Innate Immunity Flashcards
What must our immune system be able to distinguish between?
Self from non-self
Self from dangerous self (think normal vs. cancer cells)
Non-self vs. dangerous non-self
What 4 classes of pathogen does the immune system protect against?
Bacteria
Viruses
Fungi
Parasites (Protozoa, worms)
What are the 2 arms of the immune system?
Innate: protects early, nonspecific, no memory, fixed, constant, genetic
Adaptive: comes in later, specific, memory, improves during response
What acronym describes the innate immune system functions?
Prevents infection
Recruits immune cells
Identifies and remove foreigners
Activates complement cascade
Activates adaptive immune system
What are the 5 components of the innate immune system?
Physical barriers
Cytokines
Acute phase proteins
Cells
Inflammation
What are the physical barriers of the innate immune system?
Skin, mucous membranes, normal flora
Cilia
Secretions (mucous; ph: sweat, stomach acid; chemical factors: lysozymes, fatty acids, phospholipase, defensins, surfactants; tear film)
What are cytokines?
Produced in response to antigen
Chemical mediators
Cell to cell communication
Stimulate cell movement to sites of inflammation, infection, trauma
Effect nearly every biological process
What are chemokines?
Enable leukocyte (immune cells) migration from blood to tissues at site of inflammation
Define pleiotropic, redundant, and multifunctional.
Pleiotropic–act on different types of cells, not just a
single cell type.
Redundant–different cytokines can carry out the same function.
Multifunctional–same cytokine regulates several different functions.
What are interferons (type of cytokine)?
Interfere with virus replication through gene activation
Describe Type 1 Interferons.
Pleiotropic
Produced by plasmacytoid dendritic cells (antigen presenting immune cell), virus-infected cells, and other defense cells
Induce uninfected cells to produce enzymes that degrade
viral mRNA and block translation in eukaryotic cells.
Treat chronic viral infection, inhibit tumor growth (suppress proliferation, induce apoptosis)
Enhance immune cells to induce chemokines that attract leukocytes
Describe Type 2 Interferon.
Interferon y stimulates inflammation
How does Interferon deficiency lead to severe COVID 19?
Type 1 interferon induced upon detection of viral RNA
Bind to cell surface receptors, transcription of genes that block virus replication and spread
IFN deficiencies may be inherited or induced by auto antibodies
What are TNFa (tumor necrosis factor alpha) and IL-1 Interleukin-1 involved in?
Mediating acute inflammation
What is IL-6 involved in?
Activation and regulation of the immune response
Stimulate acute phase proteins
Stimulate production of neutrophils in bone marrow
Support B cells growth
Antagonistic to regulatory T cells
What are acute phase proteins?
Produced in liver in response to infection and inflammation
Assist host defense
– Aid recognition of invading microbes
– Mobilize leukocytes into the circulation
– Increase blood flow to injured or infected sites
– Enhance local inflammation and antimicrobial defense
Prevent inflammation in uninvolved tissues
Describe C reactive protein.
Acute phase protein
Functions as opsinin, enhances ability of phagocytize cells to take up invaders
Activates complement
Elevated CRP is an inflammation indicator, correlated with coronary artery disease and stroke risk
Describe complement proteins.
Acute phase proteins
Plasma and cell surface proteins that fight invaders
Describe how levels of APP’s change with inflammation?
Significant changes in serum concentration during inflammation
Positive acute-phase proteins: increase (CRP, SAA, fibrinogen)
Negative acute-phase proteins: decrease (albumin, transferrin)
Describe complement. How is it activated?
Group of plasma proteins activated directly by pathogens or indirectly by pathogen-bound antibody
Major non-cellular component
Fight invaders through OIL
Describe the steps of OIL in the complement cascade to fend off microbial invaders.
Opsonization: binding/coating of a microbe by
complement (or an antibody) that results in enhanced
phagocytosis.
Inflammation: complement induces histamine release
from mast cells and basophils, causing blood vessel
dilation and leakage
Lysis: complement induces bacterial lysis
Describe the 3 pathways by which complement can be activated?
Classical: Antgien-antibody complexes (adaptive)
MB-Lectin: lectin binding to pathogen surfaces (innate)
Alternative: pathogen surfaces (innate)
What C3 in the complement pathway?
Plays central role in all pathways
Most abundant complement proteins leading to OIL
Describe the process of opsonization.
Bacterial cell surface cleaves and activates complement
One complement fragment bonds to bacteria and other to effector cell
Both complement fragments bind with bacteria and effector attached
The effector engulfed the bacterium, kills it, breaks it down
Describe the process of Lysis. What does it produce?
Membrane attack complex
Complement proteins forms a hole in cell membrane, initiates event that lead to lysis or apoptosis
Describe how inappropriate activation of complement can lead to AMD.
Drusen, the hallmark of AMD, contain many activated complement factors that may promote growth of blood vessels (complement role in inflammation causes bv dilation and leakage)
Describe how Complement factor H can affect the eye? How can this be treated?
Regulate alternative pathway; ensures that complement targets pathogens, not host tissue.
CFH is expressed in RPE and choroid, where it dampens complement-mediated inflammation.
SNPs in the CFH gene cause 50% of AMD cases, fuels alternative complement pathway activation.
One target for therapeutic intervention in AMD is blockade of complement activation.
Age and smoking, two important risk factors for AMD, influence plasma levels of complement factor H.
From what precursor do most innate immunity cells derive from? Describe the progression of lineage.
Derived from myeloid precursors (NK and dendritic from lymphoid)
Bone marrow to hemotopietic stem cell to lymphoid, myeloid and erythroid lineage
What are the cells of the innate immune system?
NK cells (lymphoid lineage)
Dendritic cells
Macrophages
Neutrophils
Eosinophils
Basophils
Mast cells
What are macrophages?
Phagocytosis and activation of bacterial mechanisms
Derived from monocyte that migrate from blood to tissues
named based on tissue there they are located
No cytoplasm is granules rely on lysosomes
Antigen presentation
Dendritic cells?
WBC that alerts immune system about infection, activate innate and adaptive
Present in tissues in contact with the external environment, such as skin (Langerhans cell), inner linings of nose, lungs, stomach and intestines.
Antigen uptake in periphery
Antigen presentation in lymph nodes
Neutrophils?
Phagocytosis and activation of bactericidal mechanisms
Predominant WBC in blood
First to arrive at injury
Contain three types of granules to fight infections (azurophilic, secondary, and tertiary granules)
Produces pus
Eosinophils?
Killing of anti-body coated parasites
Basophils?
Unknown
Mast cells?
Release of granules containing histamine and other active agents
What are the phagocytic cells of the innate immune system?
Neutrophils and macrophages and dendritic
Describe the function of dendritic cell in the innate immune system? What kind of cytokines do they produce? What mediates their response?
Induce inflammation
Activate NK Killer cells
Present antigens to T cells along with MHC 2
Produce protective cytokines (interleukin 12 and type 1 interferons)
Mediated by PRRs
How does the innate immune system distinguish invaders from self?
PAMPS on pathogens not found on host
Bind to PRRs to trigger immune response
Describe PRRs and one example.
Distinguish foreigners from self
Toll-like receptors: recognize PAMPS and DAMPS
Present on dendritic, macrophages, B cells, mast cells, eosinophils, NK cells, epithelial cells (bladder, intestine, liver)
Describe process once TLRs are stimulated.
Recognize non self patterns
Stimulation induces phagocytosis and activates transcription factors leading to increase in cytokines and chemokines
Some located intracellularly
Describe TLR activation in the cornea.
Induces antimicrobial peptide expression
Describe DAMPS.
Derived from host cells
Altered metabolism products of necrotic or stressed cells
Alarm signals of innate immune system
How are DAMPs related to inflammation?
Play a role in correcting the altered physiological state, but in excess they can be lethal due to signal transduction roles
Inflammatory agents are DAMP generators and DAMP create pro-inflammatory state
What do TLRs recognize?
Recognizes viral double stranded RNA, siRNA, self RNA from damaged cells
Pathogens (non self)
What do intracellular TLRs recognize?
Nucleic acids
DNA stimulates the mammalian innate immune
system through activation of TLRs.
RNA also signals through human TLRs.
DCs and TLR-expressing cells are activated by bacterial and mitochondrial RNA, but not by mammalian RNA, which is abundant in modified nucleosides.
Describe Dendritic cells correlation to mRNA vaccines.
MRNA vaccine hade modified nucleosides that enhance mRNA stability and suppress the anti RNA immune response
Dendritic cells (DCs) exposed to modified RNA express
significantly less cytokines and activation markers than those treated with unmodified RNA.
What is one explanation for the high efficacy of mRNA vaccines?
incorporation of modified nucleosides reduces inflammation but doesn’t eliminate it completely
Reasons why people react to covid vaccine
What are scavenger receptors? What does binding to it trigger?
PRR that recognize polyanions on bacterial surface
Innate immunity and phagocytosis
What are complement receptors? What does binding to it trigger?
PRR that recognize component C3b
Innate immunity and phagocytosis
What are Fc receptors? What does binding to it trigger?
The Fc part of an antibody is the stem of the Y (PRR)
Innate immunity and phagocytosis
What mechanisms allow the innate immune system to distinguish invader from self?
PRRs on phagocytes: TLRs, scavenger receptors, complement receptor, and Fc receptor
What happens when bacteria and/or bacterial components bind to receptors on phagocytes?
Engulfment and destruction or induction of cytokines for inflammation
How do phagolysosomes kill bacteria?
By oxygen dependent respiratory burst (ROS)
Or
Oxygen independent (less toxic)
What reactive oxygen species are involved in respiratory bursts?
Superoxide anion (O2-)
H2O2
Singlet oxygen (*O2)
Hydroxyl radical (OH•)
Toxic hypochlorite (OCl-)
What mechanisms are involved in O2 independent phagolysosome function?
Cationic proteins (e.g. cathepsin) damage bacterial
membranes.
Lysozyme degrades bacterial cell walls.
Lactoferrin chelates iron that bacteria need.
Hydrolytic enzymes break down bacterial proteins.
What do natural killer cells target? What immune system are they involved in?
Both innate and adaptive
Do not recognize specific antigens
Target tumor cells and a wide variety of infectious bacteria and viruses
Secrete cytokines and influence immuno-regulation
Bind target cells and delivery lethal chemical from cytoplasmic granules: perforins and granzymes (apoptosis)
What is the target for NK cells?
Virus infected cells
Cells infected with intracellular bacteria
Cancer cells
Different from T cell receptors
Inefficient at killing
Produce Interferon y that activates macrophages so they can kill ingested microbes
What results from an NK cell deficiency?
Persistent viral infection, particularly Herpes virus
How do NK cells distinguish infected and normal cells?
NK cell activation determined by balance of ligand binding to activation receptors (KARs) vs. inhibitory receptors (KIRs).
MHC class I molecules found on all normal cells bind to KIRs so normal cells are not killed by NK cells.
Even if a ligand binds to KAR, killing is inhibited if ligand binds to KIR
Describe how viral infection/cancer after NK KARs and KIR as well as MHC class 1?
Upregulate expression of ligands that bind to activation receptors and down regulates expression of MHC 1 so there is no binding to KIR
What is the most important response for dealing with microbial infection?
Inflammation
One of the first immune response to infection or irritation
Injured cells release chemical that stimulate infection
What are the classical indicators for inflammation?
Tumor (swelling)
Rubor (redness)
Calor (heat)
Dolor (pain)
Loss of function
Why is inflammation a good thing?
Localizes
Recruits proteins and cells to infected tissues
Increase flow of lymph to nearby lymphatic tissue to help initiate adaptive
Recruits antibodies and T cells
Should patients with infections be treated with anti-inflammatory drugs?
NO
(Excess, prolonged can be harmful)
What plasma components enter damaged tissues during inflammation?
Complement proteins
Antibodies (eventually)
Clotting factors
Lysozymes
Beta-defensins
Transferrin (iron)
What leukocytes enter tissues during inflammmation?
Neutrophils
Monocytes: become macrophages
Eosinophils
Basophils
Later:
• B-lymphocytes
• T-lymphocytes
Describe antigen presentation and processing/
Required for activation of adaptive
APCs are phagocytes
Use PRRs to recognize bacteria and viruses and induce uptake APCs process and digest antigen
Peptides combine with MHC 1 and 2 to bring them to cell surface
What recognizes MHC and process pathogen fragment?
CD4 helper
CD8 T lymphocytes
What happens when the immune system isn’t working properly?
Immunodeficiency
Autoimmune diseases
Allergies
