Neuroinflammation Flashcards
What is Neuorinflammation? What is an early sign of this ? Explain why?
Neuroinflammation: refers to a *chronic, sustained inflammatory response, which contributes to neuronal injury, generally worsening the disease process
-Microglial activation is an early sign that usually precedes neuronal cell death.
-Initial immune response may be beneficial, however a sustained inflammatory response by microglia can have a detrimental effect
What kind of effects has microglial activation been linked to?
Microbial activation has been linked to pathology and disease progression in several neurodegenerative disorders and other CNS diseases
ex; Alzheimer’s, Parkinson’s, HIV-associated neurocognitive disorders, Huntington’s MS, ALS, stroke and others.
What is the role of Microglia in the Central Nervous System? What are the classical immunological and classical neurotransmitter receptors ?
Microglia:
-Resident macrophage of CNS (central nervous system)
-Highly specialized for the CNS
-classical immunological receptors (ex: complement, cytokine, chemokine, Fc, antigen presentation and scavenger receptors)
-Classical neurotransmitter receptors (ex: glutamate, GABA, and purines, transporters)
Describe the structure of the microglia and what happens to microglia under physiological conditions? How does microglia play a role in CNS?
Under physiological conditions, microglia in the CNS exist in a “resting state”
-Characterized by a small cell body and many elaborated thin processes with multiple branches that extend in all directions
-The CNS is under constant immunologic surveillance
“resting” microglia are actively screening their environment
Differentiate what happens with microglia when there are disturbances in the CNS vs a normal CNS.
Microglial activation;
-Disturbances in the CNS trigger a rapid transformation of ramified (“resting”) microglia towards a more rounded, amoeboid (“activated”) phenotype
-CNS under content immunological surveillance
In normal CNS, microglial activation is restricted
-once activated,(microglia) it is rapidly subdued to prevent or reduce secondary neural damage.
How do Neuronal signaling molecules play a role in microglial activity?
Neuronal signaling molecules participate in maintaining microglial quiescence (inactivity) in the normal brain and inhibiting microbrial activity under inflammatory conditions
Describe the regulation of microgial quiescence. which molecules play a role maintaining this quiescence. What contributes to role of maintaining microglial quiescence or activation?.
Under physiological conditions, neurons and astrocytes coordinately sustain microglial quiescence, thereby limiting the development of inflammatory responses
-Neuron-mediated “Off” and “On” molecules contribute to the maintenance of microglial quiescence or activation
When are OFF signals expressed compared to ON signals. How does microglia play a role when it comes to these signals?
OFF signals are constitutively expressed in HEALTHY brain
-Disappearance of these signals promotes microglial responses
-Microglia are activated by the disappearance (of off signals)
-LOSS of OFF signals causes over-activation of microglia and contributes to pathology
ON signals are found in DAMAGED neurons
-microglia are activated by appearance
What are the different types of Off signals? What are the Membrane bound off signals and their functions?
OFF signals can be Soluble or Membrane bound
-Membrane bound “OFF” signals:
-believed to be involved primarily in quieting microglial activation during close interaction between neurons and microglia in inflammation
1. CD47: constitutively expressed and involved in myeloid suppression, however, its receptor (CD172a) has not been identified o microglia
2. CD22 & CX3CL1: Inhibits cytokine release
-act on microglial CD45 and CX3CR1 respectively
3. CD200: inhibits myeloid activity in a variety of tissues
-may be very important for maintaining immune suppression in CNS
What are the soluble Neuronal OFF signals?
Soluble neuronal OFF signals:
-TGF-Beta: anti-inflammatory cytokine constitutively expressed in the brain-several animals studies suggest a role in microglial quiescence
-CD22 & CX3CL1: inhibits cytokine relate
-Both can be cleaved and act on CD45 and CX3CR1 respectively
-Neurotransmitters and neurotrophins
What are examples of the Neurotrophins and neurotransmitters that are OFF signals and how they impact microglial activation or quiescence?
Neurotransmitters:
ex: norepinephrine, glutamte, ATP
-microglia sensing synaptic activity may play a role in maintaining quiescence in the normal brain
-Possibly, extra-synaptic neurotransmitters signal to microglia that neurons are active and thereby suppress microglial activation
(ATP important in acting on microglia and quieting their response)
Neurotrophins
-ex: NGF, BDNF, and NT-3
-suppress expression of MHC II (antigen presenting cells) and co-stimulatory molecules CD40 and CD80 that are essential for antigen presentation
Explain how Astrocyes are used to regulate microglial quiescence . What molecules do astrocytes express that can inhibit its activation? What can happen to amoeboid (active, rounded) microglia that is cultured with astrocytes? What are the astrocyte-derived factors and their roles ?
Regulation of microglial quiescence
Astrocytes are also reported to iNHIBIT microbial activation, possibly through astrocyte expression of ;
-IL-10- suppresses antigen presentation capacity by down-regulation expression of MHC II and co-stimulatory molecules on microglia
- TGF Beta- INHBITS microglial activation
In vitro studies have shown that amoeboid microglia become ramified (resting state) when cultured with astrocytes or astrocytic-conditioned media
-Astrocyte-derived factors also induce morphological ramification
-Cytokines: M-CSF, GM-CSF, TGF-Beta
-Glial substrata: fibronectin, laminin
What kind of neuronal ON signals are there? When are they present?
neuronal ON signals are present in stressed or impaired neurons
Membrane bound ON signals:
- TREM-2-Ligand
ligation with TREM2 (microglia) promotes phagocytosis of apoptotic neurons and reduces inflammation
Majory of ON signals are Soluble:
-Glutamate; can also be an OFF signal
-CCL21, CXCL10: induce microglia migration (in vitro)
-Matrix metaloproteinase-3 (MMP-3)
demonstrated to be related in its active form from apoptotic neuronal cell cultures
Mediates the release of TNFalpha, IL-6 and IL-1B in “microglia: cultures
Purines: ex: ATP, UTP
Explain how microglia responds to CNS injury in terms of defense. What happens to their structure and function ?
Microglial response to CNS Injury:
DEFENSE
-Upon activation, ramified (resting) microglia retract their processes, increase their volume and become amoeboid
-numerous surface receptors and other factors are up-regulated that trigger or amplify innate and acquired immune responses that allow for the rapid killing and removal of foreign pathogens
-The type, degree and length of these responses can determine whether they are neuroprotective or contribute to neurodegeneration
What are the different factors that neuronal injury/dysfunction can result from?
Neuronal injury/dysfunction can result from:
-Weakening of neuronal inhibitory (“OFF”) signals
-presence of “ON” signals-extended or constitutive
-Continued stimulation of microglia by external factors
-can be activated by external factors alone
Explain how microglia responds to the CNS injury in terms of Repair? What do the microglia do? Discuss the hypothesis regarding microglia and synapses.
Microglia response to CNS injury: REPAIR
-Microglia assist neurons in overcoming damage that may have resulted from activation
-express and relate various growth factors (NGF, BDNF, NT-3, NT-4)
-Microglial activation often leads to high expression of EAAT-1, which assists in clearing excess glutamate
-(Hypothesis) Microglia may be capable of selectively removing glutamatergic synapses (synaptic stripping)
-Further limiting glutamate release into compromised brain regions.
What is inflammation? Compare and contrast acute inflammation vs Chronic inflammation and the body’s response. What are other effects of inflammation?
Inflammation: an organism’s immune-mediated protective response to a harmful stimuli, designed to remove the injurious agent and promote healing of damaged tissue
Acute inflammation: The body’s IMMEDIATE response to injury.
-initiated by cells already present in the tissue; (ex marcrophages and Dendritic cells )
Chronic inflammation: PROLONGED persistent inflammation in which the injurious agent persists
-may be long-standing and self-perpetuatin after the injurious agents is removed
-can be “idiopathic”- of unknown cause
-Causes or worsens many disorders
-Inflammation of the CNS was first unrecognized but is now known to contribute significantly to acute and chronic CNS disorders
What is primary function of immune system (immunology) ? What are the two main systems of the Immune system? How are they related?
General immunology
Primary function (immune system): protect the organism from external harmful agents- usually infectious, but also can be toxic (ex: endotoxin)
-Also play an important role in eliminating altered cells perceived to be “foreign”
Two main components:
1. Innate- respond IMMEDIATELY to a variety of agents
2. ADAPTIVE- provides a response to a SPECIFIC antigen
Two systems are NOT independent of each other (they work together0
-Response of one system profoundly affects the response of the other.
What occurs in Innate immunity and which cells are involved?
Innate immunity
-Front line of host defense
-does NOT require immune cell differentiation and maturation
-Rapid response to infectious or toxic agents
** Pattern recognition receptors (PRR)’-Pathogen-associated molecular patterns (PAMPS)
-Signaling PRRs- relay an intracellular signal after binding that promotes inflammation
ex: toll-like receptors- recognize structurally conserved molecules derived from microbes
*Damage-assocaited molecules patterns (DAMPS)- associated with cell components released during cell damage
-Endocytic PRRs- promote phagocytosis Without relaying an intracellular signal
ex; Scavenger receptors- recognize charged particles and mediate removal of apoptotic cells.
What are the different innate Immune cells and what roles do they play? Where are they located? What do innate immune cells do at the site of injury? What is the role of activated Dendritic cells?
Innate Immune cells
-Granulocytes, Macrophages, Dendritic cells, Natural Killer (NK) and gamma-delta T cells
-Macrophages and Dendritic cells reside in areas most likely to be exposed to infectious or foreign agents
-Initiate inflammation and promote the ADAPTIVE immune response
-at site of injury, innate immune cells secrete a number of cytokines and Chemokines that determine the subsequent pattern of response by the adaptive immune system
-Activated Dendrite cells migrate from the site, to the lymph nodes, where they present antigens they encountered at the site of injury to native T cells.
What is the role of Adaptive Immune system? What occurs? Which cells are involved? Why is this system considered adaptive?
Adaptive Immune system
-Responds to Specific antigens
-initial adaptive immune response can evolve over hours to days
-requires recognition of the specific antigen-followed by maturation, differentiation, and (clonal ) proliferation
Lymphocytes- T cells and B cells
-highly adaptive due to
=V(D) J recombination
-Somatic Hypermutation
Explain what the V(D)J recombination is? How is the variable region of Ig heavy and light chain encoded?
What are the components of these chains (light and heavy) ?
V(D) J recombination: Site-specific recombination reaction that occurs in T-cells and B cells and generates a diverse catalog of T-cell receptors (TCRs) and immunoglobulins (Ig) for specific antigen recognition ‘
- The variable region of an Ig heavy and light chain and TCRs are encoded in several gene segments referred to as Variable (V), diversity (D) and Joining (J)
-Through a systematic process, the Ig heavy chain and the alpha- and Beta chains of the TCR (T-cell receptor) are assembled by combining one V, D, and J segment. Only ONE V and J segment are in IG Light chains.
(Heavy- VDJ; Light chain: VJ)
Describe the V, D, J segments and how they are invited in generating antibodies. Why are gene rearrangements irreversible?
There are Multiple copies of each type of gene segment. Different combinations of these segments allow for the generation of vast number of antibodies and receptors with different antigen specificities
-Gene rearrangments are irreversible- progeny of the cell will inherit genes encoding the same Ig or TCR specificity (memory B and T cells) which confer long-lived antigen-specific immunity.
What occurs in Somatic hypermutation and where does it occur?
Describe the two step process of B-cell activation ?
What are the roles of the Effector (plasma) cells and Memory-B cells?
Somatic hypermutation:
extremely high rate of somatic mutation occurs in the B-cell receptor locus that is 10^6 fold greater than the mutation rate across the genome
-Occurs in the Antigen binding sites (VARIABLE region) of the Ig (antibody)
-B cell activation- 2 step process
1. Encounters its matching antigen
-engulfs, digests and displays antigen via MHC II
2. Matching “CD4” T-cell helps further activate the B-cell
-Effector (plasma cells): produce copies amounts of antibody
-Memory B-cells: travel to germinal centers and proliferate (where somatic hypermutation occurs)
-allows for selection of B-cells that express Ig that recognize and bind specific antigens
-Generates a larger “library” of Ig that will recognize foreign/harmful antigens
Describe the steps of B-cell activation
B-cell activation:
1. A B cell is triggered when it encounters its matching antigen
2. The B-cell engulfs the antigen and digests it
3. Then, it displays antigen fragments bound to its unique MHC molecules
4. This combination of antigen and MHC attracts the help of a mature matching T cell.
4. Cytokines secreted by the T-cell help the B cell to multiply and mature into antibody producing plasma cells
5. Released into the blood, antibodies lock onto matching antigens. The antigen-antibody complexes are then cleared by the complement cascade of the liver and spleen
Why is Antigen presentation important? What occurs in this process? What is the result? What is the role of MHC I and MHC II?
Antigen presentation
-Crucial for the generation of protective-T cell responses against pathogens
-T-cell receptors only recognize small peptides presented to the by an antigen presenting cells (APC) in the antigen-binding groove of a major histocompatibility complex (MHC) molecule
-induces T-cell expansion, maturation and activation
MHC I- all nucleated cells
-present INTRACELLULAR antigens
-MHC II- professional APC’s (antigen presenting cells)- Dendritic cells, B-cels and Macrophages
-present EXTRACELLULAR antigens
Differentiate between the MHC I and MHC II in terms of T cells that they are associated with and functions.
MHC I has immature CD8 T cell that will turn into mature cytotoxic T cell (induces APOPTOSIS)
MHC II : has immature CD4 T cell that will turn into Mature Helper T cell
which induces factors that helps establish and maximize innate immunity (Ex; IFN-gamma)
What is the role of cells in MHC II ? What are the signals required for T- cells to be fully activated?
MHC II
-APC’s (antigen presenting cells) phagocytose exogenous pathogens in tissues and then migrate to Lymph nodes where they present antigen to CD4+ T -cells
T-cells require two signals to become fully activated:
-1st- antigen-specific
-T-cell receptor interacts with peptide-MHC molecules on the surface of the APC (“need a match”)
2nd (Co-stimulatory) : Antigen-Nonspecific
-interaction between co-stimulatory molecules expressed on the membrane of the APC and the T- cell
-Interaction of the CD28 on T-cells with CD80 and CD86 on the APC
-Necessary for T cell proliferation differentiation and survival.
Discuss the cells that are part of Immune surveillance. and what each of their roles are. What happens when T cells are activated?
Immune surveillance
-Most tissues contain APC’s (antigen presenting cells)
-Traffic to the draining lymph nodes for initiation of T-cell activation.
-Once activated, T-cells leave lymph nodes and survey tissues for foreign antigens that are being displayed on resident APC
-Fully activated T-cells proliferate, differentiate and acquire an increased sensitivity to antigen on re-stimulation in tissues.
What kind of tissues does Immune surveillance occur in? Where does CNS allograft survive longer? What does it mean to be “immune privileged”
This coordinated APC and T- cell immune surveillance occurs in most peripheral tissues but may be limited in CNS
-CNS allograft survives longer without rejection than those in other tissues
-“immune privileged” - able to tolerate the introduction of antigen without eliciting an inflammatory immune response
Explain why CNS may be believed to be “immune privileged? Discuss some reasons behind this belief. What are the some anti-inflammatory factors found to be produced from CNS?
CNS is “immune privileged”
-belief largely attributed to the Blood-Brain Barrier (BBB)
-restricts the entry of plasma proteins and components of the immune system (ex: lymphocytes, antibodies and complement) from the periphery into the CNS.
-Also to the belief that the brain parenchyma lacked resident APC and lymphatic drainage
-CNS environment would be inefficient for eliciting immune-mediated inflammation, necessary for defeating pathogens.
-CNS was also found to produce anti-inflammatory factors
-TGF-Beta, vasoactive intestinal peptide, gangliosides, and FasL
-Involved in inactivating and or killing activated immune cells.
What can produce CNS disease in immunocompromised individuals ? What does this suggest? What molecules are present in the CNS, as and also seen in many CNS infections/pathologies?
Some Latent viruses (JC and varicella zoster) produce CNS disease- mainly in immunocompromised individuals
-suggests there is some degree of immune surveillance of the CNS in preventing disease development
-Resident “immune cells” are present in CNS.
-MHC and co-stimulatory molecules are strongly up-regulated in many CNS infections and pathologies
Ex: ischemia, neoplasm, MS, HIV, Alzheimer’s and Parkinson’s
What Describe Immune activation in the CNS and immune reactivity. What are two results of immune reactivity?
How immune activation in the CNS occurs and is regulated is NOT completely understood
-Immune reactivity in the CNS can be destructive, particularly when regulatory mechanisms are lost or inadequate
-Autoimmune disease
-Chronic inflammation
