Immuno 5 Flashcards
T or F. Innate responses are most
important over the first 4 days (96 hrs), but these responses will continue until the pathogen is cleared.
T.
What mechanical barriers prevent microorganisms from reaching our tissues?
the skin (epidermis) and epithelium that lines the GI and respiratory tracts is the most important of these barriers. It is difficult for most microbes to penetrate this barrier and gain access to our tissues. The flow of air or fluid across the epithelium and gut helps to prevent attachment by microbes. This is critical because attachment is typically the first step in gaining access. The airways of the lungs have cilia that move mucous along the lumen of the respiratory tract that also help to prevent attachment.
What chemical barriers prevent microorganisms from reaching our tissues?
fatty acids in our skin prevent attachment,
enzymes such as pepsin and lysozyme that are produced in the gut and eyes/nose, respectively. The low pH in the gut also interferes with or kills many potential invaders.
antibacterial peptides (defenses) in the skin, gut, and lungs. At a minimum, the production of defensins increases the minimum infectious dose of a microorganism. The higher inoculum that is needed to cause disease, the less likely an organism is to cause a symptomatic infection.
What microbiological barriers prevent microorganisms from reaching our tissues?
normal flora of microbes int he skin and gut are very important because they compete with other microbes for colonization of our tissues, and they produce substances that are damaging or toxic to other microbes.
What are dermcidins?
the major family of human antimicrobial peptides (a type of defensin).
These make a helical wheel diagram that demonstrates that these peptides form what is known as an amphipathic alpha-helical structure. What this means is that the hydrophobic amino acid side chains of the alpha helix are all segregated to one face of the helix while the hydrophilic amino acid side chains partition to the other face of the helix. These peptide are always rich in positively charged amino acids (arginine and lysine).
Multiple copies of these peptides can multimerize via hydrophobic interaction, and their overall positive charge causes the multimers to insert across the negatively charged outer envelop of bacteria (much more effective for gram-negative bugs). Once inserted, the hydrophobic faces of each peptide monomer interact with the hydrophobic lipids of the outer envelop while the hydrophilic faces come together to form a pore in the surface of the pathogen. This results in osmotic disintegrity and death of the microbe.
What is one of the primary sources of defensins in the gut?
Paneth cells
What are Cathelicidins and where are they produced?
a type of antimicrobial peptide and it is produced in the lysosomes of macrophages and neutrophils as well as epithelial cells.
T or F. The proteins of the alternative complement cascade are constitutively made in the spleen
F. They are constitutively made in the liver and can be activated almost immediately following encounter with a microbe that has gained access to host tissues.
Is the MAC much more effective as a defense against gram-negative or gram-positive bacteria?
gram-negative because of the differences in their outer envelop construction.
What happens if a bacterial pathogen can survive the first few hours of attack by the innate immune system?
an inflammatory response results in recruitment of many more phagocytes.
What happens once the phagocytes arrive to the infectious tissue?
Tissue macrophages recognize the bacteria via their pattern recognition receptors, and following that recognition they begin to produce inflammatory cytokines.
What are the most abundant cells that are recruited early in the response?
neutrophils (brought in by IL-8 from macrophages and C5a)
What are the initial steps of response following the introduction of a pathogen into the body?
an injury to the skin has resulted in deposition of a bacterial pathogen in the tissues. A resident tissue macrophage recognizes the bacterium via its PRRs and begins to produce inflammatory cytokines that activate the vascular endothelium, resulting in movement of fluid and inflammatory cells into the tissues. The most abundant early phagocytes that will be recruited are neutrophils (there will be recruitment of some macs as well). The newly recruited phagocytes will take up bacteria that they encounter and will begin to produce additional inflammatory cytokines (IL-1, IL-6, and TNF-alpha).
The movement of fluid into the tissues will result in flow of fluid via the lymphatics toward the draining lymph nodes where APCs can present antigen to naïve T cells.
In many cases, this innate phagocyte-mediated response can completely clear the bacterial infection before it becomes symptomatic. If not, an amplified innate response will be produced to hold the infection down until an acquired response can be primed.
What happens when neutrophils are recruited to inflammatory sites?
they cross the vascular endothelium in a process that is mediated by surface adhesion molecules.
Who do neutrophils cross the vascular endothelium using surface adhesion molecules?
Addressins on the surface of the neutrophils (GlyCam-1 and/or CD34) bind to selectins (P-selectin and E-selectin) that are expressed on the surface of the vascular endothelium. As those interactions happen, the neutrophil is brought in close contact with the endothelial cells and begins to roll. Once this occurs, chemokines that are bound to the activated endothelial cells bind to chemokine receptors on the neutrophil and LFA-1 on the neutrophil binds to ICAM. Ultimately, these interactions bring the cell close enough to the endothelial cells that CD31 (PECAM-1) on the surface of neutrophils binds to CD31 that is expressed in the tight junctions between the endothelial cells. These interactions facilitate migration of the neutrophil through the tight junction and into the underlying tissue.
A similar mechanism results in extravasion of circulating monocytes as the inflammatory response continues.
How do phagocytes actually kill microbes (bacteria and fungi, primarily)?
Once a bug has been phagocytosed, the initial events that occur are binding of several types of azurophilic granules with the phagosome. These granules contain antimicrobial substances that can begin to have toxic effects on the bugs.
What kinds of antimicrobial substances are found in the azurophilic granules inside of phagocytes?
myeloperoxidase (MPO), elastase, lysozyme, defensins
What is the next step that occurs once the phagosome has binded with the azurophilic granules?
The next step is fusion of the phagosome with lysosomes, to create the phagolysosome.
What do Lysosomes contain that target the bacteria?
degradative enzymes that are collectively known as acid hydrolases.
Fusion of the phagosome with the lysozome causes what to happen?
NADPH oxidase is created which results in what is known as the respiratory burst because there is a transient increase in oxygen consumption during this process that results in the creation of toxic reactive oxygen species. Specifically superoxide particles are released that eventually turn into hydrogen peroxide.
These reactive oxygen species are not completely confined in the phagocyte and can cause damage to surrounding tissue. Some of this is mitigated because during the respiratory burst, the phagocyte also produces enzymes (such as catalase) that degrades hydrogen peroxide to water and oxygen. Some bacteria make catalase to interfere with the respiratory burst, giving them a survival advantage.
What is NETosis?
NETosis is a type of cell death that neutrophils can undergo that results in what is essentially the opposite of apoptosis. When a cell dies via apoptotic death, its genome is digested into small pieces and then the cell blebs off small small fragments of the cell that are encased in cytoplasmic membrane. These small pieces are easily taken up by phagocytes. NETosis is very distinct from this because instead of the genome being digested, it is actually expelled from the cell in undigested form, allowing it to create a web or net of chromatin material that can entrap pathogens, preventing their dissemination. NETosis also results in expulsion of cytoplasmic contents, including digestive enzymes, anti-microbial peptides, etc.
What are Pattern recognition receptors (PRRs)?
recognize common components of pathogens that are commonly known as pathogen-associated molecular patterns or PAMPS.
When phagocytes recognize PAMPS via their PRRs, they are triggered to phagocytose the material, produce inflammatory cytokines, and begin to express B7 (co-stimulator) on their surface.
There are three broad classes of PRRs. What is the first type?
endocytic PRRs (e.g. mannose receptor, glucan receptor, and scavenger receptor).
These PRRs generally recognize carbohydrates and they promote phagocytosis on the material that they recognize. The receptors do not need to transmit a signal to the cell nucleus to initiate phagocytosis.
These are non-signaling receptors.
What is the second type?
signaling PRRs. There are a set of ten of these that are membrane-anchored receptors, called Toll-like receptors (some of them must be combined with another to create the receptor, while others by themselves (either in monomeric of homodimeric form) serve as the receptor.),
and the others are cytoplasmic receptors known as the NOD-like receptors (that recognize bacterial products) and RIG-1-like receptors (that are sensors for viral RNAs). Engagement of these receptors with their ligands results in cytokine production.
