Immune System Physiology: Innate System Flashcards
immunity: a tradition predating history
-innate immune system is highly conserved
-around for years and has evolved over time
Ex. drosophila, starfish, frogs, chickens, zebrafish —> all have immune systems similar to humans
what is the biggest challenge of innate immunity?
recognizing major classes of organisms that cause problems
what are the four categories of organisms that are threats to the immune system?
- viruses
- intracellular and extracellular bacteria
- fungi
- parasites
what is the goal of innate immunity?
-recognize anything that falls within the four broad classes
-want to swiftly and efficiently ID potential health threats and
1. slow or halt their invasion
2. alert adaptive immune system
3. minimize damage to the organism
why are the majority of potential threats no threat at all?
the innate immune system is so effective
innate immune system is very fast-acting
causes inflammation, complement activation, phagocytosis, and destruction of pathogens within minutes and can last for days
what are the three main jobs of the innate immune system?
avoidance, resistance, and tolerance
physical and chemical barriers (avoidance)
-epithelial barriers
-mucus
-enzymes
-pH
-commensal microflora
professional profilers (resistance)
-humoral components
-cellular components
pathogen pathway
anatomic barriers (skin, oral mucosa, respiratory epithelium, intestine) —> complement/antimicrobial proteins (C3, defensins, Regllly) —> innate immune cells (macrophages, granulocytes, natural killer cells) —> adaptive immunity (B cells/antibodies, T cells)
prevention of damage (tolerance)
tolerate area to prevent extensive damage
cellular components of innate immunity
macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, and natural killers (NK) cells
macrophages
-huge component of the innate immune system- very specialized
-arise during embryonic development
-added by monocytes circulating blood
-have long lives like microglia living for decades
-major phagocytotic cell
what are the functions of macrophages?
-engulf pathogens and destroy them
-help orchestrate the innate immune system by putting out cytokines and letting other cells know about an infection
-when an infection has spread, they stick around and transition to repair- they help with tissue repair
monocytes —> macrophages
monocytes are the precursors to macrophages and they both have phagocytotic capabilities
what happens if you have too many microphages sticking around to repair?
could cause fibrosis in the liver or other issues near the site of infection
dendritic cells
-capability to phagocytose but actually do macropinocytosis, which is the drinking of the area around them with long dendrites that help with surveillance
-also in tissues like macrophages
-leave the site of infection and exit to the lymph node to get T cells
what do dendritic cells do?
survey for infection —> find it —> report it to specialized cells
what are three different granulocytes?
neutrophils, eosinophils, and basophils
neutrophils
-help phagocytose pathogens and spill innards to catch pathogens —> can cause tissue destruction
-leave bone marrow at night and in the morning they are very active then die
eosinophils and basophils
granulocytes released to kill pathogens but primarily focus on parasites and allergic responses
mast cells
respond to allergies by releasing histamines
natural killer (NK) cells
-bridge from innate to adaptive immune systems
-respond with specificity but not as much as adaptive
-release granules to pathogens
platelets
part of the circulating innate immunity system
innate-like lymphocytes
these are located within the tissue and they are cells that look like lymphocytes but innate functions since not that specific
Ex. ILCs in the gut, NK T cells, beta-alpha T cells (skin defense), and B-1 B cells (mouth for cavity defense)
circulating innate immunity
granulocytes (neutrophils, basophils, eosinophils), mast cells, monocytes, NK cells, platelets
tissue/cavity innate immunity
macrophages, dendritic cells, innate-like lymphocytes
macrophages + dendritic cells
-macrophages and dendritic cells- antigen-presenting cells of innate immunity- link between innate and adaptive immune systems
-present antigens to T and B cells to induce adaptive response
-without them there would be no way to tell adaptive system what to respond to
what induces an adaptive response?
interaction between macrophages, T cells, B cells, and dendritic cells
how does the innate immune system ID potential threats?
pattern recognition receptors (PRRs)
PRRs
-allow for innate immune system to respond w/in hour
-invariant in genome and don’t require recombination to form a specific receptor
-expressed rapidly and upregulated rapidly in response to infection
-don’t need an activation signal to be upregulated
pathogen associated molecular patterns (PAMPs)
-structural patterns common in pathogens that allow PRRs to accurately ID patterns
-conserved on pathogens for PRRs to recognize
PAMPs
-bacteria (gram positive or gram negative) like lipoteichoic acid LTA, peptidoglycan PGN, lipoproteins, DNA, flagellin, and lipopolyssacharide LPS
-viruses
-parasites
-yeast
-there are specific building blocks in these pathogens that without them they won’t survive and the immune system evolves to respond to these pathogens
what are some defense mechanisms of the PAMPs?
-viruses have coat proteins that prevent the immune system from seeing them
-parasites have GPI anchors
-bacteria are able to go intercellular and begin replication inside Ex. salmonella
-yeast have zymosan (beta-glucan)
what are the two types of PRRs?
humoral and cellular
humoral PRR
-made by the liver and circulates in the blood
-C1 complex of complement
-mannose-binding lectin
-C reactive protein
-surfactant proteins like A and D in the lung that create poor environment for bacteria
Ex. complement sets off chain reaction —> creates pore in lipid bilayer of bacteria
what does mannose-binding lectin do?
binds to the mannose in the cell surface of bacteria and yeasts and activates the complement system
cellular PRRs
extracellular and intracellular
extracellular PRRs
-extracellular membrane bound
-phagocytic receptors: recognize mannose-binding lectin, complement-bound cells, scavenger receptors
-signalling receptors: toll-like receptors (TLRs) 1, 2, 4, 5, 6
intracellular PRRs
-membrane bound: TLRs 3, 7, 8, 9
-cystolic in the cytosol of the cell like NOD1 and 2, inflammasomes
extracellular TLRs
-extracellular proteins that recognize something that lives outside the cell
-TLR1:TLR2 and TLR2:TLR6 are heterodimers on the surface of cells —> recognize different ligands associated with bacteria or yeast
-TLR4 recognizes LPS on bacteria
intracellular, membrane-bound TLRs
-primarily focused on viruses since they only survive inside cells
-TLR3- dsRNA
-TLR7- ssRNA
-TLR8- G-rich oligonucleotides
-TLR9- unmethylated CpG DNA
TLRs
best known PRRs
downstream of the TLRs
Ex. TLR4
-LPS binds to it —> cascade of MyD88 —> interferon kappa (IkBa) —> pro-inflammatory cytokines
-TLR4 induces MyD88 cascade which leads to NfKB and also an interferon cascade —> IRF3 and interferon production
what occurs when a PAMP binds to a PRR?
- destruction of PAMP’s source
- recruitment of other cells
- priming of PRR-bearing cells
what are ways of destroying the PAMP’s source?
phagocytosis, cytotoxic killing, secretion type I IFNs: interferon alpha and beta, and inducing “climate change”
phagocytosis
-through mannose-binding lectin bind to the outside of the pathogen or cell-to-cell interaction
-macrophage sees bacteria and phagocytoses it
-done by neutrophils and macrophages
-irreversible oxidative destruction
how does a macrophage kill a pathogen?
bacteria that binds to a complement receptor —> bacteria is coated in complement —> brought in by phagosome —> merges with lysosome with low pH that wllows for oxidative pathways to destroy the pathogen
how do neutrophils kill a pathogen?
bacteria gets into lysosome —> enters into phago lysosome —> gets destroyed by oxidative destructive pathways
cytotoxic killing
-through membrane attack complex
-series of different C proteins that follow a specific chain of command
-end result of complement is formation of C9 pore —> leads to destruction of pathogen where all the sodium exits and it dies
NK cells
-kill with perforin
-a lot of positive and negative receptors- positive more than negative then you have degranulation and the same effect with the membrane and Na gradient shifting
-granzyme and granulysin —> apoptosis
secretion of Type I IFNs: interferon alpha and beta
-very potent cytokines and they bind to interferon receptors and lead down pathway of induction
-tell cells that see PAMP to turn on restriction factors and the nearby cells to turn them on —> inhibits replication of viruses and creates a silo of replication
inducing “climate change”
-fevers induce global climate change
-macrophages secrete IL-1B, IL-6, TNFalpha —> acts on different organs for specific functions
-liver- has acute phase protein synthesis, which activates complement opsonization
-bone marrow endothelium- releases neutrophils which lead to phagocytosis
-hypothalamus- increase the body’s temperature
-fat and muscle- increase the body’s energy and and cell response
-dendritic cells- get help from the lymph nodes
mast cells, monocytes, and platelets
-not only do the dendritic cells leave but others involved
-neutrophils and monocytes in the blood normally just circulate but sometimes they attach to vessels to draw away
vasoactive peptides
-production of vasoactive peptides like histamines and serotonin and cytokines from monocyte, mast cells, and platelets
-takes blood vessel and makes it leaky for cell to leave near infection
TNFalpha
-induces integrins and selectins, which increases the permeability
-monocytes bind to these on the endothelium and as the amount increases in a row, it slows down the cells
what are involved in recruitment of other cells?
-vasoactive peptides and cytokines, activating cytokines and chemokines, and the end result: rolling and diapedesis
-essentially the role is to get cells to exit the blood vessels and follow the bread crumbs to infection
-CCL2 engages monocytes, CCL8 engages neutrophils and T cells
chemokines
- monocytes, macrophages, and dendritic cells —> CCL2 —> monocytes
- macrophages and endothelial cells —> CXCL8 AKA IL-8: neutrophils and T cells
cytokines: Signal 3 —> Th1 vs Th2
- platelets —> RANTES —> monocytes
- macrophages —> IL-12 —> NK cells
- macrophages —> IL-1beta and IL-6 —> lymphocytes
Th1 + Th2
types of helper cells that differ in their roles in the immune system and the cytokines they release
Th1 cells
produce cytokines such as IL-2 and IFN-γ
chemokines role in recruiting other cells
-need chemokines and cytokines to be produced simultaneously and they filter out to blood
-monoctyes or neutrophils recognize a chemokine with a receptor on its surface and a lot of CCL2 will draw them in that direction
-CXCL8 is the same idea but with neutrophils and T cells and pulls them from blood to site of infection
cytokines role in recruiting other cells
drive platelets and macrophages to a particular pathway
rolling and diapedesis
rolling adhesion with the CXCL8R —> tight binding —> diapedesis (passage of blood cells through the capillaries) —> migration to site of infection
priming of PRR-bearing cell
-upregulation of two important proteins: MHC Class II or MHC Class I
-MHC II and I present peptides to adaptive system
-MHC II: macrophages and dendritic cells
-MHC I: all cells, including neurons, except for RBCs
-must present the peptide in context
MHC Class II
take invading pathogen —> put it on peptide holding protein —> show CD4+ or CD8+ to get them to generate a response
MHC Class I
CD8 will kill the pathogen
what is needed to activate CD4+?
upregulation of MHC I/II must include a co-stimulatory molecule to activate CD4+ —> cannot activate T cell through one signal
where does activation of CD4+ or CD8+ occur?
-dendritic cells travel to the lymph node near site of infection (like in the armpit, arms and legs, neck, breasts) and present to T cells that are circulating in the lymphatic vessels
-naive T cells will bind to the antigen and once the infection has happened, there is a ramp-up of T cells
what is involved in the priming of PRR-bearing cells?
upregulation of MHC II or MHC I, induction of co-stimulatory molecules, and migration to lymph node
summary of innate immune system
-innate immune system has PRRs recognize PAMPs
-slow/halt expansion through the humoral/cellular components
-destroy PAMPs and recruit other cells
example of cut
-pathogen in cut —> infection —> recruit cells to kill it and it fails —> recruit macrophages and dendritic cells and they fail —> adaptive immune system comes in
-get through failure points and adaptive system kicks in
what is one of the key ways that the immune system knows you’re not infected?
-if you’re showing self —> MHC on your surface presenting normal peptides and every cell in the body besides RBCs show MHC class I then the NK will keep moving
-not showing self then the innate immune system knows you are infected
C1 complex of complement pathway
binds to antibodies bound to bacteria or virus and triggers pathway of complement —> downstream pathway of complement is to cause punctures in the wall of the bacteria
