Innate Immunity Flashcards
What happens to someone experiencing inflammation in response to an infection?
1) Blood supply increases, helping carry immune cells to affected area
2) Infected areas near surface of the body become red and warm
3) Peripheral blood vessels become permeable to plasma proteins and immune cells (infected tissue swells)
4) Immune cells leave blood, are recruited to and decontaminate microbes and dead cells (tissue debris) in the infected tissue
- White Blood Cells (Leukocytes) attack invading microbes and release mediators that continue process of inflammation
5) Many inflammatory mediators produced by immune cells stimulate nerves, causing pain
6) Body reactions to substances released during inflammation include:
- Chills
- Fever
- Muscle Aches
Is innate immune response sufficient to prevent infection within tissues or the blood?
Yes innate immune response is sufficient to prevent infection within tissue or the blood.
HOWEVER, inflammatory response may not be able to overcome large numbers of microbes
Is inflammation an efficient mechanism of host defense against intracellular pathogens, such as viruses?
NO, inflammation is not enough to fight against intracellular microbes, it requires other mechanisms of the innate immune system.
What are the 6 general steps causing inflammation?
1) Damaged tissue attracts mast cells which release Histamine, which diffuses into the blood vessels
2) Histamine causes the vessels to dilate and become leaky
- Complement proteins leave the vessel and attract phagocytes
3) Blood plasma and phagocytes move into infected tissue from the vessels
4) Phagocytes engulf microbes and dead cells
5) Histamine and complement signaling cease; phagocytes are no longer attracted
6) Growth factors from White Blood Cells and platelets stimulate cell division in skin cells, healing the wound.
What are the two mechanisms of the innate immune response responsible for acting against viral intracellular infections?
1) Type 1 Interferons (Non-Immune alpha/beta IFNs)
2) Natural Killer Cells (NK Cells)
What are Type 1 Interferons?
Type 1 Interferons (alpha/beta IFNs) are signals that protect protect cells against viral infections by blocking viral replication within the target host cells
What are NK Cells?
Natural Killer Cells
Kill cells infected with intracellular microbes, including viruses
How do innate immune cells discriminate between self and non-self?
Innate Immune Cells use specialized receptors known as PRRs (Pattern Recognition Receptors) which detect PAMPs (Pathogen Associated Molecular Patterns)
PAMPs have no structural similarity to with self antigens
What are PAMPs?
Pathogen Associated Molecular Patterns
- Effective indicators of presence of particular pathogens
- Unique to classes of pathogens
- Are often required for pathogen survival and thus cannot be altered, suppressed or easily hidden by pathogens
- Have NO structural similarity to self-antigens
What are PRRs?
Pattern Recognition Receptors
- Detect PAMPs
- Germ-line encoded (refers to sequences that are found in gamete producing cells)
- Limited Diversity
- Non-clonal distribution; identical receptors on all cells of same lineage
Examples:
- Mannose Receptor
- Toll-Like Receptors
- NOD-Like Receptors
- Scavenger Receptor Family
- Lectin Receptor Family
What are Mannose Receptors?
Pattern Recognition Receptor
Recognizes glycans with terminal mannose
Mannose-tailed glycans are essential surface moleucles for various microbes
There are NO glycans with terminal mannose in humans
What are TLRs?
Toll-Like Receptors
- Recognize PAMPs and activate inflammation
- Various types of TLRs
- Some TLRs are located on the CELL SURFACE where they recognize extracellular microbes
- Other TLRs are located in ENDOSOMES, into which microbes are ingested (intracellular)
- TLR-1, -2, -4, -5, and -6 are cell surface receptors (recognize extracellular microbes)
- TLR-3, -7, -8, and -9 are endosomal receptors (recognize intracellular microbes)
- Endosomal TLRs respond only to NUCLEIC ACIDS
What are the Cell Surface TLRs and what are the specific antigens each one is looking for?
Cell Surface TLRs = TLR-1, -2, -4, -5, -6
TLR-1:TLR-2 = Bacterial Lipopeptides
TLR-2 (alone) = Bacterial Peptidoglycan
TLR-4 = LPS (Lipopolysaccharide)
TLR-5 = Bacterial Flagellin
TLR-2:TLR-6 = Bacterial Lipopeptides
What are the Endosomal TLRs and what are the specific antigens each one is looking for?
Endosomal TLRs = TLR-3, -7, -8, -9
TLR-3 = dsDNA
TLR-7 = ssDNA
TLR-8 = ssDNA
TLR-9 = CpG DNA
What is the signaling cascade that occurs when PAMPs bind to PRRs?
PAMP ligands bind to PRRs
Activated PRRs signal the activation of MyD88 (Myeloid Differentiation primary response gene 88 adaptor protein)
MyD88 activates the IRAK (Interleukin-1 Receptor Associated Kinase) Family Enzymes
IRAK Family Enzymes activate TRAF6 (TNF Receptor Associated Factor 6)
TRAF6 promotes the translocation of NF-(kappa)B
NF-(kappa)B is a Transcription Factor that promotes the generation of pro-inflammatory cytokine proteins and their secretion
Which TLRs require the activation of only MyD88 to activate NF-kB?
TLR-1, -2, -5, -6, -7, -8, and -9
all TLRs except TLR-3 and TLR-4
Which TLRs require the activation of only TRIF to activate NF-kB?
TLR-3
Which TLRs require the activation of both MyD88 and TRIF to activate NF-kB?
TLR-4
Which TLRs are react with Bacterial PAMPs?
TLR-1, -2, -4, -5, -9
Which TLRs react with Viral PAMPs?
TLR-3, -7, -8, -9
Which TLRs react with Fungal PAMPs?
TLR-2, -6
On which cells are TLRs expressed on?
Monocytes, Neutrophils, Macrophages, and Dendritic Cells
What is the result of of TLR-dependent signaling pathways which activate NF-kB?
Transcription of Pro-Inflammatory Genes
What does IL-12 do?
Controls the adaptive T-cell Immune Response
How can TLRs be detrimental to the host?
TLRs can contribute to cell apoptosis
Can also lead to life-threatening symptoms of septic shock
How do Epithelial Barriers provide defense against infection?
1) Physical barrier preventing entry
2) Locally produced microbial secretions (Defensins, Cathelicidins)
3) Intraepithelial CD8+ T-Cells kill microbes
What are Defensins?
Antimicrobial peptides produced by epithelial cells of mucosal surfaces and granule-containing leukocytes (Neutrophils, NK Cells, Cytotoxic T Cells)
They have direct toxicity towards microbes (bacteria, viruses and enveloped viruses)
What are Cathelicidins?
Antimicrobial peptides produced by Neutrophils and barrier epithelial cells in the skin, GI tract, and respiratory tract
Have multiple mechanisms of actions, including direct toxicity to microbes and activation of leukocytes
What are the 3 primary actions of the innate immune cells?
1) Phagocytosis and intracellular killing of microbes
2) Recruitment of other inflammatory cells
3) Presentation of Antigens
What is the role of neutrophils in the innate immune response?
Neutrophils are the first cells to arrive at the site of tissue damage.
Activation of neutrophils leads to respiratory bursts and release of granule to control bacterial growth
What is the role of macrophages in the innate immune response?
Engulf organisms via multiple mechanisms and release many inflammatory mediators
What is the role of eosinophils in the innate immune response?
Eosinophils contain cationic granule proteins
They fight helminthes and other multicellular parasites
What is the role of Natural Killer Cells?
NK Cells are large granular lymphocytes that kill infected host cells by a cytolytic mediator called Perforin
During development, where do macrophage precursors go and what do they become?
Mcrophage precursors go to the Brain, Liver, Spleen, Lungs, and epithelium
Brain --> Microglial Cells Liver --> Kupffer Cells Lungs --> Alveolar Macrophages Spleen --> Sinusoidal Macrophages Epithelium --> Macrophages
What do N-formylmethionyl Peptides, Chemokines, and Lipid Mediators have in common?
They all bind to PRRs and in doing so help initiate phagocyte migration into infected tissues, so it can consume the infecting microbes.
N-Formylmethionyl Peptides are only found in prokaryotes (not eukaryotes)
What is the difference in phagocyte response to activation of TLRs vs Mannose Receptors?
TLRs promote production of cytokines and Reactive Oxygen Intermediates, resulting in the death of microbes
Mannose Receptors promote the phagocytosis of microbes into phagosomes as well as the production and release of cytokines and reactive oxygen intermediates, thus also causing microbe death
What is the primary function of microbial ligand binding to PRRs?
Macrophage Activation
What are the three broad categories of Dendritic Cells?
Classical DCs
Myeloid DCs (mDCs)
Plasmacytoid DCs (pDCs)
What are mDCs derived from?
Myeloid Dendritic Cells are derived from Monocytes
Which Dendritic Cells are derived directly from stem cells?
Classical DCs
Plasmacytoid DCs (pDCs)
Langerhans Cells in the epidermis
What is the function of Dendritic Cells?
Dendritic cells acquire Ags via Receptor-Mediated endocytosis and Pinocytosis (NOT PHAGOCYTOSIS)
Consumed Ags are then expressed
DCs find Ags by expressing receptors that recognize Ags typically made by microbes
Activated DCs also secrete cytokines
What is the difference between Classical DCs and Plasmacytoid DCs?
Classical DCs are found in the skin, mucosa, and organ parenchyma
- Upon activation, they migrate to Lymph Nodes and display Microbial PROTEIN Ags to T Lymphocytes
Plasmacytoid DCs are early cellular responders to Viral Infection
- Recognize nucelic acids of intracellular viruses and produce soluble Interferons (INF alpha/beta)
- IFN alpha/beta both have potent antiviral activites
What are Mast Cells?
First line defenders against infections
Prevalent in skin, gut, respiratory tract, urinary tract
- In close association with blood vessels, lymph vessels and nerves
Responsible for Type I Hypersenstivity Reactions
- Mast cells become activated by cross-linking of high affinity IgE Receptor (FCeRI)
- Cross-linking results in release of several preformed molecules stored in granules
- Histamine, serotonin, tryptase, chymase, Prostaglandin D2 (PGD2), Leukotriene B4 (LTB4)
What Activates Mast Cells?
Receptor-Binding Agonists
- IgE+ antigen or IgE alone
- Ig Light Chain
- Complement
- Neuropeptides
- Microbial Products
- Cytokines
- Chemokines
Physical Activators
- Temeprature
- Pressure
Cell-Cell Contact
What are the Preformed Mediators released by Mast Cells?
- Histamine
- Proteases
- Serotonin
- Heparin
- IL-4
- TNF
- GM-CSF
What are the Newly Synthesized Mediators released by Mast Cells?
LIPID DERIVED:
- Prostaglandins
- Leukotrienes
- PAF
- Cytokines
- Growth Factors
- Chemokines
- Free Radicals
- Sub
OTHER:
- Substance P
What are NK Cells?
Natural Killer Cells
- Generate from lymphoid progenitor, but functions in innate immunity
The ability of NK cells to kill a target cell is inversely related to target cell expression of MHC Class I molecules
- Infected Cells or Cells under stress express fewer MHC Class I molecules, thus NK Cells kill them
Killing infected cells releases intracellular pathogens for phagocytosis
How do NK Cells kill target cells?
NK Cells have two important receptors expressed on their cell membranes
KIRs (Killer Cell Immunoglobulin-Like Receptor); aka the ACTIVATING RECEPTOR - Binds with target cell ligand and initiates activation of the NK Cell via a Protein Tyrosine Kinase Mechanism
INHIBITORY Receptor - Recognizes MHC Class I molecules, inhibiting the NK Cell activation.
- If there is a reduction in MHC Class I Molecule expression on a target cell, then NK Cell will be activated and the target cell will be killed
MHC Class I molecules expression reduces when the target cell is infected or under stress.
When activated, NK Cells release Perforins
- Perforins are proteins that polymerize in target cell membrane forming a pore
- NK Cell then secretes granzymes that enter target cell through perforin pore and activates apoptosis in the target, virus infected, cell.
Activated NK Cells also secrete IFN-gamma, which activates Macrophage phagocytosis of the cellular debris
What are the three complement pathways?
Alternative Pathway
Classical Pathway
Lectin Pathway
What do all three Complement Pathways lead to?
The conversion of C3 into C3a and C3b
Which Complement Pathways are part of the Innate Immune Response and which are part of the Adaptive Immune Response?
Alternative Pathway and Lectin Pathway are part of the Innate Immune Response
Classical Pathway is part of the Adaptive Immune Response
What triggers the Alternative Complement Pathway?
Alternative Pathway occurs when complement proteins are activated on microbial surfaces
Complement regulatory proteins are not found on microbes, thus it cannot be controlled
What triggers the Classical Complement Pathway?
Triggered by antibodies that bind to microbes or other antigens
Thus it is part of the adaptive immune response (due to necessity of antibodies)
What triggers the Lectin Pathway?
Carbohydrate-binding plasma protein, Mannose Binding Lectin (MBL) binds to terminal mannose residues on the surface glyoproteins of microbes
This pathway activates the proteins of the classical pathway, however since it is not initiated by Antibodies, this pathway is part of the innate immune system
How is C3 Convertase formed in the Classical Pathway?
IgM or Two IgGs bind to microbial surface
C1 protein is activated when bound to IgM/IgGs
Activated C1 protein cleaves both C2 and C4 into C2a, C2b, C4a, and C4b
C4b binds to microbial surface, C2a binds to microbial-bound C4b
The complex formed by Microbe-bound C4b and C2a makes C3 Convertase
C3 convertase breaks C3 into C3a and C3b
What are the roles of C3a and C3b?
C3a is responsible for inflammation and chemotaxis
C3b binds to microbe surface serving as an opsonin tag (targeting the microbe for phagocytosis)
C3b while bound to microbe can also form a complex with C3 Convertase (C4b, C2a) to form C5 Convertase (C4b, C2a, C3b)
What does C5 Convertase do?
C5 Convertase breaks C5 into C5a and C5b
What do C5a and C5b do?
C5a is a POTENT mediator of inflammatory response and chemotaxis (anaphylatoxin)
C5b initiates the assembly of the Membrane Attack Complex
- C5b binds to microbe surface
- Causes recruitment and binding of C6, C7, C8, and several C9 molecules to the microbe surface
- Together they form the MAC, which creates a pore in the microbe cell membrane, leading to cell lysis
What are the 3 main functions of the Complement System?
1) Lysis of foreign cells and bacteria
- MAC (C5b, C6, C7, C8, and many C9s) forms on microbe cell membrane causing cell lysis
2) Opsonization and Bacterial Phagocytosis
- C3b acts as an Opsonin Tag
- Opsonization causes phagocytes to become attracted to C3b-tagged microbes, which they then consume via phagocytosis
3) Chemotactic Anaphylatoxin
- C3a, C4a, C5a act as chemotactic anaphylatoxins
- They induce vasodilation and signal degranulation of Neutrophils, Basophils, Eosinophils, and Mast Cells
- Causes smooth muscle contraction
What are acute phase proteins?
Proteins secreted as part of the systemic acute phase response
Their release accompanies inflammation
They are produced by Hepatocytes
Their production in the liver is regulated by cytokines, ESPECIALLY IL-6
Their functions are highly variable and diverse
What is CRP?
C-reactive Protein is an acute phase protein
It binds to phosphocoline on dead/dying cells and some microbes, resulting in activation of the Classical Complement Pathway
It also acts as an opsonin tag
What is MBP?
Mannose Binding Protein is an acute phase protein
It activates the Lectin Complement Pathway
What are chemokines?
Chemokines are small protein chemoattractants important for trafficking immune cells
What are cytokines?
Small proteins (peptides) that are secreted from many various cells
Cytokines produced by immune cells mediate INFLAMMATION, IMMUNITY, and HEMATOPOIESIS
Cytokines can act as endocrine (over long distance), paracrine (over short distance), and autocrine (self signaling) factors
Cytokines can have many different functions, depending on which type of cell they interact with
Cytokines of INNATE IMMUNITY are subdivided into 2 classes:
- Pro-Inflammatory Cytokines
- Anti-Inflammatory Cytokines
Which cytokines are anti-inflammatory?
IL-10
TGF-beta
What are neutropils and monocytes?
Neutrophils and Monocytes are immune cells that arise from the bone marrow and circulate in the blood
They circulate until they are recruited through cytokine signaling, causing them to exit the blood and enter the infected/injured tissue
They don’t need to be activated to be recruited
They are myeloid leukocytes and they eliminate infectious pathogens, clear dead tissues, and repair damage
Through where do myeloid cells (monocytes and neutrophils) enter enter injured/infected tissue?
Monocytes and neutrophils enter tissues through POST CAPILLARY VENULES
However, in the case of Parenchymal Tissues (liver, lungs, and kidneys) they enter these tissues through CAPILLARIES
What are the 5 steps of Myeloid Cell (Neutrophil/Monocyte) Immune response?
1) Inflammatory chemicals (cytokines, chemokines) are secreted in response to tissue damage/microbe infection from various cells (such as Mast Cells, damaged cells)
2) Myeloid Cells undergo Margination (cells adhere to endothelial wall of Post-Capillary Venules)
3) Myeloid cells undergo Diapedesis (migration of cells from Post-Capillary Venule to infected tissue)
4) Myeloid Cells locate site of infection/damage via Chemotaxis (follow concentration gradient of cytokines to source, like they’re smelling their way to the microbes and damaged cells)
5) Myeloid Cells consume damaged tissue and microbes via phagocytosis and then begin to conduct tissue repair
Which cells of the innate immune system actively fight against viral microbes using IFNs?
Plasmacytoid Dendritic Cells
They produce and secrete IFN-alpha and IFN-beta, which interact with virus infected cells, inhibiting viral replication and directly activating NK Cells to eliminate the infected cells
What are the strategies microbes use to evade the innate immune system?
1) Resistance to Phagocytosis
2) Resistance to ROS in phagocytes
3) Resistance to Complement activation (alternative pathway)
4) Resistance to anti-microbial peptide antibiotics
How do microbes evade phagocytosis?
They grow capsules that prevent phagocytes from consuming them
How do microbes evade ROS when consumed by phagocytes?
Microbes produce Catalase
Catalase breaks down reactive oxygen intermediates
How do microbes evade complement activation?
Microbes can event complement in 2 ways:
1) They produce Sialic acid expression, which inhibits C3 and C5 convertase activity
2) They produce M Protein, which blocks C3 from binding to the microbe and blocks C3b from interacting with Complement Receptors
How do microbes evade antimicrobial peptide antibiotics?
Some microbes produce a modified Lipopolysaccharide that resists the action of peptide antibiotics
How many signals are needed for lymphocyte activation, and what are these signals?
2 Signals required, but up to 3 can be detected
1) Recognition of the microbe by the lymphocyte is the first signal
2) Detection of substances produced during innate immune responses to microbes provide the second signal
3) The third signal is the detection of cytokines, for more potent activation of lymphocytes
When the first and second signals are detected, the lymphocyte will differentiate and proliferate
What links the innate and adaptive immune responses?
Pathogen recognition through PRRs is an important bridge between innate and adaptive immunity
PRR pathogen recognition causes activation and maturation of Antigen Presenting Cells (APCs)
APCs process the antigen and present it to naive T cells
With antigen presentation, costimulation, and cytokine detection together cause the naive T cell to become a mature T cell
