Week 2 Flashcards
1
Q
Importance of cytokines
A
- Local signaling of inflammation: Part of inflammatory process
- for communication and recruitment
- General reason: drive immune response; Any immune response that occurs is due to cytokines
2
Q
cytokines and access to tissues
A
- certain cytokines can increase vascular permeability which can allow for infiltration of immune cells
- Certain cells (macrophages) are already in tissue but other cells (ex. Neutrophils) have to travel through the blood and require cytokines in order to get to the site of inflammation
3
Q
Immune privileged site
A
- do not normally have immune cells but cytokines can give immune cells access to the tissue
- examples: CNS, because of brain blood barrier; Eye, has barrier around it; Testicles
4
Q
Inflammatory cytokines
-secreted by
A
- macrophages
- IL1beta, TNF alpha, IL6, CXCL8, IL-12
5
Q
IL-1 beta and TNF alpha
A
induces blood vessels to become more permeable enabling effector cells to enter the infected tissue
6
Q
IL-6
A
induces fat and muscle cells to metabolize which creates heat and raises temperature in the infected tissue
7
Q
CXCL8
A
- recruits neutrophils from the blood and guides them to infected tissue
- very strong chemotractant; for monocyte and nk cell recruitment
8
Q
IL-12
A
- recruits and activates NK cells that in turn secrete cytokines that strengthen the macrophages response to infection
- helps t cells to differentiate to T1 cells
9
Q
1 role of innate immune system
A
Indiscriminate attack of foreign invaders which creates inflammation at site of infection which activates adaptive immune system
10
Q
4 primary aspects of inflammation
A
- Heat
- Pain
- Redness
- Swelling
11
Q
How do we get inflammation?
A
- cytokines
- able to create inflammation by causing vasodilation of endothelial cells which causes blood to trickle out which causes redness and warmth; also causes gaps between the cells which allows for release of fluid which causes edema; Edema causes compression of local nerves which causes pain
12
Q
Inflammasome function
A
-amplify innate immune response by increasing IL-1 beta
13
Q
IL-1RA and IL-1B
A
IL-1RA competitively inhibits IL-1 beta
14
Q
TNF-alpha causes vasodilation and fluid leakage
A
- homozygous mutation means more susceptible for septic shock
- Will cause systemic edema, and lead to shock
15
Q
What is sepsis
A
clinical syndrome that is caused by dysregulated inflammatory response to infection; pathogen must be involved
16
Q
How does sepsis occur?
A
- Usually gram neg bacteria
- Immune system would be responding to LPS (PAMP); when it kicks up out of hand it causes systemic vasodilation which allows for infection to spread
- Binds to TLR 4
17
Q
Where in body are cells binding to LPS with TLR 4
A
- Liver or spleen because they have macrophages (white pulp) in tissue; the tissue has blood vessels running through it and if bacteria is in the blood then the macrophages are able to recognize bacteria LPS with TLR 4 and begin to secrete a lot of TNF alpha/ IL-1 beta
- Lots of secretion of TNF alpha causes systemic edema which can lead to shock
18
Q
What happens in shock
A
- TNF alpha secreted inappropriately causes increased vasodilation, causes a drop in BP (hypotension), heart will try to compensate by increasing rate (tachycardia), increased heart rate will cause increased lactate which leads to acidosis, acidosis will lead to tachypnea
- There will be decrease in perfusion to tissue
- Can cause DIC
19
Q
DIC
A
- disseminated intravascular coagulation
- Will form clots all over body
- This will continue to cause decrease in perfusion to tissue (no oxygen to organs)
20
Q
A patient admitted to the hospital with a dangerously high temperature and allergic to general analgesics could be given which of the following to alleviate the fever?
A
IL-6, TNF alpha, and IL-1 beta are all pyrogenic and anti meds could help reduce fever
21
Q
Is fever always bad?
A
- No; benefits of fever
- Adaptive cells work better at higher temp (immune cells)
- TNF alpha does less damage to own tissue at higher temp
- Bacteria and viruses replicate less (slower) at higher temp
22
Q
A patient with a bleeding disorder underwent thorough testing to identify the nature of her disease and discovered she had low levels of factor 1; which of the following treatments would increase her ability to clot?
A
- IL 6 would be used in patient with decrease in factor 1 because it activates the acute phase proteins that help to activate coagulation
- One of acute phase proteins is fibrinogen-factor 1 in clotting cascade
- Acts on hepatocytes to induce them to make acute phase proteins (look at picture to left)
23
Q
What do RLR’s detect, and where?
A
-viral RNA in the cytoplasm of host cells
24
Q
RLR pathway
A
- viral replication in cytoplasm produces uncapped RNA with a 5’ triphosphate
- RLR binds to viral RNA inducing association with MAVS and dimerization
- Dimerization initiates signaling pathways that activate IRF3 and NFkB
- IRF3 causes synthesis and secretion of type I interferon and NFk causes synthesis and secretion of inflammatory cytokines
25
Type I interferons
- have autocrine and paracrine effects
- binding of type I interferons leads to IFN-alpha and beta creating a response that:
- induces resistance to viral replication in all cells
- increase expression of ligands for receptors on NK cells
- activate NK cells to kill virus infected cells
26
Does interferon only help infected cell
- No; sends signals out to neighboring cells alerting them that there is virus in the area so that they can start to make proteins to protect themselves
27
What happens to NK cells when stimulated by interferon alpha and beta?
-drives the differentiation of NK cells into cytotoxic effector cells, which will kill virus-infected cells by inducing them to undergo apoptosis
28
Relationship between NK cells and macrophages
- macrophage activated by viral infection secretes inflammatory cytokines that recruit and stimulate more NK cells
- NK cell and macrophage form a conjugate pair with a synapse in which IL-12 and IL-15 activate the NK cell
- NK cells proliferate and differentiate into effector NK cells, causing them to secrete interferon gamma
- interferon gamma binds to macrophage and activates them to increase phagocytosis and secretion of inflammatory cytokines
29
SXS of SIRS
- fever/hpothermia
- elevated pulse
- tachypnea
- leukocytosis (WBC > 12,000) or leukopenia (WBC<4,000)
30
SIRS
- Systemic inflammatory response syndrome
| - Inappropriate immune response of inability of the immune system to keep up with a unique pathogen
31
Causes of SIRS
○ Trauma: external force on body that causes injury; including burn
○ Infection: but can still have infection and not have SIRS
○ Pancreatitis not due to viral infection
-Bacteremia
32
Difference between SIRS , sepsis, and septic shock
- Sepsis: two sxs of SIRS sxs plus suspected infection
- Severe sepsis: sepsis + lactate above 2 or organ dysfunction
- Septic shock: severe sepsis + hypoperfusion despite adequate resuscitation or lactace above 4
33
Infection with signs of inflammation
○ Leukocytosis (WBC>12000)
○ Leukopenia (WBC<4000)
○ Normal WBC with 10% immature forms
○ Plamsa C-reactive protein w/ upwards of 2 standard deviations above the normal value
○ Plasma procalcitonin w/ upwards of 2 standard deviations above the normal value
○ Hypotension
34
Pathogenic sequence of events with septic shock
-infectious source causes inflammatory response--leads to coagulation response & cardiomyopathy, vasodilation, and increased vascular permeability which leads to hypotension and shock--coagulation response and shock leads to tissue hypoperfusion--causes cell death which leads to organ failure
35
Gram negative pleiomorphic rod with safety pin appearance
Gram negative organism Yersinia pestis (bubonic plague) which can develop into plague sepsis
36
Forms of plague in humans:
- Bubonic plague
- Septicemic plague
- Pneumonic plague:
37
Bubonic plague
- looks like incarcerated strangulated inguinal hernia, with severe pain, and fever.
- found in fleas on rodents
- Cats will eat mice, flea will jump onto cat, and then from cat spreads to human
- Found in Cali, four corners area,
38
Pneumonic plague
incredibly contagious, will probably die in 12 hours and everyone in room that you were in when started coughing is probably infected and will most likely die
39
Treatment of DIC
- treat underlying precipitating disorder: vol resuscitation, antibiotics, external cooling
- platelet transfusion for thrombocytopenia
- plasma for prolonged PT, PTT, or low fibrinogen
- fibrinogen concentrate for persistent low fibrinogen
- Vit K for prolonged PT
- tranexamic acid for trauma related DIC
40
What flu vaccine can you give to pregnant patient?
-trivalent inactivated influenza vaccine
41
what flu vaccine is contraindicated in pregnant patients?
-live attenuated influenza vaccine
42
what is major influenza viral PAMP?
cytoplasmic RNA
43
How does genetic material of influenza induce innate immune system?
- can be detected by the internal cell receptors (TLRs) that will trigger the production of cytokines
- RIG-1 and the inflammasome components and NOD-like receptor protein 3 induce that innate immune response which helps with production of interferons and IL-1 and other cytokines
- The innate immune response leads to proinflammatory cytokines signaling the induction of the adaptive immune response
44
resident alveolar cells contribute to the initiation of the adaptive immune response and T-cell activation in this infection
Conventional dendritic cells
45
Conventional dendritic cells
○ professional antigen presenting cells and resident in almost all tissues of the body
○ live in the lung tissue
-respond to various antigen and are professional antigen presenting cells that phagocytize it and carry it to the regional lymph nodes
-chemoattractants lead them back to the lymph node and they're able to present the antigen in the context of MHC2 T-cells which have T-cell receptors
46
What does T-cell receptor resemble
-Fab portion of antibody
47
Diversity of T cell receptor
-germline DNA goes through recombination which rearranges the DNA--DNA is then transcribed, spliced, and translated creating a t-cell receptor protein--
48
T cell receptor
- has alpha chain (chromosome 14) and beta chain (chromosome 7) on variable region
- contains a constant region, transmembrane region, and cytoplasmic tail
- connected to a CD3 complex
49
CD3 complex
- made of
- function
- two epsilon polypeptide chains, a dimer of zeta polypeptide chains, 1 gamma, and 1 delta + TCR
- signal transduction once ligand binds to TCR
50
second class of T cells
alpha and beta chains are replaced with gamma and delta chains
51
diversity of TCR vs BCR before antigen encounter
-T-cells have more diversity
52
Are MHC's identitical in one patient to another?
- what do they present? why?
- types?
- how many AA?
- No, there is a huge amount of variability with MHC
- they present different peptides and the presenting of different peptides leads to more effective immune responses than others
- two types of MHC molecule for recognizing intra- and extracellular antigens
- MHC I recognizes 8-10 AA
- MHC II recognizes 13-25 AA
53
MHC and macrophage
-Marophages have MHC1 and 2
54
MHC and regular cells
- RBC
- tissues low in MHC1
- Regular cells only have MHC1
- RBC is only exception
- liver, neural, corneal tissue low
55
TCRs and antigens
- TCR's recognize antigens bound to MHC molecules
| - the antigen is in phagocytic cell, broken down, and then presented with the MHC
56
HLA
- human leukocyte antigen complex
- human form of MHC's
- HLA polymorphism leads to different disease progression outcomes
57
Is it possible for normal cells to express MHC2?
yes, Non-APC cells can express MHC2; this usually happens when interferon gamma is within the local environment
58
IFN gamma and MHC2
-secretion of IFN gamma causes expression of MHC 2 from regular cells, but regular cells do NOT always induce it which is why they cannot function as APC
59
gene products of HLA class II
○ TAP
○ Tapasin
○ LMP2 and LMP7
○ HLA2 molecules
60
TAP
Transports peptides from proteasome to ER
61
Tapasin
Positions the MHC1 binding groups so that it can receive the peptides
62
LMP2 and LMP7:
Subunits that go into the constitutive proteasome to make it the immunoproteasome
63
HLA2 molecules
DP, DQ, DR
64
what turns on class II HLA genes
○ C2TA, which is the MHC2 transactivator, a special transcription factor
65
What induces C2TA to go in and start transcribing those genes
INF-gamma induces CT2A to go in and start transcribing
66
antigen recognition is restricted by
T cell recognizing MHC with specific HLA
67
When do you give flu vaccine to someone who was already infected with the flu?
-wait a week after infection because the patient would have been on neuraminidase inhibitor, so you should not administer any vaccine
-
68
what generates peptides?
| -where
- proteasome
| - cytosol
69
where do peptides generated in cytosol bind?
MHCI in the ER
70
How MHC-I binds antigenic peptide
MHC heavy chain is bound to calnexin to stabilize in ER membrane-- B2M binds MHC and calnein is released--calreticulin, tapasin, TAP and ERp57 bind to B2M/MHC complex forming the peptide loading complex-- peptide made from proteosome is processed through TAP and binds to MHC--MHC dissociated from the peptide loading complex and is exported from ER
71
Peptide editing
- ensure tight binding and good fit of peptide to MHC-I group
- ERAP removes extra N-terminal AA to ensure MHC is only carrying a peptide 8-10 residues long
72
peptides for MHC II
- generated in acidified vesicles
- antigen taken from ECS into intracellular vesicle
- acidification of vesicles activates protease to degrade antigen into peptide fragments
- vesicles containing peptides fuse with vesicles containing MHC class II molecules
73
Invariant chain and MHC II
| -CLIP
- Invariant chain blocks binding of peptides to MHC II in ER
- Invariant chain is cleaved in vesicles, leaving CLIPR fragment bound
- CLIP blocks binding of peptides to MHC class II in vesicles
- HLA-DM releases clip from MHCII allowing peptides to bind
74
HLA-DM antagonizer
-HLA-DO
75
cross presentations
enables extracellular antigens to be presented by MHCI
76
dendritic cells
- function
- where do they drain
- carry Ag from sites of infection to secondary lymphoid tissues
- enter into the draining lymph node where they settle in the t-cell area
77
Morpholgy of DC
-changes as it carried antigen to secondary tissues
78
DCs and TLRs
carry all TLR's except TLR9
79
Dendritic cell phenotypes
- immature:
- mature: little/no phago, high CCR7
- high MHC I and MHC II
80
DCs process Ag from pathogens
- receptor mediated endocytosis of bacteria
- macropinocytosis of bacteria or viruses
- viral infection
- cross presentation of exogenous viral antigens
- transfer of viral antigens from infected dendritic cell to resident dendritic cell
81
receptor mediated endocytosis of bacteria
- receptor on DC cells binds to ligand
- endocytosis of receptor and ligand then break down of the ligand
- vessicle with MHCII binds the vessicle with receptor and broken down ligand.
- MHC II binds piece of ligand then creates own vessicle again to move towards membrane.
- MHC II will then bind to membrane and present the piece of ligant to a CD4T cell
82
Macropinocytosis of bacteria or viruses
delivers antigens to endocytic vesicles for presentation by MHC class II molecules to CD4 T cells
83
Viral infection of the dendritic cell
delivers peptides processed in the cytosol to the endoplasmic reticulum for presentation by MHC class I molecules to CD8 T cells
84
Cross presentation
Viral particles taken up by the ‘class II’ pathways of phagocytosis and macropinocytosis can be delivered to the cytosol for processing and presentation to CD8 T cells by MHC class I
85
transfer of viral antigens from infected dendritic cell to resident dendritic cell
- Antigens taken up by one dendritic cell can be delivered to a second dendritic cell for presentation by MHC class I molecules to CD8 T cells (fifth panel).
86
Dendrites and naive t cells
- specialized microanatomy of the lymph node allows antigen-bearing dendritic cells to interrogate millions of naive T cells, and identify the few that will be recruited to the adaptive immune response.
87
Function of cell adhesion molecules
-allow for naive t cells to home to secondary lymphoid tissue
88
Homing
- Guided by CCL21 and CCL19 through binding of CCR7 receptor
- T cell is slowed down and is able to bind to the epithelium of the vessel through the interaction of L-selectin with the vascular addressins GlyCAM-1 and CD34--- Chemokines, which are also bound to the endothelium, activate the integrin LFA-1 on the t-cell surface, enabling it to bind tightly to ICAM-1 on the endothelial cell which strengthens the contact between the T-cell and the endothelium--- Establishment of tight binding allows the lymphocyte to squeeze between two endothelial cells, leaving the lumen of the blood vessel and entering the lymph node proper.
89
Naive T cell can also enter secondary lymph tissue from lymph
- pathogen-specific T cells can enter an ‘upstream’ lymph node that is draining healthy tissue. Since they do not encounter their antigen there they can be carried to the infected lymph node via a connecting lymphatic vessel. There, they will become activated by dendritic cells presenting pathogen antigens.
90
What enhancer T-cell binding to antigen on dendritic cell?
When a T cell binds to its specific ligand on an antigen-presenting dendritic cell, intracellular signaling through the T-cell receptor (TCR) induces a conformational change in LFA-1 that causes it to bind with higher affinity to ICAMs on the antigen-presenting cell.
91
Activation of a naive T cell requires
- antigen-specific signal: T-cell receptor and its co-receptor CD4 recognize the peptide:MHC class II complex
- co-stimulatory signal: T-cell receptor CD28 binds to B7 on dendritic cell
- these must be delivered together!
92
Which T cell requires stronger activation?
-CD8
93
How can CD8 be activated?
- directly by a virus-infected dendritic cell
- if dendritic cell by itself is not strong enough then CD4 will secrete IL2 which will interact with CD8 that is interacting with dendritic cell
94
How are T cells not activated with self antigen?
-In absence of infection dendritic cells do NOT express B7 so the T cells cannot be activated
95
What happens when self-reactive T cell are let out into the system?
- recognize their antigens presented by cells in healthy tissue that have no B7 By giving an antigen-specific signal without a co-stimulatory signal, this interaction induces anergy in the self-reactive T cells
- If anergic T cells encounter their self antigen on a mature dendritic cell during an infection they cannot signal to activate the cell
96
What causes activated naive T cells to proliferate and differentiate?
- IL2
- Activation of naive t cells induces the synthesis and secretion of IL2 and high affinity IL2 receptors
- IL2 will bind to its receptor and promote t cell proliferation
97
How does T cell become inhibited after activated?
B7 on APC will bind to CTLA on T cell preferentially which will stop the signal from being conducted through the t cell receptor
98
Polio
- causative organism
- kind of bug
- sxs
- incubation
- culture
- mode of transmission
- enterovirus (picornavirus)
- RNA virus
- unilateral inability to bear weight, Infects muscle and can get into CNS, associated w/ paralysis, iron lung, diaphragm stops working
- 1 to 35 days
- from feces on EMB or MacConkey agar
- fecal-oral
99
OPV
- oral polio virus vaccine/ sabin vaccine
- live vaccine
- if immune compromised there is slight chance that the live vaccine mutates into a virulent strain and cause infection
100
Can you culture viruses on agar plates?
-No, requires tropism because they can only infect certain cells
101
Why can viruses only affect certain cells?
receptor specific and every cell type has different types of receptors
102
What are you looking for when culturing viruses?
-cytopathic effect: cell lysis
103
What technique could you use that my be faster than culturing to dx polio infection?
- RT-PCR: because it is RNA have to do reverse trasncriptase first and then can amplify with PCR
- serology: looking for IgM or IgG (chronic infection)
104
Salk vaccine
inactivated trivalent polio vaccine
105
Difference between live and inactivated vaccine
- live attenuated: still virus but has been weakened; not usually able to replicate and then infect
- inactivated: just being exposed to antigens
106
Difference of administration of salk vs sabin vaccine
- sabin: given by mouth
- salk: given by injection
- live one is very similar to getting the virus so you want to make sure you are exposed to areas you would normally get it (gut) while inactivated is just antigen so you dont want it chewed up by stomach, better immune response when injected
107
How to classify viruses
- DNA or RNA
- single or double stranded
- If RNA, will be either positive or negative
108
RNA virus and replication
-if positive, can be used by cell because it looks like our mRNA and can bind directly to our ribosomes and start making proteins and capsid so they can leave cell they infected
109
Capsid
- provides protection for virus
| - resistant to pH changes because it allows them to live in environment
110
Naked virus
-no envelope, allows for capsid to immediately attach to cell receptor on our cells
111
Envelope
-It is easier to stick. Easier fusion. Harder for cells to attack an envelope
112
How did we eradicate polio?
- humans are only host which means that with vaccine we are able to completely stop them
- if a virus has a reservoir we are not able to kill all the virus
113
Vaccination for polio
- how many doses are required?
- form in US
- 4: at 2 months, 4 months, 6-18 months, 4-6 yrs
| - IPV: injected
114
How do you contain polio infection?
- isolation for people showing symptoms and quarantine for people who are in class contact with patient but are not showing signs/sxs of infection themselves
- for people that could have been exposed make sure to vaccinate and keep them under surveillance (35 days to make sure they do not show symptoms)
- if patient under surveillance shows symptoms put them into isolation
115
Measels
- causative organism
- sxs
- dx
- virulence factors
- transmission
- incubation period
- public health concern
- Paramyxoviruses
- spots on mucous membrane, cough, conjectivits, coryza, fever, rash
- RT-PCR, IgM, Serology, ELISA, can isolate and look for cytopathic effect but in clinical setting go off of sxs and treat empirically Negative sense, single stranded RNA, helical capsid with envelope
- infectious: from person to person (4 days before rash and 1-4 days after rash); aerosol droplets
- 7-21 days
- falls under the homeland security diseases that can be used for terrorism
116
Bacteria that can cause measles sxs
Strep pyogenes
117
What would you see when looking at cells infected with measles under microscope?
- Giant cells, syncytia (virulent factor because of cell to cell spread; can invade host immune response)
- the virus starts to replicate in one cell if the cells come together it can quickly spread around and keep making a bigger and bigger cell so they don’t ever have to leave that cell bc once you leave the cell you're a target
118
Measles vaccine
| -doses
- one of most contagious diseases
| - 2: 12-15 months, 4-6 yrs
119
Measles exposure
- everyone who is exposed to person infected with measles would have to be quarantined and checked to see if vaccinated, if not would have to start prophylaxis
- Anti-vaxxers: quarantine for 35 days & if no signs & symptoms they can leave
120
Measles prophylaxis
- Vitamin A: this is the key, because there is a significant decrease in Vitamin A when someone gets infected
- Start booster w/ MMR vaccine, w/in 72 hr period
121
Clinical course of measles
- eposure (7-18 days before rash)
- prodome (4 days before the rash when patient is contagious)
- rash (when the infection is identified--patient is infectious for 4-8 days after rash begins)
122
Hep A
- sxs
- transmission
- onset
- Dx
- causative organism
- jaundice (sometimes), elevated liver enzyme levels, fever, headache, malaise, nausea, vomiting, diarrhea, abdominal pain; can sometimes have yellow color due to enzyme levels w/ dark urine and pale stool
- fecal-oral; can be STD (not usual, more likely for B&C)
- sudden/acute
- Anti HAV-IgM
- picornavirus, single stranded RNA, naked, resistant to detergents
123
Types of Hepatitis
```
A: fecal/oral; sudden and acute
B: STD
C: STD
D: defective virus; needs to have co-infection with Hep B
E: fecal-oral; mostly in pregnant women
```
124
Hep A public health
- vaccination
- why so soon?
- reportable
- 3 dose series: combo of Hep A & B given at 0(birth), 3, 6 months OR 4 dose series: day 0, 7 months, between 21-30 months
- risk of exposure is high (fecal-oral) at birth & you want to build antibodies asap
125
How to contain Hep A if spread at single restaurant
- Go to restaurant and have to make sure that every employer is vaccinated; regulation for restaurant is that every employee must have Hep A vaccine
- Everyone that was exposed and previously vaccinated will need a booster and immunglobulin
- If unvaccinated worker does not want vaccine make sure they are no where near the restaurant for 28 day incubation period
126
Yellow fever
-jaundice, fever, headache, flu like syndrome, bloody diarrhea (seen in severe case), and mosquito
127
How to confirms Yellow fever
RT-PCR: bc it's an RNA virus
128
Yellow fever viral family
○ Arboviruses: arthropod borne vectors
| ○ This is a flavivirus: In same group as west nile and dengue
129
Yellow fever vaccine
-can infect primartes but humans are dead end hosts (cannot transfer human to human)
130
Yellow fever
- vector
- segmented genome?
- mosquitos Aedes aegypti
| - no, not rearranging its sequence so easy to vaccinate
131
What happens if someone infected with yellow fever is bit by mosquito?
- Will transfer the virus to the mosquito and the mosquito can go around an infect other people
- will need to isolate that person for 2 weeks
132
West nile
- vector
- host
- mosquito (culex) or bird
| - dead end: human and horses
