukocytes
A
Specialized cells of the immune system.
6
Q
First line of defence for innate immune system
A
Barriers that block entry/invasion. These include ears, eyes, mouth and nasal cavity, skin, stomach, trachea and bronchi, vagina, urethra and anus.
7
Q
Second line of defence for innate immune system
A
Once a pathogen has made it past the first line of defence, the second line of defence is activated and involves cells and fluid attacking invaders
8
Q
Adaptive immune response
A
Specific response that involves the 3rd line of defence. develops after exposure to a pathogen.
9
Q
True or false: the innate and adaptive immune systems are mutually exclusive.
A
False, they typically work together; the innate system informing the adaptive immune system.
10
Q
Defensins
A
Antimicrobial peptides which can kill and inhibit growth of pathogens - found in the mucous layer surrounding the GI tract.
11
Q
Overall function of innate immune cells (IICs)
A
- getting rid of pathogen by “eating” it or releasing signals that destroy it
- send signals to recruit other immune cells for help
- send signals to alert and mobilize the adaptive branch
12
Q
Mast cells will recognize bacteria and then release _____________
A
Heparin/histamine
13
Q
Heparin/histamine
A
Causes blood vessels to dilate which increase in white blood cell concentration at the affected area
14
Q
How do innate immune cells recognize pathogens?
A
Pathogens have PAMPs attached to them which is recognized by receptors on the innate immune cells (PRRs)
15
Q
PAMPs (Pathogen associated molecular patterns)
A
Non-specific shared characteristic of different types of pathogens that are not present on human cells.
16
Q
What do innate immune cells do once their PRRs are activated?
A
Initiates phagocytosis which includes engulfing, breaking down and digesting the pathogen
17
Q
What is the main cell type involved in phagocytosis
A
Macrophages
18
Q
Neutrophils and Phagocytosis
A
The most abundant and rapid responders who roam through blood and infectious tissue - they engulf and destroy microbes (especially bacteria)
19
Q
Macrophages and Phagocytosis
A
Found throughout the body as roamers and reside in various tissues
20
Q
Eosinophils and phagocytosis
A
embedded in tissue and are used to kill parasites larger than bacteria
21
Q
Dendritic cells and phaogcytosis
A
Embedded in tissue and are antigen presenting cells - they phagocytize part of the antigen and then present its parts to the adaptive immune system.
22
Q
Describe the 3 methods of attack for neutrophils
A
1) Phagocytosis
2) Degranulation - this involves releasing chemicals such as defensins(which are attracted to the pathogen’s membrane) which then poke holes into the membrane of the pathogen inducing apoptosis
3) Release of Neutrophil Extracellular Traps (NETS): involves a net like extension which will trap the pathogen and then bring it to the neutrophil to perform phagocytosis
23
Q
How do innate immune cells attack very large pathogens?
A
Phagocytic cells will act to destroy it as well as release toxic chemicals such as defensins, ROS (reactive oxygen species) and lysosomes to chemically break it down.
24
Q
Cytokines
A
Small glycoproteins that are involved in chemical signalling in which are released into the blood stream by IICs upon recognition of a pathogen.
25
Primary role of cytokines
Recruits, activate/deactivate, and/or stimulate production of immune cells.
26
Autocrine signalling
Signal that acts on the same cell it was released from
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Paracrine signalling
Signalling the affects cells in the immediate vicinity
28
Endocrine signalling
Signalling that affects cells remote from the secreting cell
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Pro-Inflammatory cytokines
Used to amplify the immune response.
Examples: TNFa, IFN-gamma, Interleukin-6 (IL-6)
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Anti-inflammatory cytokines
Used to decrease an inflammatory response
Examples: IL-4,IL-10, IL-20
31
Complement system
A set of 20 proteins present in the blood (compliment proteins) that are activated by pathogens. Their role is to enhance inflammation, cause opsonization, cytolysis
32
Opsonization
Tagging of a pathogen for destruction
33
Cell types involved in the adaptive immune system
B cells and T cells
34
Cellular immunity typically involves __________
T cells
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Humoral immunity typically involves ___________
B cells
36
Antigen
Specific molecular markers of different bacteria (sometimes a pathogen can be referred to as an antigen)
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How does a B cell recognize a pathogen?
B cells have B cell receptors that can recognize one specific antigen on a pathogen.
38
Antibody specificity
A B cell can only recognize one type of pathogen - one that can recognize influenza cannot recognize herpes.
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How do B cells proliferate?
An antigen binding to a BCR will cause a cascade that will lead to the proliferation of that B cell. The b cell will make effector B cells which will then mature into plasma cells. Plasma cells will release the antibodies against the antigen.
40
What is the main function of an antibody
To neutralize and/or eliminate a pathogen/antigen
41
How does an antibody neutralize a pathogen?
It does so by binding to the antigen which anchors it - therefore it cannot enter cells and replicate.
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What is an antibody's role in opsonization?
The antibody's constant region is exposed which signals macrophages and other phagocytes to come engulf the pathogen.
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Variable region of an antibody
Binds to the antigen on the pathogen, leaving constant region exposed
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Constant region of the antibody
Not attached to the antigen: they recruit macrophages and phagocytes to the pathogen to be phagocytized.
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Fc Region
receptor on a phagocyte which allows them to recognize antibodies that are bound to pathogens.
46
Active immunity
Immunity that occurs by exposing someone to the virus (vaccinations)
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Passive immunity
Natural immunity that is derived from without activating the individuals immune system.
Example: mother's breast milk or blood plasma transplant
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Memory b cells
Created during the B cell proliferation stage and remain once a pathogen has been eliminated. Allows prompt recognition of that same pathogen should we be infected again.
49
Function of T cells
1) Help other immune cells
2) Regulate immune response
3) Kill and mobilize a response against infected cells
50
What are the 4 types of T cells
1) CD 8+ Cytotoxic T cells (Tc)
2) CD 4+ T helper cells (Th)
3) CD4+ T Regulatory cells (Treg)
4) T memory cells
51
Role of Cytotoxic T cells
To kill infect cells
52
MHC proteins
Major histocompatibility complex that all cells have. Once infected, the MHC will turn the virus into fragments, hold its parts on its cells surface and it present it outside the cell for the Tc to kill.
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MHC1
All nucleated cells in the body have this complex
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MHC2
Found in antigen presenting cells such as phagocytic Innate Immune Cells (dendritic cells) and B cells
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How does a Tc recognize and initiate elimination of an infected cell.
The CD8 protein in Tc will recognize the MHC1 on the infected cell and bind to it. The CD8 protein will move the cell closer to the TCR and if it recognizes the pathogen it will initiate apoptosis of the cell. The Tc and the infected cell will also release cytokines that will call the Tc to make clones of itself. The clones (Effector Tc cells) will now be circulating to find more infected cells. They will bind and force the cell to self destruct through exocytosing perforin and granzymes that will poke holes in the infected cells membrane.
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Role of the T helper cells
They help engage an immune response by secreting cytokines which help activate other cells of the immune system
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Lymphatic system
part of a vascular system comprising a large network of lymphatic vessels that contain fluid called lymph
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Proliferation of Th cells
When the MHC2 binds to the Th cell cytokines are released. These cytokines will initiate proliferation of 2 types of TH cells: Th1 or Th2.
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What cytokine initiates Th1 proliferation?
IL-12
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Sterile inflammation
Factors that cause an immune activation in our body that is not provoked by a pathogen.
Example: Trauma, stroke, toxins, etc.
61
What is the blood brain barrier?
A membrane that assists in making our peripheral immune system decentralized, prevents harmful substances from entering into the brain, and allows selective passage of essential nutrients such as oxygen and hormones.
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What cells make up the BBB?
Brain capillary endothelial cells (BCECs)
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What is the neurovascular unit(NVU) made up of?
BCECs, pericytes and astrocytic endfeet.
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How does the BBB restrict things from entering the brain?
The BCECs are joined together by tight junction proteins.
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Paracellular transport across BBB
Refers to transport that occurs in between cells, passing through an intercellular hollow pathway. Not tightly regulated and relatively unselective (based on size and charge). (H2O, electrolytes)
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Transcellular Diffusion across BBB (Passive diffusion)
Transport of small lipophillic molecules through brain capillary endothelial cells from the blood into the brain
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Carrier Mediated Transcytosis across BBB
Molecules carried across the BCECs via specific solute carriers/carrier proteins. Solute will bind to the protein transporter leading to a conformational change, allowing the carrier to then transport the substance to the other side of the membrane (typically with its concentration gradient) (if against gradient, ATP is used)
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Absorptive Mediated Transcytosis across BBB
Positively charged substance in bloodstream is attracted to negatively charged membrane, this induces membrane invagination and vesicle formation. The substance-containing vesicle will enter intracellular space and move to the brain side of the capillary endothelium -- then integrating with the cell membrane and releasing its contents.
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Receptor mediated transcytosis across BBB ** will be an exam question **
Macromolecules enter via receptor binding which triggers an endocytotic event and subsequent transport across the BBB. The ligand binds to the receptor, initiates invagination of membrane and endocytosis; in cell, the vesicle can be 1) recycled back out into the capillary, 2) fuse with membrane on the other side for content release, or 3) fuse with lysosome and be degraded.
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Flaw of the BBB
Prevents treatment administration for certain brain illnesses.
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How might scientists overcome the flaw of the BBB when administering brain treatments
We can inject antibodies into the brain were created to target certain brain pathogens or proteins for destruction or for tagging.
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How are antibodies created for immunostaining?
Inject antigens into an animal species (rat, rabbit, etc). Antigen will activate the B cells and then produce antibodies against that antigen. We then collect the plasma and extract the antibodies from the plasma. (Primary antibody)
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Method for utilizing antibodies against Alzeimer's (removal of beta ameloid plaques)
Using the Receptor mediated transcytosis system, there are many transcytosis receptors (TfR) on the BCECs.
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Antibody conjugation
Method of antibody delivery that involves taking a part of the protein that binds to TfR and fusing it with the antibody. This antibody/protein complex can then cross the BBB and bind to the antigen in the brain.
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True or false: Antibodies are immunoglobulin proteins?
True
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Antigen binding region
Portion of the antibody that binds to the antigen.
77
5 classes of antibodies
IgG, IgM, IgD, IgA, IgE
78
Role of IgG
To neutralize toxins and perform opsinization.
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Bispecific antibodies
An antibody that binds to 2 different antigens, one being the BBB receptor and the second being the Ag target.
80
Other methods of treatment delivery into the brain (not including receptor mediated transcytosis)
1) Utilizing other receptors on BCECs
2) Linking drugs with amino acids that are known to cross BBB
3) Using BBB permeability enhancers.
4) Non-invasive techniques
81
Leaky BBB
This describes when the BBB becomes compromised and leads to infiltration of toxic substances into the brain.
82
Microglia
The brain's immune cells, they act as guards detecting first signs of pathogenic invasion, tissue damage, cancerous or defective cells.
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True or False: Microglia come from the same source as other cells of the CNS
False, they are though to come from progenitor cells in our yolk sac.
84
Characteristics of microglia as surveyors
They are in their non-reactive form where they move around our neurons and cells looking for "trouble". Microglia in this state have a small cell body and highly ramified branches.
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Overall function of microglia in their non-reactive form
- Clean up cellular debris and foreign materials in the environment.
- Maintain homeostasis to ensure integrity of neuronal circuits.
86
What causes microglia to exit their non-reactive form
If their recognition receptors are activated they will morph into their reactive form which consists of reactive-non-phagocytic or reactive phagocytic.
87
Two pathways of morph from a non-reactive microglia
1) Non- reactive --> Reactive-non-phagocytic --> reactive phagocytic
2) Non-reactive --> reactive non-phagocytic
Non-reactive can turn into either RNP or RP, depends on whether phagocytic receptors get activated or not.
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Role of microglia in their reactive form
- Release molecules to recruit and activate other immune cells
- Release factors that induce destruction/protection of neurons and dendrites.
- Regulate amount of inflammation
- **engage in phagocytosis**
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5 Steps in phagocytosis **guaranteed exam question**
1) recognition of pathogen, debris or apoptotic cells
2) ingestion and formation of phagosome
3) formation of the phagolysosome (merging of a phagosome and a lysosome)
4) killing of target molecule
5) elimination and exocytosis
90
Are non reactive microglia typically pro- or anti- inflammatory?
Anti-inflammatory
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Are reactive microglia typically pro- or anti- inflammatory?
Pro-inflammatory
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Two types of receptors present on microglia
1) Damage recognition receptors (DRRs) - recognize damage/apoptotic cells (DAMPs)
2) Pattern/pathogen recognition receptors (PRRs) - recognize PAMPs
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How do microglia recognize damage?
Their DRRs will be activated by nuclear or cytosolic proteins released by the damaged cell.
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What happens when a DRR is activated?
It will engage in chemotaxis, release cytokines and engage in phagocytosis
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Chemotaxis
Process where microglia and other cells move in response to a signal
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NFKB pathway resulted from PRR activation
1) the NFKB complex is resting in the cytosol and not moving because it is attached to IKB.
2) When TLR4 is activated, IKB gets broken down which leads NKFB to be free to act as a transcription factor
3) NFKB will translocate from cytosol into nucleus to interact with DNA/promoter regions of pro-inflammatory cytokines to be transcribed.
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Neuroinflammation
Brain's inflammatory response to various triggers, such as injury, infection, stress or neurodegen. conditions. It involved the accumulation of reactive microglia.
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Acute neuroinflammation
Rapid inflammatory response which occurs immediately following CNS injury or xenobiotic detection in the brain, often involving activated microglia (RNP and RP) for a period of time
99
How can microglia protect against stroke damage?
1) Swiftly clearing debris, removing dead cells and preventing harm to neurons.
2) Release growth factors like VEGF and BDNF.
3) Promote formation and maintenance of tight junctions for the BBB
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How microglia can be more damaging in terms of stroke damage?
Instead of being strictly anti-inflammatory, microglia can promote inflammation thru the release of pro-inflammatory cytokines and ROS which can cause damage to surrounding tissue.
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VEGF
Vascular endothelial growth factor. It promotes angiogenesis (growth of blood vessels)
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BDNF
Brain derived neurotropic factor. Its a factor that is engaged to protect neurons, involved in synaptic plasticity, growing of dendrites to make new connections following an ischemic stroke.
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Minocycline
An antibiotic that has been shown to have neuroprotective factors as it promotes an anti-inflammatory environment.
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Chronic neuroinflammation
prolonged and sustained inflammatory response within the CNS, characterized by a presence of reactive microglia.
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Pathogen that can inhibit phagocytosis/induce cell death
Listeria monocytogenes
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What cells do microglia recruit in order to replenish?
BMDMs and PVMs, they can replace lost microglia.
107
How do microglia distinguish between active vs inactive synapases?
1) Detecting number of AMPA receptors on the synapses. More AMPA receptors = preservation of that synapse
2) Unused synapses will send out filopodia projections to the microglia to be engulfed.
3) Unused synapses will use chemokine signalling to attract the microglia to engulf them.
108
What did Ader & Cohen's 1950 experiment with rats, saccharin water and Cyclophosphamide (CP) demonstrate? Recall in this experiment saccharin water was
paired with CP (a chemotherapy drug that attacks dividing cells) and then the CP was taken away. Following CP removal rats only drank saccharin water. Despite this they still had a reduction in their immune response.
This showed that the CNS can influence our immune response.
109
Which cells are activated by MHC1-peptide/Ag complex in response to viruses?
CD8 cytotoxic T cells
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What does the Type 1 Interferon Response primarily defend against?
Viral infections
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What role do Type I Interferons (e.g., IFN-alpha & IFN-beta) play?
They have powerful antiviral properties.
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How do type 1 interferons pose an antiviral defense mechanism?
1. block viral replication
2. enhance the activity of other immune cells like cd8 and nk cells
3. increase the expression of mhc1 molecules on infected cells
4. induce apoptosis in virus infected cells
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if a person exhibiting high loneliness scores is exposed to a virus, what might you expect
in their immune response?
impaired ability to clear the virus
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In a lab study, lonely monkeys exposed to the SIV virus showed __________
reduced type 1 IFN response.
115
What is sickness behaviour?
constellation of behavioural effects that an organism uses to defend against an immunological threat.
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Anhedonia
Loss of pleasure in things we once found pleasurable.
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If a mouse shows reduced grooming and disturbed sleep rhythms, what can be inferred?
The mouse is likely experiencing sickness behaviour.
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According to theorists, what is the primary purpose of adopting sickness behaviors?
To reorganize priorities for survival.
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What is the primary cause of sickness behavior?
Cytokines (endogenous pyrogens) influencing the brain.
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What happens when the body exceeds normal set point?
Warm-sensitive neurons in the pre-optic nucleus of the hypothalamus (PNOH) become activated and signal to the automatic nervous system (sweat glands and blood vessels) telling them to dilate and secrete fluids in order to decrease heat.
121
What happens when the body's temperature decreases?
Cold sensitive neurons become activated and signal to blood vessels to constrict and sweat glands to remain inactive in order to conserve body heat.
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Fever
An increase in the set point for temp regulation set by the hypothalamus.
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Endogenous pyrogens
Pro-inflammatory cytokines such as IL1beta
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Exogenous pyrogens
Different pathogens such as parasites, bacteria and viruses.
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What is the fever inducing prostaglandin?
(PG)E2
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How is PG(E2) synthesized?
Arachidonic acid (fatty acid) is converted into prostaglandin H2 (PGE2) by cyclo-oxygenase.
127
How do prostaglandins affect the warm-sensitive neurons in the pre-optic nucleus of the hypothalamus (PNOH) during fever?
When PG(E2) binds to its receptor in the PNOH (EP3R), there is a decrease in neuronal firing therefore the hypothalamus will not send any signals to the blood vessels and the sweat glands, this ultimately increases the hypothalamic set point.
128
Besides interacting with cells of the OVLT to increase prostaglandin release leading to fever, how else do pyrogens contribute to fever?
Through activation of vagal nerve afferents (the neural pathway)
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Circumventricular organs
Areas in the brain that lack a BBB. Lines the 3rd and 4th ventricle close to the hypothalamus.
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How do immune cells respond to increased body temperature?
By enhancing phagocytosis of the innate immune cells
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What is the effect of COX-2 inhibitors like ibuprofen on fever?
To decrease fever by inhibiting the synthesis of PG(E2) through antagonizing its enzyme (cyclooxygenase).
132
How do pyrogens induce anorexia during sickness?
By suppressing AgRP neurons, which inhibits the inhibition of satiety neurons, therefore they continue to tell us we are full
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If a person's body temperature rises during an infection, how might POMC neurons respond?
By reducing appetite, through activation of satiety neurons that tell us we are full.
134
What is the role of the sympathetic nervous system (SNS) in the initial immune response?
To enhance the immune response.
135
Steps to transrepression
1) cortisol will bind to GR which will become activated and undergo a conformational change
2) activated GRs translocate from the cytoplasm into the cell nucleus
3)within the cell nucleus, activated GRs interact with pro-inflammatory transcription factors (TFs)
4) this interaction prevents the activation of these TFs and ultimately their ability to promote pro-inflammatory cytokine transcription
end game one = reduced expression of pro-inflammatory cytokines.
136
Steps to transactivation
1) cortisol will bind to GR which will become activated and undergo a conformational change
2) activated GRs translocate from the cytoplasm into the cell nucleus
3) within the cell nucleus, GRs bind to specific DNA sequences call glucocorticoid response elements (GREs) which are typically located in the promotor regions of anti-inflammatory target genes
4) this interaction of GRs binding to GREs results in the production of anti-inflammatory cytokines.
end game 2 = increased expression of anti-inflammatory cytokines
137
Which receptors are expressed by B cells, T cells, and macrophages to allow for their mobilization during the initial stages of the stress response?
Adrenergic receptor
138
What is the primary purpose of cortisol release during an immune response?
To serve as an anti-inflammatory agent
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What can prolonged cortisol elevation lead to as a result of chronic stress?
Chronic inflammation and immune dysregulation
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In an infection, what is a direct consequence of (PG)E2 interacting with GABA neurons they inhibit CRH neurons in the stress response?
To decrease GABA neuron firing
141
Biological hallmarks of PD
1) degeneration of dopamine neurons in the substantia nigra
2)presence of Lewy body inclusions
3)neuroinflammation
142
Symptoms of PD
- Bradykinesia
- Rigidity and postural instability
- Tremors
- Walking or gait difficulties
- Gastro dysfunction
- Fatigue
- Anxiety
- Depression
143
How pathogens may trigger microglia activation leading to DA cell death in PD?
1) entry of pathogen
2) triggers immune response
3)cytokine gain entry/or cause more cytokine activation which causes prolonged proinflammatory microglia
4) leads to death of DA neurons in the SNc
5) results in PD motor characteristics.
144
Non-cell autonomous theory (neuroinflammation)
1) pathogen enters into the brain
2) reactive microglia become activated and release things like ROS and proinflammatory cytokines
3)that leads to cell death of DA cells in the area
4) those dead cells are gonna release DAMPS which signals microglia to come clean up and initiate apoptosis
5) this cycle continues and triggers a cascade of events
145
Cell autonomous theory (neuroinflammation)
1) Problem in the DA neuron which leads to the activation of microglia
2) Toxin will enter DA neuron and DA neuron will die and release DAMPs that will cause activation of microglia
3)Activated microglia will release ROS and proinflammatory cytokines which results in the cyclic cycle of killing DA cells.
146
How are the peripheral immune cells recruited from the CNS?
1) Activated microglia recruit peripheral pro-inflammatory immune cells through cytokine release - decreasing the selectivity of the BBB, allowing peripheral immune cells to enter.
2) Infiltration of peripheral immune cells
3) Peripheral immune cells contribute to neuroinflammation
147
Proposed role of peripheral immune cells in parkinsons
1) Macrophages assist the microglia in phagocytosis
2) B cells release auto-antibodies to coat neurons with misfolded alpha-synuclein aggregates (least supported theory of PD)
3) T cells (depending on the type)
- Th(CD4+) cells amplify neuroimmune response
- May be involved in contributing to cell death (CD8+)
148
How do CD4+/CD8+ cells induce cell death in DA neurons?
Involved RP and RNP microglia.
- A DA neuron will die and then release lewy bodies, subsequently releasing a-syn. The microglia will phagocytosize the a-syn and break it down and the present it on cell surface. RNP will release pro-inflammatory cytokines to recruit immune cells to the site (CD4). When they enter the brain, the T cells will turn into effector cells and then proliferate. THe effector T cells will have a FAS ligand and that will bind to the FAS receptor on the DA cells, inducing apoptosis.
149
Describe what happens to KO CD4+ T cells in mouse model exposed to MPTP.
MPTP is a compound that exerts the death of DA neurons. KO CD4+ cells showed less DA cell death when exposed to MPTP compared to wildtype mice exposed to MPTP.
150
Immune priming effect (in terms of PD)
Something that occurs that predisposes us to another "hit" in PD. For example - we may have genetic vulnerability/early pathogen exposure and then we are more primed to be vulnerable to envio toxins - which can subsequently lead to PD
151
Paraquat
Herbicide used to spray crops to prevent weeds.
152
What did they find in the paraquat animal model of PD
Expose animal to paraquat and find that it induces behavioural abnormalities associated with PD: motor coordination deficits, decreased home cage activity, impaired fine motor skills, increased anxiety, increased behavioural despair, increased cognitive deficits.
153
#1 genetic contributor to PD
Mutations are typically genetically inherited on the LRRK2 gene
154
What does LRRK2 do?
Strongly upregulated in our leukocytes and microglia after the have been exposed to immune activating agents. Seem to be involved in chemotaxis.
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How do G2019S mutation mice react to LPS
Increased chemotaxis
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How do LRRK2 KO mice react to LPS
No microglia activation/no increase in microglia staining. This is exactly how a mouse would react to a saline injection as well.
157
TNF alpha receptors
TNFR1 (p55) or TNFR2(p75). TNFR1 is found in most cells and TNFR2 are found in the cells of the innate immune system.
158
TNFR1 levels are ________ in brains of PD patients
increased
159
How does TNFalpha induce death of DA neurons?
activation of the TNFR1 receptor induces signalling cascades, first causing activation of TRADD. Following TRADD, there are 2 pathways that lead to apoptosis: death signalling pathway, and the MAPK pathways. It can also activate a 3rd pathway to enhance neuroinflammation: NfKB pathway.
160
Antibiotic used to block TNFalpha production
Minocycline
161
IFNgamma
Microglia signalling factor that leads to inflammation and apoptosis when bound to its receptor expressed on neurons and microglia. Effects on microglia/neurons occur via JAK/STAT pathway
162
Key steps to JAK/STAT pathway
1) IFNgamma binds to receptor
2) JAK then phosphorylates receptor
3) Two STAT proteins then bind to phosphates
4) JAK will then phosphorylate stats and then form a dimer
5) Dimer enters into nucleus and acts as transcription factor binding to target genes (e.g FAS, IFNgamma)
163
How might cannabis protect against PD?
Different components in cannabis can activate the CB2 receptor found on the microglia. Binding of the CB2 receptor can reduce microglia activation thus reducing microglia's contribution to inflammation and thus contribution to DA cell death.
164
Gut brain axis
bidirectional communication network that links the CNS with the gastrointestinal tract and its resident microbiota
165
How does the gut communicate with the brain?
Through neural pathways such as the vagal nerve, endocrine signalling, immune responses (cytokines) and microbial metabolites (SCFAs)
166
Gut
The entire tract from mouth to anus
167
Organization of the intestines
Small intestine comprised of the duodenum, jejunum and the ileum. Then the large intestine (colon).
168
4 specialized cells of the intestines
Enterocytes, enteroendocrine, goblet and paneth cells.
169
Enterocytes
Epithelial cell responsible for nutrient uptake, tightly joined together to make up intestinal barrier
170
Enteroendocrine cells
Cells that produce hormones (hunger/satiety hormones)
171
Goblet cells
Creates mucus that lines the gastrointestinal tract which prevents microbes from interacting with our enterocytes/human cells because if they do it can result in gut inflammation (they can activate TLR4 on enterocytes)
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Paneth cells
Specialized immune cell that releases antimicrobial peptides such as defensins
173
The _____________ connects our gut to the rest of the body
lamina propria
174
Where do most of our immune cells reside?
70% of our immune cells exist in our lamina propria waiting for a pathogen to breach intestinal barrier. Consists primarily of innate immune cells, but consists of some adaptive immune cells.
175
Peyers patches
Lymphoid structures in the gut that contain adaptive immune cells, waiting to be activated by innate immune system (where antigen presentation takes place)
176
Gut microbiome
collection of genes from microbiota in the gut (balance between of good and bad microbes)
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How does our immune system know to not attack the good microbes in our gut?
Early in dev, our microbiota trains our immune system to not attack it therefore immune cells learn what microbiota are good vs bad.
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Functions of gut microbiota
1) protection against pathogens
2) essential nutrients
3) digestion and NRG
4) train immune system
5) critical defense mec. of the brain
179
Delivery important in training immune response to fetus
Vaginal birth
180
Individuals more likely to get asthma and immune deficiency are born ___________
via c-section
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2 tight junction proteins
Occludin and claudin-5
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3 types of SCFA metabolites
acetate, propionate, and butyrate.
183
Multifactorial etiology of gut microbiome
sex differences, genetics, Diet, delivery method, medication, social interaction, environment
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Germ Free (GF) mice when compared to control (Pathogen Free; PF) mice show what in regard to BBB?
GF mice has increased permeability in BBB and decreased expression of TJ proteins (increased Evans Blue in brain)
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What in the diet cant normally be digested?
Fibre (plant polysaccharides)
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What helps digest fibre?
different bacteria microbiota
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Short Chain Fatty Acids (SCFA)
resulting end product from fibre digestion, which is important in the integrity of BBB
188
What did mice that had colonized bacteria and produce SCFA (CONV mice) show when compared to GF mice?
Restored BBB integrity and increased TJP (claudins/occludin); (reduction in Evans blue in brain)
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what does Clostridium tyrobutyricum produce?
butyrate
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What does Bacteroides thetaiotaomicron produce?
acetate and propionate
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What does R4A (NMDA receptor for Ab) do?
induce cell death
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Microbiota play what role in relation to microglia
1. Promoting microglia maturation
2. Training microglia to appropriately respond to pathogens
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Microglia from adult GF mice show what when compared to PF mice?
increase in immature markers; decreased inflammatory response genes
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Dysbiosis
ecological balance of our gut microbiota disrupted in a way that shifts this balance so there are more bad bacteria compared to good bacteria
195
Has been linked to reduction in bacterial diversity
old age and a variety of pathologies
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What do obese individuals have greater proportions of?
more firmicutes than Bacteroidetes
197
SCFA act to __________ food intake directly & indirectly via activation of ___________ neurons
decrease, pomc
198
Increase Lipoprotein lipase results in
increased energy storage by increasing uptake of fatty acids and triglycerides.
199
Fasting-induced adipocyte factor (FiaF)
released from enteroendocrine cells which inhibit LPL therefore LPL cannot induce storage of fatty acids and triglyceride.
200
FiaF in obese individuals
FiaF levels are reduced therefore LPL activity is increased and therefore an increase in energy storage in fat cells leading to an increase in fat tissues
201
FiaF in lean individuals
FiaF levels are increased which leads to a decrease in LPL activity.
202
Emulsifier
chemical compound added to processed food to prevent separation between liquids. exposure to this might result in decreased microbiota diversity which enhances inflammation which can in turn induce anxiety like behaviours.
203
What can emulsifiers do regarding intestinal permeability?
increase permeability of gut barrier -> increased peripheral inflammation measured by antibodies specific to bacterial components of LPS & Flagellin (ie. activated innate & adaptive immune system)
204
What neuropsychiatric disorder has been linked with dysbiosis of microbiota? also inflammation
anxiety
205
structures involved in the neurobiology of anxiety
amygdala, hippocampus, hypothalamus (PVN) & PFC
206
Clinical evidence of patients with GAD have shown___________
increased serum pro-inflammatory cytokines compared to anti-inflammatory cytokine ratios
207
Emulsifiers overall.......
1. alter gut mcirobitoa
2. increase gut permeability
3. increase systemic inflammation (ie. peripheral)
4. increase anxiety-like behaviours
208
Amygdala activation occurs via release of _______________
glutamate
209
2 parts of amygdala
basolateral amygdala (BLA) & central amygdala (CeA)
210
BLA receives glutamate that then activates _________________
Central amygdala (CeA)
211
What makes BLA more responsive to glutamatergic input?
Pro-inflammatory cytokines
212
Mice exposed to emulsifiers show what in BlA?
Increased genes related to amygdala hyperactivity
213
Immediately following a break in the skin, phagocytes engulf bacteria within the wound. This is an example of an _________ immune response which is __________ against a pathogen
innate, nonspecific
214
____________ are responsible for the production of antibody against pathogens.
B cells
215
Virus, bacteria and fungi can be considered:
A pathogen
216
Passive immunity in a developing infant can happen as a result of:
Exposure to breast milk
217
Humoral immunity is a type of adaptive immunity that results in the circulation of which of the following throughout the blood?
B cells/antibodies
217
Defensins can be considered:
an antimicrobial peptide which can kill or inhibit the growth of pathogens
218
Cells of lymphoid origin include:
T cells and b cells
219
T or F: The adaptive branch of the immune system is a slower response that the innate branch of the immune system
True
220
At the preclinical level, in an Alzheimer's disease transgenic (Tg) mouse model, researchers have conjugated an antibody to the portion of the transferrin protein that binds to the transferrin receptor (TfR) creating a protein complex. In the brain of these mice, as discussed in class, what is the primary outcome of injecting the protein complex into Tg mice engineered to express Aβ plaques?
Tagging of Aβ plaques for destruction by the brains immune cells
221
In adsorptive mediated transcytosis what is the primary process that occurs when a positively charged substance in the bloodstream associates with a negatively charged membrane surface?
Membrane invagination and vesicle formation
222
A professional antigen presenting cells like dendritic cells express which MHC protein?:
MHC2
223
Which type of T cell is primarily responsible for assisting other cells of the immune system, including B cells and cytotoxic T cells?
CD4+ T helper cells
224
What is the key feature of active immunity?
It involves the production of antibodies by the individual's own immune system (e.g., via vaccination)
225
What is the primary characteristic of passive immunity?
It involves the transfer of pre-formed antibodies or immune cells from another individual or source.
226
What is the primary role of T cell receptors (TCRs) on T cells?
To recognize and bind to a specific antigen-presenting complex
227
Which of the following is the primary function of cytotoxic T cells in the immune system?
Killing infected or cancerous cells
228
What typically happens to the concentration of antibodies in the blood following a secondary exposure to the same antigen?
The concentration of antibodies increases rapidly and significantly.
229
Otis's neurologist is considering the use of minocycline as a potential therapeutic approach to modulate microglial activation and promote a protective phenotype in her ischemic stroke. What is minocycline typically used for?
Antibiotic treatment
230
During chronic neuroinflammation, microglia primarily exhibit which phenotypic state?
Proinflammatory
231
What growth factor released by microglia helps fortify the Blood-Brain Barrier (BBB) by promoting the formation and maintenance of tight junctions?
Transforming Growth Factor-β (TGF-β)
232
How does microglia's release of VEGF contribute to their protective role in response to stroke?
By promoting angiogenesis and ensuring adequate blood flow
233
Which action by activated microglia contributes to their protective role in response to stroke?
Swiftly clearing debris and dead cells
234
In a study involving the OCD-like HoxB microglia deficient mouse, researchers replaced the deficient microglia with peripheral bone marrow-derived macrophages (BMDMs). What was the outcome of this intervention?
The OCD-like behavior improved and was reduced.
235
What role do peripheral bone marrow-derived macrophages (BMDMs) and perivascular macrophages (PVMs) play when recruited by microglia during distress in the CNS?
BMDMs and PVMs replace lost microglia to supplement the population
236
How does Listeria monocytogenes primarily impair microglia during infection?
Listeria interferes with phagolysosome formation, reducing microglial effectiveness.
237
Case Study Scenario: In a research study investigating the role of microglia in neuroinflammation, scientists exposed microglial cells to various pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). They aimed to determine how microglia recognize and respond to different types of cellular damage.
Question: During their experiments, the researchers observed that microglial cells rapidly detected and responded to the presence of certain molecules released during cellular damage. Which type of receptors on microglia are primarily responsible for recognizing these molecules?
Damage recognition receptors (DRRs)
238
Which of the following best describes the role of pyrogens in relation to fever?
Pyrogens are substances that initiate fever, either endogenously or exogenously.
239
When the hypothalamic set point is adjusted, resulting in fever, which of the following molecules moves to the PNOH and influences the firing tone of warm-sensitive neurons?
(PG)E2
240
Dr. Smith is studying the physiological response of the body during fever. He noticed that certain neurons in the PNOH are not firing as frequently as they typically would. Which of the following is the most likely reason for the reduced firing of these neurons during a fever?
Interaction of IL-1β with EP3R receptors on warm-sensitive neurons.
241
Sarah is studying the vagus nerve's role in fever. After extensive research, she concludes that there's a specific pathway that allows the vagus nerve to influence fever. What is this pathway termed as?
Neural pathway
242
aria is working on a research project to explore the feedback mechanisms in immune cells. She observes that when there's a rise in temperature, the immune cells show a notable change in one of their functions. What is this specific change?
Enhanced phagocytosis of pathogens
243
Which enzyme is responsible for the production of prostaglandins, specifically (PG)E2, and is targeted by drugs like ibuprofen to reduce fever?
Cyclooxygenase-2 (COX-2)
243
Dr. Evans is conducting a ground-breaking experiment to understand the intricacies of feeding behavior. After days of research, she notices a specific set of neurons that become highly active when subjects are deprived of food or exposed to a hormone known as ghrelin. However, when she introduces LPS to simulate immune activation, the activity of these neurons decreases, suggesting the involvement of certain cytokines and the vagus nerve. Which neurons is Dr. Evans most likely studying
AgRP neurons
244
A student asks Professor Chris about the mechanisms by which immune factors activate the stress response. Chris explains that there are several pathways, emphasizing one route involving the production of (PG)E2 from BCECs. How does this particular route impact CRH neurons?A student asks Professor Chris about the mechanisms by which immune factors activate the stress response. Chris explains that there are several pathways, emphasizing one route involving the production of (PG)E2 from BCECs. How does this particular route impact CRH neurons?
It causes a reduction in GABA neuron firing, leading to an increase in CRH.
245
Dr. Martinez is treating a 68-year-old patient diagnosed with Parkinson's disease. The patient has been on L-DOPA therapy and reports diminished effectiveness of the medication. Upon further testing, Dr. Martinez discovers an infection in the patient's stomach. The bacterium responsible for this infection is known to colonize the stomach lining, often causing chronic gastritis, and can potentially affect the absorption of L-DOPA. Which bacterium is most likely responsible for the patient's infection?
Helicobacter pylori
246
Which theory suggests that the degeneration in DA cells is driven by harmful factors originating from neighboring non-neuronal cells, such as microglia?
Non-cell-autonomous (NCA) theory
