Innate Immunity Flashcards
2 broad roles of the innate immune system
- First line of defense that slows the growth of infectious diseases until adaptive immune responses develop
- Means of directing adaptive immunity
Innate vs. Adaptive Immunity: Response time
Minutes/hours vs. Days
Innate vs. Adaptive Immunity: Specificity
Innate immunity is specific for molecules and molecular patterns associated with pathogens and molecules produced by dead/dying cells
Adaptive immunity is highly specific and can discriminate between very minor differences in molecular structure
Innate vs. Adaptive Immunity: Diversity
Innate immunity has a limited # of conserved germ-line encoded receptors
Adaptive has highly diverse receptors arising from genetic recombination
Innate vs. Adaptive Immunity: Memory responses
Innate immunity has some (observed in certain organisms and human NK cells)
Adaptive has persistent memory
Innate vs. Adaptive Immunity: Self/nonself discrimination
Innate is perfect
Adaptive is good but has some occasional failures that result in autoimmune diseases
Innate vs. Adaptive Immunity: soluble components of blood
Innate: many antimicrobial peptides, proteins, and other mediator like cytokines
Adaptive: antibodies and cytokines
Innate vs. Adaptive Immunity: major cell types
Innate: Phagocytes (neutrophils, macrophages, monocytes) NK cells, other leukocytes, epithelial and endothelial cells
Adaptive: T cells, B cells, and antigen presenting cells
what are 4 barriers that are important in the innate immune defense?
- Anatomical barriers
- Physiologic barriers
- Soluble factor-based and chemical barriers
- Phagocytic and other cellular barriers
What are 3 components of physiologic and chemical barriers?
- Acid pH
- of lactic acid and fatty acids in sweat and sebaceous glands prevents microbe growth
- of the stomach kills most ingested microorganisms - Body temperature (fever response) can inhibit the growth of certain microbes
What is the structure of antimicrobial peptides?
Short cationic peptides (29-35 AA) with an amphipathic structure
- negatively charged portions tend to be buried in the protein while the positive parts are exposed
What are defensins and what produces them?
One of the most important antimicrobial peptides; made by intestinal paneth cells, epithelial cells, neutrophils, and macrophages
Can kill bacteria very efficiently
-can precent DNA and RNA synthesis by binding to negatively charged structures in the pathogen
What are antimicrobial peptides active against?
Bacteria, fungi, and enveloped viruses
What is the mode of action for antimicrobial peptides?
Bind to negatively charged microbial structures and membranes
What are the mechanisms of killing of antimicrobial peptides?
Disruption of microbial membrane integrity, inhibition of DNA, RNA, and or protein synthesis
Lysozyme location
Mucosal/glandular secretions like tears and saliva
Antimicrobial activities of lysozyme
Cleaves the glycosidic bonds of peptidoglycan in bacteria leading to lysis
Lactoferrin location
Mucosal and glandular secretions
-milk, intestine mucus, nasal + respiratory + urogenital tracts
Lactoferrin antimicrobial action
Binds and sequesters all free iron which limits the growth of bacteria and fungi as well as disrupts microbial membranes and limits the infectivity of some viruses
Defensins (alpha and beta) location
Skin, mucosal epithelia
Defensins antimicrobial activities
Disrupt membrane of bacteria, fungi, protozoan parasites, and viruses
Additional intracellular toxic effects
Kill cells and disable viruses
What are 5 examples of ways to penetrate the epithelial barrier and what are example pathogens that make use of this route
- via the airways (Streptococcus pneumoniae)
- via the gastrointestinal tract (E. coli
- via the genitourinary tract (Human Immunodeficiency Virus)
- via cuts in the skin (Staphylococcus aureus)
- via mosquito bites (West Nile Virus)
What are 3 elements that are activated after the penetration of epithelial barriers?
- Soluble innate immune recognition elements
- Phagocytic and other cells
- Cellular receptors present on innate immune cels that function as sentinel cells in tissues
what are small proteins that cause bacteria to aggregate (enhancing phagocytosis) as well as causing cell wall disruption?
Collectins
What are the 3 major types of interferons?
- Alpha-interferon produced by leukocytes
- Beta-interferon produced primarily by fibroblasts
- Gamma-interferon produced by T cells and NK cells
- not directly induced by viruses
What are interferons?
Anti-viral agents
What are examples of secretions with antibacterial activity?
gastric juice - acid
semen - spermine and zinc
milk – antimicrobial peptides, lactoperoxidase tears, saliva, nasal secretions - lysozyme.
The action of complement involves both:
the innate and the adaptive immune systems
What is complement?
a group of ~30 serum proteins that act in an orderly sequence to exert their effect
What is the most important component of the complement pathway?
C3
How does the complement pathway progress?
via a cascade of reactions where the product of one reaction is the catalyst for the next
What is the end result of the complement pathway?
Membrane damaging reaction and enhances clearance of pathogens
What 3 things can trigger the complement cascade? Which specific pathways do they trigger?
- Mannose binding lectin and C-reactive protein (activates lectin pathway - innate immunity)
- Microbial cell wall components (alternative pathway - innate immunity)
- Antibody-antigen complexes (classical pathway - acquired immunity)
What are the 2 anaphylotoxins of the complement pathway?
C3a and C5a
What complement protein is referred to as opsonin?
C3b
Where is mannose binding lectin found?
Tissue fluid and plasma
Binds mannose residues on the glycoproteins and glycolipids of which 3 things:
- Bacteria
- Fungi
- Viruses
What is CRP and where is it found?
called C-reactive protein and it is a protein found in tissue fluid and plasma
What does CRP bind to and what does it activate?
Binds to phosphatidylcholine and pneumococcal polysaccharide
Activates complement cascade
What is the acute phase response and what is it responsible for?
The acute phase is the period of disease preceding recovery or death and it is responsible for the production of innate immune effector cells and soluble molecules
What are the major signallers of the acute phase response
Pro-inflammatory cytokines
IL-1, IL-6, and TNF-α
What is the effect of the proinflamatory cytokines of the liver?
Tells it to produce more APR proteins
-including complement components
What is the effect of the proinflamatory cytokines of the bone marrow?
Increase production of white blood cells
What is the effect of the proinflamatory cytokines of the hypothalamus?
Produce prostaglandins for the fever response and also stimulate the adrenal cortex to produce corticosteroids
-this acts on the liver to increase production of APR proteins
Which 2 major cell types are responsible for phagocytosis?
Neutrophils and Macrophages
What are the 3 mechanisms that phagocytes use to kill microbes?
- Respiratory burst that generates reactive oxygen and nitrogen intermediates
- Non-oxidative methods: hydrolytic enzymes, antimicrobial peptides
- Inducible nitric oxide synthase (produces NO)
5 steps in the process of phagocytosis
- Bacteria attached to pseudopodia that form membrane evaginations
- Bacteria ingested, forms phagosome
- Phagosome fuses with lysosome
- Bacteria killed, digested by lysosomal enzymes
- Digested products released from cell
What 2 features of PAMPS make then a good target for recognition
- Highly conserved and very difficult for microbes to change
- Absent from host cells
What is recognized by the TLR and NOD receptors?
Structural motifs (PAMPs) in microbes
TLRs that recognize nucleic acids are located where?
Inside the cell (endosome/lysosome)
repeats of which amino acid form the ligand binding exterior domain of TLRs?
Leucine rich repeats
What 3 things can the TLR signal following activation ?
- MAP kinase pathway
- Interferon regulatory factor 3/7
- NF-κB
What are the 5 inflammation promoting genes that are regulated by NF-κB?
- Inflammatory cytokines
- Chemokines
- Adhesion molecules on endothelial cells
- Immune effector molecules
- Costimulatory molecules
- critical for the initiation of adaptive immunity
TLRs are direct inducers of the maturation of which cell type?
Dendritic cells
What do the TLRs induce the DC to produce/express
CD80/CD86/CD40
Upregulation of MHC II
Production of IL-12
What 2 cytokines can induce dendritic cells to mature indirectly?
TNF and IL-1
What are the 4 innate immunity effector cells
Neutrophils, Macrophages, Dendritic cells and NK cells
What are the 2 type 1 interferons?
IFN-α and IFN-β
What activates IFN-α and IFN-β production?
Presence of viral RNA or DNA in the cell
-via TLR stimulation
What do x then induce (antiviral mechanism)
Antiviral responses in neighbouring cells by binding to the IFN-α/β receptors
This leads to mRNA degradation within the cell and the inhibition of protein synthesis
The cell is then refractory to viral growth
What cells can the IFN-α/ß activate? What effect does this have on the cell
NK cells which increases their lytic activity of virally infected cells
How does the NK cell use a dual receptor mechanism to discriminate between healthy and infected cells?
Virally infected cells will down regulate class I MHC
NK cells have a dual receptor mechanism and if there is no class I MHC to interact with the inhibitory receptor, the cell will be killed
What type of cell produces 100-1000x more type I interferon when it comes into contact with viruses
Plasmacytoid dendritic cells
What do plasmacytoid cells recognize?
viral ssRNA using a TLR
