Innate Immunity- Hunter Flashcards
What are these a part of:
epithelial barriers
anti-microbial enzymes and peptides
the complement system
macrophages, dendritic cells, and neutrophils (myeloid cells)
patter recognition receptors that are germline encoded
inflammation (rubor, calor, tumor, and dolor)
cytokines, chemokines, adhesion molecules, and acute phase proteins
interferons and NK cells
Innate immunity (first line of defense)
What does it mean to be colonized by a microbe?
you have an organism that is on or in your tissues but barriers have not been perturbed and therefore there is not immune response
What does it mans to be infected by a microbe?
An organism has penetrated you tissues but the response is subclinical (not presenting readily observable symptoms)
NOTEdisease has observable symptoms**
What is this:
a pathogen that resides on or in the body but causes disease only when the host is immunosuppressed.
opportunistic pathogen
What are three sources of pathogens?
environmnt
humans
animals (zoonotic diseases)
What is the mode of transmission to be infected by a pathogen in the airways?
inhaled droplets and spores
What pathogen can you get by inhalin a droplet and pentrating the mucosal surface of your airway?
What does this cause?
influenze virus
influenza
What pathogen can you get via spores that pentrate the mucosal surface of your airway?
What does this cause?
neisseria meningitidis->meningococcal meningitis
bacillus anthracis-> inhalation anthrax
What is the mode of transmittion to infect the GI tract?
comtainated food or water
What pathogen can you get by eating or drinking contaminated food or water?
What does this cause?
salmonella typhi-> typhoid fever
rotavrius-> diarrhea
What is the mode of transmission to infect the reproductive tract?
physical contact
What pathogen can you get through physical contact that will affect your reproductive tract?
What does this cause?
treponema pallidum-> syphilis
HIV-> AIDS
What are the three mucosal surfaces that are suscpetible to pathogens?
airway
GI Tract
Reproductive Tract
What are the three routes of entry into your external epithelia?
external surface
wounds and abrasions
insect bites
What is the mode of transmission to infect your external surface?
physical contact
What pathogen can you get through physical contact that will affect your external surfae?
What will this cause?
trichophyton-> athlete’s foot
What is the mode of transmission to infect wounds and abrasions?
minor skin abrasions
puncture wounds
handling infected animals
What pathogen can you get through minor skin abrasions?
What does this cause?
bacillus anthracis-> cutaneous anhrax
What pathogen can you get through puncture wounds?
What does this cause?
clostridium tetani-> tetanus
What pathogen can you get through handling infected animals?
What does this cause?
francisella tularensis-> tularemia
What type of insect bites can infect your external epithelia?
mosquito bites (aedes aegypt) deer tick bites mosquito bites (anopheles)
What pathogen can you get through mosquito bites (aedes aegypti)
What does this cause?
flavivirus-> yellow fever
What pathogen can you get through deer tick bites?
What does this cause?
barrelia burgdorferi-> lyme disease
What pathogen can you get through mosquito bites (anopheles)?
What does this cause?
pasmodium spp. -> malaria
Do all organisms have to penetrate tissues to cause sickness?
no (think cholera)
If you have an aborgated immune response such as AIDS or malnutrition, what are these people susceptible to?
opportunistic pathogens
the immune system is assisted by what three kinds of barriers?
Mechanical
chemical
microbioloical
What kind of barriers are these: longitudinal flow of air or fluids movement of mucus by cilia tears nasal cilia EPITHELIAL TIGHT JUNCTIONS
mechanical barriers
What kind of barriers these:
fatty acids, Beta defensins, lamellar bodies, cathelicidin
chemical barriers for the skin
What kind of barriers are these:
low ph, enzymes (pepsin), alpha-defensins (cryptdins), regIII (lecticidins), Cathelicidin
chemical barriers for the gut
What kinds of barriers are these:
pulmonary surfactant, alpha densins, cathelicidin
chemical barriers for the lungs
What kinds of barriers are these:
enzymes in tears and saliva (lysozyme), histatins, beta defensins
chemical barriers for eyes/nose/oral cavity
What is the microbiological barriers for the skin, gut, lungs, eyes/nose and oral cavity?
normal microbiota
endotoxins are caused by what kind of bacteria?
gram negative
Vibrio cholera, strep and staph are all what kind of toxin?
exotoxin (meaning they release toxins to allow for the penetration of tissues)
E. Coli, salmonella are what kind of toxin?
endotoxins (a toxin that is present inside a bacterial cell and is released when the cell disintegrates. It is sometimes responsible for the characteristic symptoms of a disease)
AN endotoxin has a lipopolyscharide toxin found in the (blank) of the organism and will perturb the immune system in massive ways by triggering a bunch of cytokines and a over active immune response
cell wall
What kind of mechanism is this: a pathogen gets inside a cell and uses the cells machinery and then destroys the cell and moves on to a new one
direct cytopathic effect
What do you call a direct mechanism of tissue damage by pathogens?
microbial pathogenesis
What do you call indirect mechanisms of tissue damage by pathogens?
immunopathology
What are the three pathogenic mechanisms that cause direct tissue damage?
exotoxin production, endotoxins, and direct cytopathic effects
What are immune complexes?
It’s when really large antibodies attach to antigens and then you cant get them filitered out of your body
(they get stuck places like blood clots)
What are anti-host antibodies?
When your body makes antibodies that attack the self
What are the three types of anti-microbial enzymes?
lysozyme
pepsin
secretory phospholipase A2
How does lysozyme work?
it chews up the outer petidoglycan layer of the cell wall of gram-positive bacteria.
Do gram positive bacteria and gram negative bacteria have the same type of cell wall?
no
Do both gram positive and gram negative bacteria have peptidoglycan layers in their cell wall?
yes
Which type of bacteria has teichoic acid and lipteichoic acid, gram negative or gram positive bacteria?
gram-positive bacteria
What are the four major classes of anti-microbial peptides?
defensins alpha
defensins beta
cathelicidins
histatins
Are anti-microbial peptides, short or long?
short
Anti-microbial peptides are activated by proteolysis to relases (blank) peptides
amphipathic
How do defensins work?
They have a positive charge on one side and a hydrophobic charge on the other which will allow them to enter the lipid membrane and create a pore in the microbial membrane.
How do you make an anti-microbial protein?
they are pro hormones that are cleaved into an active form
Are antimicrobial proteins a primary or secondary defense
primary defense
Pathogens that breach epithelial barriers encounter (blank) that trigger (blank)
Macrophages
inflammation
How do macrophages recognize pathogens?
by genome encoded receptors (e.g TLRs)
(blank) cause vasodilation, increased vascular permeability, and upregulate expression of adhesion molecules on endothelium
cytokines (e.g TNF-alpha)
Activation of the (blank) and (blank) systems cause pain and blood clotting
kinin and coagulation systems
(blank) attract neutrophils (CXCL8) and monocytes as a second line of defense
chemokines
(blank) an (blank) componenets like complement engage the pathogens and often eliminate them before an adaptive immune response is generated.
phagocytic cells and plasma components
What is the most important component of adaptive immunity?
inflammation
How do macrophages trigger inflammation?
they trigger cytokines and chemokines, neutrophils and more macrophages
What is sepsis?
when the inflammatory process gets out of hand (release of massive amounts of cytokines and you have too high of permeability in your vascularization)
What is the most important pro-inflammatory cytokine that causes vasodilation and vascular permeability?
TNF alpha
After macrophages tell cytokines to come to the tissues, what do they call next to come help?
neutrophils and other macrophages
Which or the stronger phagocytic cells, macrophages or neutrophils?
neutrophils
What do macrophages recognize?
pathogen associate molecular patterns
Can macrophages recognize common motifs? what is a very common one?
yes
peptidoglycan
What do macrophages recognize easily on gram-positive bacteria?
peptidoglycan
What do macrophages easily recognize on gram-negative bacteria?
Lipopolysaccharide (LPS)
What does endotoxin bind to?
Toll receptors (TLR
What are recognized by their motif F-Met-Leu-Phe?
bacteria
What carry mannose receptors?
bacteria, fungi, viruses
What carry scavenger receptors?
acetylated lipoproteins on bacteria
What carry dectin-1 glucan receptors?
fungi
What carry LPS binding proteins, TLR-4 and CD14?
gram negative bacteria
What are Toll-Like Receptors?
pathogen recognition and signaling molecules
How many human TLR genes are there?
10
TLR proteins are (blank) receptors
PAMP (pathoen associated molecular patterns)
TLR 5 evolved to recognize what?
flagelin
You can find (blank) inside vacuoles inside of macrophages.
TLR
In innate immunity (blank) have evovled to create the initial self-non self discrimination of the immune system.
TLR Receptors
Where do you find TLR receptors?
on the cell surface and intracellularly
TLR activation engages the transcription factor (blank) and induces the production of inflammatory mediators.
NF-kB
(blank) are similar in structure to TLR, detect cytoplasmic bacteria, and signal inflammation
Nucleoside Oligomerization Domain (NOD)-like proteins
(blank) detect viral RNA in the cytoplasm and signal inflammation
retinoic acid inducible gene -I
(RIG)-like proteins
What does TLR 2 and TLR 6 recognize?
diacyl lipopeptides
what does TLR2 and TLR1 recognize?
triacyl lipoproteins
What does TLR-4 recognize?
LPS
What does TLR 3 recgonize?
dsRNA
What does TLR7 recognize?
ssRNA
What does TLR-9 recognize?
CpG DNA
Where do you find NOD proteins? What do they do?
in the cytoplasm
intiate inflammation
What do RIG do?
detect viral DNA
TLR signaling induces (blank)
gene transcription
Give a brief description of how TLR signaling induces gene transcription
PAMP allows for dimerization of TLR which induces intracellular signaling and the gene expression of the transcription factors and cytokines like NF-Kb
What is IRAK4?
a danger signal
What happns when you dimerize TLR receptors?
you recruit IRAK1 and IRAK4 to create an immune response
IRAK-1 deficiency is a rare autosomal (blank) defect.
recessive
What is this: any of a class of proteins present in the serum and cells of the immune system, that function as antibodies
immunoglobulin
In detail explain how TLR induces gene transcription
Dimierized TLR-> recruits IRAk1 and IRAK4-> IRAK1 and IRAK4 activate E3 ubiquiting ligase Traf-6-> Traf 6 and NEMO are polyubiquitinated-> create scaffolding-> TAK1 gets together with IKK and phosphorylates IKKB which phsophorlates IKB-> IKB degrades-> releases NFkB into the nucleus to induce expression of cytokine genes-> inflammation
What is this:
involving or relating to the production of pus.
pyogenic
The (blank) pathway involves the expression of more than 100 genes
NF-kB
What are the two major defects in intracellular killing in neutrophils?
abnormal respiratory burst
granule abnormalities
What are the two types of abnormal respiratory bursts in neutrophil function?
chronic granulomatous disease
glucose-6-phosphate dehydrogenase deficiency
What are the three types of granule abnormalities in neutrophil function?
myeloperoxidase deficiency
specific granule deficiency
chediak-higashi syndrome
What is the major defect in adhesion defects in neutrophils
leukocyte adhesion deficiency
What are the two types of adhesions defects in neutrophils?
Type 1, integrin deficiency
Type 2, E-selectin ligand deficiency
What is the most important means of defense against extracellular bacteria, fungi and protozoan parasites?
phagocytosis and intracellular killing
What are the 2 most important phagocytic cells?
neutrophils and macrophages
Invagination of cell membrane creates the (blank)
phagosome
(blank) filled with antimicrobial substances fuse with phagosomes and create (blank). This is where most microbes are killed and digested
lysosomes
phagolysosome
Assembly of the (blank) promotes intracellular microbial killing
NADPH oxidase
How do you assemble the NADPH oxidase component in the phagolysosomal membrane?
microbe phagocytosis and G-protein receptor signaling
What does NADPH oxidase generate?
antimicrobial superoxide, hydrogen peroxide and other reactive oxygen species (‘respiratory burst”)
How do you activate acid hydrolases and antimicrobial peptides within the phagolysosome so that it can kill microbes?
lower the pH
What does the C5a complement do?
augments phagocytosis (internalization and causes formation of NADPH oxidase)
What do these make up:
p67, P10, P17, P22, Gp91
NADPH oxidase
What happens if you have defect in Gp91 and how does it happen?
you cant make NADPH oxidase and therefore cannot destroy microbes…. Can be caused by X-linked defects
What is respiratory burst?
the production of oxygen species via NADPH
WHat all can you find within a phagolysosome?
acid, toxic oxygen species, NO, antimicrobial peptides (cathelicidn, defensins etc.), enzymes, competitors (lactoferrin)
What makes lactoferrin and vit B12?
neutrophils
What does lysozyme do?
digests cell walls of some gram-positive bacteria
Why do granulomas form?
when the immune system cant get rid of something
If you cant reduce dihydrorhodamine, what is the problem?
gp91 deficiency and a failed NADPH oxidase system resulting in granulomas or chronic granulomatous disease
(blank) lesions in the skin and various internal organs are caused by pyogenic bacteria and fungi
Granulomatous
What is pyoderma?
an infection of the skin (all over the outside of the skin)
When your lymph nodes interact with microbes they become (blank)
hyperplastic
What is the defect in chediak-higashi syndrome and what will you see?
defect in microtuble polymerization (decreases phagolysosomes)
recurrent pyogenic infections, partial albinism, large lysosomal vesicles in neutrophils and eosinophils
What is neutropenia?
you have a low level of neutrophils
What are the two ways you can get neutropenia?
acquired (common) and hereditary (rare)
What are the 2 ways you can get acquired (common) neutropenia?
drug-induced (especially cytotoxic drugs for cancer)
autoimmune (anti-neutrophil antibodies)
What are three types of hereditary (rare) ways to get neutropenia?
familial (benign, ethnic) neutropenia
infantile genetic agranulocytosis (severe congenital neutropenia)
cyclic neytropenia
T or F
neutropenia induced by cytotoxic anti-cancer drugs is common
T
Define neutropenia in terms of cell count
1500 to 2000 cells/mm cubed of blood
At what neutrophil count to you have an increase in infections?
below 1500 cells/mm cubed
What are the most common pathogens that take advantage of neutropenia?
staph, gram negative bacteria, other encapsulated bacteria, fungi
Nearly 15% of sepsis cases are caused by (blank)
candida albicans
Neutropenic sepsis can be caused by a variety of (blank)
pyogenic bacteria and fungi
How do you get rid of drug-induced neutropenia?
broad-spectrum antibiotics and human recombinant granulocyte colony stimulating factor (hrG-CSF) before subsequent rounds of chemotherapy (increases output of granulocytes of bone marrow)
(blank) is a genetically and phenotypically heterogenous group of nehreditary neutropenias seen in infants
severe congenital neutropenia (Kostmann disease)
What does this describe:
patients present with recurrent infections of skin, soft tissues, lungs and deep organs; sepsis is common, ANC is often below 200/ uL. Differentials includes a wide variety of conditions that impair myelopoiesis. A diagnosis is supported by characteristic findings of maturation arrent at the promelocyte or myelocyte stage.
sever congenital neutropenia (kostmann Disease)
How do you treat Kostmann disease (severe congenital neutropenia)
rhG-CSF or bone marrow transplant
What is risky about rhG-CSF?
myelodysplasia (refers to a group of disorders in which the bone marrow does not function normally and produces insufficient number of normal blood cells.)
and acute myeloid leukemia (abnormal leukocyte production)
What is the chemokine that macrophages use to call in the neutrophils if they cant handle themselves in the tissues?
CXCL8
Explain how you can get a neutrophil to diapedis across the basement mebrane into a tissue?
Neutrophils will roll along the basement membrane until they reach a place of inflammation where they will connect their integrin called LFA1 with its special CD18 component to the ICAM1 adhesion molecule on the basement membrane which will pull it through the cracks of the basememnt membrane
What is ICAM-1?
it is an immunoglobulin-like molecule that works as an adhesion molecule
What is an immunoglobulin?
any of a class of proteins present in the serum and cells of the immune system, that function as antibodies.
What is CD18?
a special component of the integrin LFA1 that is found on neutrophils
What is LFA-1?
the integrin found on neutrophils that binds to ICAM-1
WHat is a rare autosomal recessive disorder presenting with recurrent bacterial infections due to defects in neutrophil adhesion?
leukocyte adhesion deficiency (type I)
What will adhesion molecule defects result in?
poor neutrophil chemotaxis, phagocytosis, neutrophilia (too many neutrophils in thie blood because they are stuck and cant get into the tissues)
Infants who have (blank) will suffer from infections such as omphalitis, pneumonia, ginigivitis, and peritonitis
leukocyte adhesion deficiency (type I)
What is the defect in leukocyte adhesion deficiency type I?
beta-2 integrin subunit CDI8
How do you determine if someone has leukocyte adhesion deficiency (type I)?
How do you treat it?
you look at CD18 levels
bone marrow transplant
The acute phase responses is mediated by (blank)
acute phase proteins
Bacteria induce macrophages to produce (blank), which acts on hepatocytes to induce synthesis of acute-phase proteins.
IL-6
What is this:
an antibody or other substance that binds to foreign microorganisms or cells, making them more susceptible to phagocytosis.
opsonin
(blank) is an opsonin and is used to identify patients with active inflammatory processes
c reactive protein
(blank) binds and sequesters iron to inhibit microbial growth
ferritin
(blank) is a coagulation factors, its levels correlate w/ erythrocyte sedimentation rate (ESR), an inflammation indicator
fibrinogen
(blank) production is downregulated during acute phase response.
albumin
What all are involved in the acute phase response induced by IL6?
C-reactive protein (CRP) ferritin fibrinogen albumin mannose-bindin lectin
What does mannose-binding lectin do?
it is an opsonin that activates complements
Where does IL6 bind?
the liver
Viral RNA induces (blank) gene expression
interferon alpha/beta (a protein that inhibits virus replication)
How does Viral RNA induce interferon gene expression in an endosome?
in an endosome TLR3 recognizes viral DNA and recruits TRIF which recruits IRF3 and IRF7 to induce gene expression
How does viral RNA induce interferon gene expression in the cytosol?
MDA5, RIG-I, CARDIF get together and recruit IRF3 and IRF7 to induce gene expression
How do antiviral type I interferons work?
an infected cell is recognizesby plasmacytoid dendritic cells that produce large amounts of interferon which will induce the interferon response
What is the interferon response?
stops virus from replicatng
increases expression of ligands for receptors on NK cells, activates NK cells to kill virus
In an interferon alpha/beta primed cell, what does viral dsRNA do?
it activates RNAse L which degrades viral/host mRNA causing apoptosis
interferon alpha/beta increases the expression of (Blank) molecules on nucleated cells/
MHC class I (molecules that present cytosolic proteins of cells to T cells to allow for the determination of whether the proteins are foreign or self i.e. they allow for self, nonself recognition)
Where do NK cells come from?
from lymphoid progenitor cells
How do you activate a NK cell?
with type I interferon and cytokines (tnf alpha and IL -12)
What will NK cells produce?
large amounts of IFN-Y
What do NK cells do?
kill virus infected cells, cells with intracellular pathogens and tumors by using cytotoxic granules to kill them
What are the cytotoxic granules that NK cells use to kill stuff?
perforin and granzymes
HOw do NK cells differentiate b/w self and non self?
through MHC class I molecule recognition and stress molecule
NK cell deficiency can result in susceptibility to what viruses?
herpes
varicella (chicken pox and shingles), simplex 1 (oral) and 2 (genital) , epstein barr (mono) and cytomegalovirus
What is antibody dependent cell-mediated cytotoxicity or ADCC?
when NK cells bind and kill antibody coated pathogens
Wha t is the quickest response in a viral infection? what is the slowest/
production of interferon,TNF alph and IL2-> NK cell killing-> T cell killing
What response lasts the longest in a viral infection?
T cell mediated killing
The epithelial surfaces of the (blank), (blank) and (blank), which together with the skin, provide the first lines of defense against infection (chemical, mechanical, and physical barriers)
gastrointestinal, urogenital, and respiratory tracts
