Hunter-Innate Immunity Flashcards
What are 3 mucosal surfaces that pathogens could potentially enter?
airway
gut
reproductive tract
What are some modes of transmission via the airway mucosal surface?
inhaled droplet (via sneeze) spore
What are some ways that pathogens could get in via external surfaces?
external surface wounds or abrasion (punctures, infected animals) insect bites (mosquito bites, deer tick bites)
Salmonella typhi in the GI could cause which disease?
typhoid fever
Rotavirus in the GI tract could cause which problem?
diarrhea
Which pathogen causes syphilis?
treponema pallidum
Which pathogen causes athlete’s foot?
trichophyton
Handling infected animals could lead to acquiring the pathogen francisella tularenis…causing which disease?
tularemia
A mosquito bite w/ flavivirus could cause which disease?
yellow fever
What are 3 potential sources of pathogens?
environment
humans
animals
If I have resistant staph in my nose….what am I considered?
not infected with staph
you are considered colonized by staph
If you have cholera are you infected?
No, b/c it doesn’t penetrate your tissues. You do get a disease from the exotoxins it secretes, however.
What are opportunistic pathogens? What is an example of when they go crazy?
these are pathogens that reside in or on the body but cause disease only when the host is immunosuppressed
Ex: AIDs; malnutrition
What are some mechanical barriers to infection of the skin?
epithelial cells joined by tight jcns
longitudinal flow of air
What is a chemical barrier to infection of the skin?
fatty acids
beta defensins
lamellar bodies
cathelicidin
What are some mechanical barriers to infection of the gut?
epithelial cells joined by tight jcns
longitudinal flow of fluid
What are some chemical barriers to infection of the gut?
low pH pepsin alpha defensins RegIII cathelicidin
What are some mechanical barriers to infection of the lungs?
epithelial cells joined by tight jcns
movement of mucus by the cilia
What are some chemical barriers to infection of the lungs?
pulmonary surfactant
alpha defensins
cathelicidin
What are some mechanical barriers to infection of the eyes/nose/oral cavity?
epithelial cells joined by tight jcns
tears
nasal cilia
What are some chemical barriers to infection of the eyes/nose/oral cavity?
lysozyme in tears & saliva
histatins
beta defensins
How does the microbiota help defend mucosal surfaces against infection? How can you wipe this out & make a person more susceptible to infection?
these good bacteria keep the really bad guys from adhering to the epithelial lining
taking broad spectrum antibiotics can wipe this out & leave you vulnerable
What is microbial pathogenesis?
direct mechanism of tissue damage by pathogens
What is immunopathology?
indirect mechanisms of tissue damage by pathogens
What are some examples of organisms that make exotoxins?
streptococcus pyogenes staphylococcus aureus corynebacterium diptheria clostridium tetani vibrio cholera
What are some examples of some diseases caused by exotoxins?
tonsillitis scarlet fever toxic shock syndrome food poisoning diphtheria tetanus cholera
What’s the idea behind exotoxins? Are they out to get us?
the reason exotoxins damage us is b/c they penetrate our tissues to get to nourishment. this obviously creates a variety of diseases.
What is an endotoxin made of? What types of organisms make endotoxins? What do they do?
lipopolysaccharide
gram negative bacteria
perturb the immune system
E Coli, Hemophilus influenza, salmonella typhi, shigella, pseudomonas aeruginosa, yersina pestis all produce what?
endotoxins!
What are some common diseases caused by endotoxins?
gram negative sepsis meningitis pneumonia typhoid fever bacillary dysentery wound infection plague
What’s the deal with a direct cytopathic effect?
in this case the bad guy uses the cell’s own machinery to reproduce
What are some examples of villains that use the direct cytopathic effect?
variola varicella-zoster Hep B virus polio virus measles virus influenza virus herpes simplex virus HHV8
What are some diseases caused by villains who use the direct cytopathic effect?
smallpox chickenpox shingles hepatitis poliomyelitis measles influenza cold sores kaposi's sarcoma
What are some things that use immune complexes to causes immunopathology?
Hep B Malaria streptococcus pyogenes treponema pallidum most acute infections
What are some diseases caused by immune complexes?
kidney disease vascular deposits glomerulonephritis kidney damage in secondary syphilis transient renal deposits
What are some things that use anti-host antibodies to cause disease? As in…this things recognizes bad guys but also attacks some of the good guys.
streptococcus pyogenes
mycoplasma pneumonia
What are some diseases caused by anti-host antibodies?
rheumatic fever
hemolytic anemia
What are some infectious agents that cause problems via cell-mediated immunity?
mycobacterium tuberculosis mycobacterium leprae lymphocytic choriomeningitis virus borrelia Burgdorferi schistosoma mansoni herpes simplex virus
What are some diseases caused by infectious agents that use cell-mediated immunity to cause immunopathology?
TB TB leprosy aseptic meningitis lyme arthritis schistosomiasis herpes stromal keratitis
What is the function of anti-microbial enzymes?
it is to eat away the cell wall of microorganisms; a defense mechanism
What are 3 anti-microbial enzymes?
lysozyme–found in tears
pepsin–gut
secretory phospholipase A2
What are 3 important classes of anti-microbial peptides?
defensins (alpha & beta)
cathelicidins
histatins
What are 2 important characteristics of anti-microbial peptides? What is their fcn?
short peptides
amphipathic
**defensins form pores in the walls of microorganisms. Mess with the osmotic gradient & destroy them.
Anti-microbial peptides begin as _______.
pro-peptides. They are cleaved into their active forms.
Inflammation is a part of which immune response? When is it needed?
early induced immune response
**it is needed when the pathogens penetrate a bunch of barriers b/c the antimicrobial enzymes & peptides were insufficient
What are the 4 parts of inflammation?
rubor, calor, tumor, dolor
Describe the early induced response in detail.
Villains make it thru the mucosal barrier (sorry antimicrobial enzymes & peptides)
Macrophages & complement system are waiting for them.
Macrophages recognize villains via TLR genome encoded receptors on their surface.
Macrophages have a meal of the villains.
But oh no–they aren’t all destroyed!!
Macrophages release cytokines & chemokines.
Chemokines get more cells from bone marrow to enter the battle.
Cytokines cause increased vascular permeability & vasodilation.
Neutrophils & macrophages are called into battle.
Kinin & coagulation pathways activated.
Hopefully, the pathogens are conquered before the adaptive immune response has to take place.
What do cytokines cause? What is an example of a cytokine? How does this relate to chemokines?
Cytokines cause increased vascular permeability & vasodilation. Ex: TNFalpha; chemokines are a type of cytokine
What do chemokines do?
they go to the bone marrow
they recruit more cells for battle
they create a gradient by which the cells can get to the battleground (like little ‘ol bread crumbs)
What’s the deal with the kinin pathway?
causes increased vascular permeability & a sensation of pain
What’s the purpose of the coagulation pathway?
macrophages orchestrate local coagulation so that microorganisms can stay imprisoned. Don’t want inflammation to become systemic–>sepsis. Yikes!!
What is CXCL8?
aka interleukin 8
chemokine that attracts neutrophils & monocytes as a second line of defense in inflammation
How does the life span of macrophages & neutrophils differ?
macrophages come from monocytes & then chill in the tissues. They live for quite a while. Neutrophils live for like a day. They have to be actively recruited as a part of the second line of defense for inflammation.
T/F The early induced innate response differs from the adaptive response in that it requires no new synthesis of proteins.
FALSE. It does require new proteins to be made.
What are PAMPs?
pathogen associated molecular patterns
these are highly conserved molecular motifs found on microorganisms.
What is an example of a PAMP?
Ex 1: Gram negative bacteria
lipopolysaccharide (endotoxin) can be recognized by TLR receptor on macrophage.
Ex 2: Gram positive bacteria
peptidoglycan can be recognized by TLR receptor on macrophage
PAMPs are important for self non self discrimination. What detects these patterns? What would f-met-leu-phe indicate?
TLR (toll like receptors) on macrophages detect PAMPs
this indicates bacteria
What does the PAMP of a mannose receptor indicate if detected by a TLR on a macrophage?
could be bacteria, fungus, virus
If a TLR detected scavenger receptors–>which villain do they have in custody?
these are acetylated lipoproteins
they prob have bacteria
What does the PAMP of a dectin-1 glucan receptor indicate?
fungus!
What is CD14?
LPS receptor
What does TLR4 detect?
gram negative bacteria
senses LPS binding protein or endotoxin
How many common TLR genes are there in humans? What do they code for?
10! They code for TLR proteins-these are PAMP receptors.
Where are TLRs found in macrophages?
some are on the cell surface
others are endosomal (intracellular)
What basically happens with TLR activation?
this engages transcription factor NF-kappa beta
induces the production of inflammatory mediators
What’s the deal with TLR-5?
this detects flaggelin–found in flagella of bacteria
What are NOD-like proteins?
nucleoside oligomerization domain-like proteins
similar to TLR
detect cytoplasmic bacteria
signal inflammation
What are RIG-like proteins?
Retinoic acid inducible gene-1 proteins
detect viral RNA in cytoplasm & signal inflammation
Describe the basics of how TLR signaling induces gene transcription.
TLR recognizes the PAMP.
TLR dimerize on the cell surface.
They recruit IRAK-4….a lot of other stuff w/ intracellular signaling.
NFkappa beta goes into the nucleus & you get gene transcription, including cytokines that give inflammation!
A 9-year-old girl was admitted to the hospital with septic arthritis due to Streptococcus pneumoniae. Her history was significant for previous hospitalizations for several deep-seated abscesses caused by Staphylococci or Streptococcus pyogenes. On each occasion, full blood counts were normal, including lymphocyte and neutrophil counts. Other screening tests such as functional complement, serum immunoglobulin levels, and antibody production were normal. When her peripheral blood monocytes were stimulated with a variety of Toll-like receptor ligands, they produced very low levels of the proinflammatory cytokine TNF-a. It was thought that she might have a defect in the NF-κB pathway; on sequencing of her IRAK-4 gene, this was found to be the case.
What does this patient have?
Interleukin 1 Receptor-Associated Kinase 4 Deficiency (IRAK4 Deficiency)
**can’t achieve inflammation–susceptible to pyogenic bacterial infections
How is IRAK-1 deficiency inherited?
via aut recessive
Give 2 diseases that are immunodeficiencies in neutrophils that are defects in intracellular killing in the form of abnormal respiratory bursts.
chronic granulomatous disease
Glucose-6-phosphate dehydrogenase deficiency
Give 3 diseases that are immunodeficiencies in neutrophils that are defects in intracellular killing in the form of granule abnormalities.
Myeloperoxidase deficiency
Specific granule deficiency
Chédiak-Higashi syndrome
Give 2 diseases that are immunodeficiencies in neutrophils that are adhesion defects, specifically leukocyte adhesion deficiency.
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 & intracellular killing, mainly via macrophages & neutrophils
Phagocytosis happens via______ & _______.
endocytosis & micropinocytosis
What is the difference b/w a phagosome & a phagolysosome?
phagosome: invagination of the cell membrane
phagolysosome: is when the phagosome fuses with the lysosome & stuff can start to be destroyed
Where is NADPH Oxidase found? What is its function?
found in the phagolysosome
fcn is to make this area a hostile environment with a low pH for proper degradation of the bad guys via respiratory burst & proton gradient
What prompts the formation of the multi-unit NADPH oxidase?
happens with microbe phagocytosis by a macrophage or neutrophil
signaling via g protein receptors (C5a)
What are some of the subunits of the NADPH oxidase?
p21
gp91
p47
p67
Which things are released by the NADPH oxidase in the respiratory burst?
antimicrobial superoxide
hydrogen peroxide
ROS
Why is it that a phagolysosome burst won’t totally kill the host?
b/c the enzymes contained in them are only active at a total low pH
Once again, what types of things are found in a phagolysosome?
ROS nitric oxide antimicrobial peptides enzymes competitors (lactoferrin)
At the age of 4 weeks, a male infant develops a staphylococcal abscess of the chest wall requiring surgical incision and a course of dicloxacillin. He had a leukocytosis with 90% neutrophils. At the age of 3 months, he was readmitted to the hospital with a large abscess on his face that grew Serratia marcescens. By the age of 2 years, he had been hospitalized five times with bacterial abscesses. Family history revealed that three older brothers had died of infections at ages ranging from 7 months to 3 years, but his parents and two sisters were healthy. On examination, he had bilateral axillary and inguinal lymphadenopathy with marked hepatosplenomegaly. A dihydrorhodamine test showed that his neutrophils failed to reduce the dye and that his mother had two populations of neutrophils, one normal and one also unable to reduce dihydrorhodamine.
What does this pt have?
chronic granulomatous disease
What causes chronic granulomatous disease?
failure of NADPH oxidase to form in phagolysosomes
How can chronic granulomatous disease be inherited?
X linked recessive (gp91)
autosomal recessive
What causes the granulomatous lesions of CGD?
pyogenic bacteria & fungi
What test helps reveal CGD?
dihydrorhodamine test; it uses flow cytometry–>shows a defective respiratory burst b/c of a messed up NADPH oxidase
What are some of the treatments for CGD?
long term antibacterial & anti fungal agents
IFN-gamma
bone marrow transplant
T/F Granulomas can be seen on chest X-ray.
True.
A 10-month-old infant presents with severe pyoderma over much of his body. His history is significant for other infections including pneumonia and for bruising easily. Both parents are healthy with no significant medical history. Physical exam reveals an ill infant with large areas of hypopigmentation of the skin, silvery hair, and very pale eyes. Gingival inflammation and bleeding of the gums and generalized lymphadenopathy are noted. A WBC count reveals moderate leukopenia and thrombocytopenia. Definitive diagnosis is made by examination of a peripheral blood smear which showed unusually large granules within neutrophils and eosinophils.
What does this patient have?
Chediak-Higashi Syndrome
What is Chediak-Higashi Syndrome? How is it inherited?
defect in microtubule polymerization involving actin–decreases phagolysosome formation
aut recessive
What is the presentation of Chediak-Higashi Syndrome?
early childhood recurrent infections of staph & strep, including gingival infections
partial albinism
large lysosomal vesicles (just can’t fuse) in neutrophils & eosinophils
see large granules on slide
What is the treatment for Chediak-Higashi Syndrome?
long term antibiotics
bone marrow transplant
What is pyoderma?
infection in the skin
What is the most common defect in granulocyte-mediated host defenses?
neutropenia: decreased absolutely neutrophil count
can be drug-induced, autoimmune, hereditary
What is considered a neutrophil level consistent with neutropenia? What does this leave the patient susceptible to?
1500-2000 cells/mm3 blood
pt susceptible to pyogenic bacteria-staph, gram negative bacteria, encapsulated bacteria, fungi
What are 3 types of hereditary neutropenia?
Familial (benign, ethnic) neutropenia
Infantile genetic agranulocytosis (severe congenital neutropenia)*
Cyclic neutropenia
What types of drugs could cause acquired neutropenia?
cytotoxic drugs used in cancer
A 72-year-old man with chronic lymphocytic leukemia (CLL) presented to the cancer care clinic for a follow-up appointment 10 days after his first cycle of chemotherapy with fludarabine, cyclophosphamide, and rituximab. He complained of mild chills and a moderate fever of 100.7°F. He did not seek medical attention before his appointment because he attributed the fever to CLL. His vital signs were normal. He was found to be neutropenic with an absolute neutrophil count of 120 cells/mm3. He was treated for neutropenic sepsis with broad-spectrum antibiotics. Blood cultures showed Candida albicans
What does this patient have?
drug-induced neutropenia
**cancer therapy caused it.
usu get the sepsis from a catheter
What causes the neutropenic sepsis?
pyogenic bacteria & fungi
What causes 15% of sepsis?
candida albicans
What is the usual treatment for drug-induced neutropenia?
broad-spectrum antibiotics
hrG-CSF (human recombinant granulocyte stimulating factor)
subsequent chemotherapy if pt has cancer.
A 3-week-old lethargic male infant was brought to the ER with a skin infection. His temperature was 40.2°C , respirations 180, and blood pressure 60/35 mmHg. He was placed on fluids and broad-spectrum antibiotics. Staphylococcus aureus was cultured from both skin and blood. His absolute neutrophil count (ANC) was 174/ml. After 2 weeks in the hospital, he was improved but his neutrophils numbers were still low. A bone marrow aspirate showed a severe block in neutrophil differentiation at the promyelocyte state.
What does this patient have?
Severe Congenital Neutropenia (Kostmann Disease)
How do patients with severe congenital neutropenia usu present?
w/ recurrent infections of skin, soft tissues, lungs and deep organs. sepsis is common.
neutrophils below 200
maturation arrent at the promyelocyte or myelocyte stage
What is the treatment for severe congenital neutropenia?
rhG-CSF
bone marrow transplants
What is there a risk of with patients with severe congenital neutropenia?
myelodysplasia
acute myeloid leukemia
Once again, what are the steps to neutrophils getting to the site of injury?
rolling adhesion
tight binding
diapedesis
migration
What are the 4 types of adhesion molecules?
vascular addressin (CD34) selectin integrin ICAM-1
What is CD18 a component of?
a component of ICAM-1.
If this is messed up–>neutrophils can’t get to proper sites well
A 2-week-old female newborn delivered at term is brought to the physician by her mother because of an increasingly severe diaper rash since birth. No congenital anomalies were noted after delivery. There are ulcerations of the skin but no purulent exudate in the area of the diaper. A culture of one of the ulcers grows Staphylococcus aureus. Physical examination shows a red and swollen umbilical remnant that has not separated. Despite antibiotic therapy, 1 month later she develops a perirectal fissure, culture of which grows Escherichia coli but a smear of which shows scarce segmented neutrophils.
What does this patient have?
Leukocyte Adhesion Deficiency (Type 1)
What is Leukocyte Adhesion Deficiency (Type 1)? How is it inherited?
aut recessive
recurrent bacterial infections (problems with neutrophil adhesion)
omphalitis, pneumonia, gingivitis, and peritonitis may happen
CD18 is messed up.
How do you diagnose leukocyte adhesion deficiency type 1 & how do you treat it?
Diagnosed by finding low CD18 on neutrophils by flow cytometry
Treatment involves bone marrow transplantation
T/F Leukocyte adhesion deficiency type 1 shows neutropenia.
False. Neutrophilia. Too many neutrophils in the blood. The problem isn’t their production, but their adhesion.
In the acute phase response…acute phase proteins are made where? What are some examples of these proteins?
made in the liver Ex: Sp-A, Sp-D (surfactants) mannose-binding lectin fibrinogen (clotting) C-reactive protein (promotes phagocytosis) serum amyloid protein
What prompts the liver to make acute phase proteins?
IL-6 released from macrophages
C-reactive protein (CRP) is an _______, and is used to identify patients with active _____________.
opsonin
active inflammatory processes
What does ferritin do?
binds iron to inhibit microbial growth
How does fibrinogen indicate inflammatory levels?
b/c it correlates with erythrocyte sedimentation rate
What happens to the production of albumin during the acute phase response?
it is down regulated
What exactly does C-reactive protein do?
it binds phosphocholine on bacterial surfaces
acts as an opsonin
activates complement
What is an opsonin?
a molecule that enhances phagocytosis by marking an antigen for an immune response
What exactly does mannose-binding lectin do?
binds mannose residues on bacterial surfaces
opsonin!
activates complement
Viral RNA induces expression of what?
inteferon alpha beta expression
In the 2 mechanisms shown…describe the one that begins in the cytosol & ends in interferon alpha beta expression.
It involves MDA-5 (mazda)
RIG-1 (big rig)
CARDIF
Of course, it involves IRF3 & IRF7.
In the 2 mechanisms shown….describe the one that begins in an endosome & ends in interferon alpha beta expression.
TLR-3 in the endosome w/ viral RNA
TRIF binds in cytosol
IRF3 & IRF7 involved somehow.
Interferons are activated in virally-infected cells. What do these interferons do?
- *induce resistance to viral replication
- *increase expression of ligands for receptors on NK cells
- *activate NK cells to kill viral-infected cells
- *activates RNAse to kill viral & host mRNA & prompt apoptosis
- *increases the expression of MHCI molecules on nucleated cells
After a viral infection has begun…what is the defense @ day 1, day 3, day 8?
Day 1: Production of IFN-alpha, IFN-beta, IFN-gamma, TNF-alpha, IL-2
Day 3: NK-cell mediated killing of viral-infected cells
Day 8: T-cell mediated killing of infected cells
NK cells are derived from _______ progenitor. They produce large amounts of ______. What is their fcn?
lymphoid progenitor
large amounts of IFN-gamma
fcn: Kill virus-infected cells, cells with intracellular pathogens, and tumors using cytotoxic granules (perforin and granzymes); Kill infected cells and tumors that express stress molecules and kill antibody-coated pathogens (antibody dependent cell-mediated cytotoxicity or ADCC
T/F NK cells kill normal MHC Class I labeled cells.
False. They do kill molecules with abnormal MHC Class I labels, as in those that are infected.
What do NK deficiencies cause?
Natural killer (NK) cell deficiencies increase susceptibility to severe and/or recurrent infection with herpes viruses, including varicella zoster virus, Herpes simplex viruses 1 and 2, Epstein Barr virus and cytomegalovirus
