L8: Innate Immunity Flashcards
What is phase 1 of innate immunity?
Non-induced innate response (non-specific)
Includes preformed defenses such as skin barrier, mucosal barrier, pH, saliva proteases
What is phase 2 of innate immunity?
Induced innate response (broadly specific)
Broadly compare innate and adaptive immunity
Innate:
Response time of minutes/hours
Specific for molecules and molecular patterns associated w/ pathogens
Has a limited number of germ line-encoded receptors
Little to no memory responses
Self/nonself discrimination is perfect; no microbe-specific patterns in host
Soluble components of blood or tissue fluids include many antimicrobial peptides and proteins
Major cell types include phagocytes (monocytes, macrophages, neutrophils), natural killer (NK) cells, and dendritic cells
Adaptive:
Response time of days
Is highly specific
Highly diverse; large # of receptors arising from genetic recombination of receptor genes
Has persistent memory, w/ faster response of greater magnitude on subsequent infection
Self/nonself discrimination is very good; occasional failures of discrimination result in autoimmune disease
Soluble comonents of blood or tissue fluids include antibodies
Major cell types are T cell, B cells, and antigen-presenting cells
Where are non-induced (phase 1) responses active?
Sites throughout the body
Skin, epithelial lining of airway and lung, epithelial lining of alimentary canal, etc.
What are epithelial barriers to infection?
Physical barrier to infection
Killing of microbes by locally produced antibiotics
Killing of microbes and infected cells by intraepithelial lymphocytes
Psoriasin
An antimicrobial peptide in the skin that is active against E. coli
Once the epithelium is breached, what occurs?
Innate response takes over in an inflammatory response
- Recruitment of effector cells/mechanisms; vasodilation, permeability
- Blood clotting to prevent pathogen spread
- Tissue remodeling to repair damage
What does inflammation allow for?
Allows right cells to get to right place to interact w/ microorganism
Rather than letting toxin spread through entire body. localized blood clotting keeps it local
Levels of what proteins increase in serum concentrations following infection?
Acute phase proteins
Where are acute phase proteins produced? In response to what?
In liver in response to IL-6 (which is produced in response to microorganisms)
What acute phase proteins are produced in the liver?
Serum amyloid protein C-reactive protein Fibrinogen Mannan-binding lectin SP-A SP-D
What does C-reactive protein do?
Binds phosphorylcholine on bacterial surfaces, acting as an opsonin, and also activating complement
What does mannan-binding lectin do?
Binds mannose residues on bacterial surfaces, acting as an opsonin and also activating complement
Why is sedimentation rate altered w/ infection?
IL-6 regulates fibrinogen, which is an APP
Increased fibrinogen increasees erythrocyte sedimentation rate as fibrinogen binds to RBC
Used as a non-specific indicator of inflammation/bacterial infection
PAMPS
Pathogen-associated molecular patterns
Components on the pathogen that are common to different pathogens and elicit a response
DAMPS
Danger-associated molecular patterns: things that are released upon stress response
Heat shock proteins
HMGB1 - a chromatin-associated protein that is secreted in response to “danger” and can induce dendritic cell maturation, induce pro-inflammatory cytokines
Purine metabolites - ATP, adenosine, uric acid; can be released upon necrotic cell death
DNA anywhere except the nucleus and mictochondria
On pathogens, what is the difference b/w PAMPs and antigens?
Antigens are unique structures that are recognized by adaptive leukocytes
PAMPs are common structures that are recognized by innate leukocytes
How do innate leukocytes recognize PAMPs? What occurs after recognition?
They have pattern recognition receptors (PRRs)
Depending on which PRRs get triggered, can get phagocytosis, target cell lysis, or inflammation
What are toll-like receptors? Describe the structure.
An example of a PRR
Has a signaling domain called TIR domain and an extracellular domain called LRR (leucine-rich repeats)
Can occur on cell membrane or in internal component.
For those in internal compartment, the LRR is inside the compartment and the TIR is in the cytoplasm)
TLR4
Is the receptor for bacterial lipopolysaccharide (LPS) that exists on the cell surface of gram negative bacteria
What intracellular sensors sense cytoplasmic RNA (think RNA viruses)?
RIG-1
MDA5
What intracellular sensors sense cytoplasmic DNA (think DNA viruses)?
AIM
TREX
STING
What are the cellular components of innate immunity?
Neutrophils
Macrophages
Dendritic cells
Natural killer cells
What are the phagocytes of innate immunity?
Neutrophils
Macrophages
Are neutrophils and monocytes/macrophages long or short-lived?
Neutrophils: short-lived (6 hr), but life extended by infection
Macrophages: long-lived (months/years)
Where do neutrophils and macrophages reside?
Neutrophils: blood
Macrophages: blood/tissues
Do neutrophils and macrophages present antigen?
Neutrophils: no
Macrophages: present antigen to CD4+ T cells
Where do neutrophils and monocytes/macrophages originate from?
Both have bone marrow origin
Myeloid precursor
What is the cellular response and functional outcome of phagocytes in response to transmembrane receptors that recognize chemokines, lipid mediators, and N-formylmethionyl peptides?
Cellular response of increased integrin avidity; cytoskeletal changes → migration into tissues
What is the cellular response and functional outcome of phagocytes in response to toll-like receptors (which recognize LPS)?
Cellular response of production of cytokines and reactive oxygen intermediates (ROIs) → killing of microbes
What is the cellular response and functional outcome of phagocytes in response to mannose receptors?
Cellular response of phagocytosis of microbe into phagosome → killing of microbes
ALSO production of cytokines and reactive oxygen intermediates → killing of microbes
Extravasation
Breaking open tight epithelial barriers (such as when neutrophils exit capillary and enter tissues in response to increased permeability when tissue damage causes release of vasoctive and chemotactic factors)
Describe initiation of extravasation of neutrophils
Selectin on epithelial cells interacts with mucin (selectin ligand) on neutrophil surface → neutrophils rolls →chemokines/chemoattractants induce change in inegrins on neutrophils → integrins adhere firmly to the ICAMs on epithelial cell → neutrophils stop → then can pry apart endothelial cells lining blood vessels and escape into tissue
Describe how phagocytosis occurs
Bacterium becomes attached to membrane evaginations called pseudopodia → bacteria is ingested, forming phagosome → phagosome fuses w/ lysosome → lysosomal enzymes digest captured material → digestion products are released from cell
What enhances effector function of marcophages?
IFN-γ
What produces IFN-γ?
T cells, NK cells
What molecules are produced in activated macrophages? What effector functions do they cause in activated macrophages?
Phagocyte oxidase → reactive oxygen intermediates → killing of microbes
iNOS → nitric oxide → killing of microbes
Cytokines (TNF, IL-12) → inflammation, enhanced adaptive immunity
Fibroblast growth factors, angiogenic factors, metalloproteinases → tissue remodeling
Increased MHC molecules, costimulators → enhanced antigen presentation
Oxidative burst
Neutrophils kill microbes by producing reactive oxygen species and therefore undergoes a metabolic burst
What are the 2 different kinds of active species produced in activated phagocytes? How are they produced?
Reactive oxygen species (ROS)
Oxygen -NADP phagosome oxidase→ superoxide anion -superoxide dismutase→ hydrogen peroxide-myeloperoxidase→hypochlorite
Reactive nitrogen species (RNS)
Arginine-iNOS→nitric oxide→nitrogen dioxide
Are natural killer cells phagocytic?
No
What lineage are NK cells of?
Lymphoid lineage
How do NK cells kill?
By release of granule contents in the area of an immunological synapse
Perforin pokes holes in the membranes and proteases digest cell
Target cell dies by apoptosis (a non-inflammatory type of cell death)
What are NK cells activated by? What do NK cells produce in response?
IL-12, which is produced by macrophages
NK cells then produce IFN-γ which leads to killing of phagocytosed microbes by macrophages
How are targets recognized by NK cells?
NK cells have activating receptor and inhibitory receptor
Inhibitory receptor binds self-MHC class I
Activating receptor binds antigens
What are NK cells inhibited by?
Expression of MHC class I
How do CTLs and NK cells differ?
CTL must see antigen with MHC class I
NK cells are inhibited by expression of MHC class I
How is NK cell activation by cells lacking MHC class I advantageous?
Many viruses dowregulate Class I to escape from TCL but become sensitive to NK
Antibody dependent cellular cytotoxicity
NK cells also carry out antibody dependent cellular cytotoxicity
NK cells have Fc receptors for IgG
Leads to killing of antibody-coated cell
What do soluble mediators of innate immunity include?
Some antimicrobial, antiviral, and antifungal peptides
What are effects of Type I interferons?
Induction of “antiviral state”
Increased expression of class I MHC molecules on infected cells → killing by CTLs
Up-regulates NK activity
Induces Th1 responses
Where is type I interferon produced?
Produced by many cells in the body as well as plasmacytoid DC, the “professional” IFN producing cells
What is the effect of IL-1β/IL-6/TNF-α on the liver?
Acute-phase proteins (C-reactive protein, mannose-binding lectin) → activation of complement; opsonization
What is the effect of IL-1β/IL-6/TNF-α on the bone marrow endothelium?
Neutrophil mobilization → phagocytosis
What is the effect of IL-1β/IL-6/TNF-α on the hypothalamus?
Increased body temperature → decreased viral and bacterial replication; increased antigen processing; increased specific immune response
What is the effect of IL-1β/IL-6/TNF-α on fat, muscle?
Protein and energy mobilization to allow increased body temperature → Decreased viral and bacterial replication; increased antigen processing; increased specific immune response
What is the effect of IL-1β/IL-6/TNF-α on dendritic cells?
TNF-α stimulates migration to lymph nodes and maturation → initiation of adaptive immune response
What are the local effects of TNF-α in gram-negative bacterial infection?
Very good local effects
Get increased release of plasma proteins into tissue, increased phagocyte and lymphocyte migration into tissue, increased platelet adhesion to blood vessel wall → phagocytosis of bacteria; local vessel occlusion; plasma and cells drain to local lymph node → removal of infection; adaptive immunity
What are the systemic effects of TNF-α in gram-negative bacterial infection?
If there is systemic infection of gram-negative bacteria (sepsis), macrophages are activated in the liver and spleen to secrete TNF into the bloodstream
This can be deadly
Systemic edema occurs → decreased blood volume, hypoproteinemia, neutropenia, followed by neutrophillia (neutrophils in tissue) → decreased blood volume causes collapse of vessels → disseminated intravascular coagulation leading to wasting and multiple organ failure → death
IL-12
Produced by cells of the innate response (macrophages, DC) and activates T cells and NK cells
Stimulates IFN-γ secretion from T cells and NK cells → macrophage activation; killing of phagocytosed microbes
Causes increased cytolytic activity of NK cells and CD8+ cells → killing of infected cell
Describe how adaptive immunity is stimulated by and interacts with innate response
Macrophage phagocytosis: antigen presentation, cytokine production, co-stimulation, resulting in T cell activation
ADCC: antibody plus innate effector cells
Opsonization by antibody to enhance phagocytosis
Cytokines of the innate response are essential to stimulate (and sometimes dampen) adaptive responses
