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Lecture

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Department
Immunology
Course Code
IMM250H1
Professor
Dana Philpott

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Tutorials
Wed, April 6th, 3-4pm, MC 102
Thursday April 7th, 3-4pm, MC 102
Final exam multiple choice covering everything taught in lecture April 28th
Last lecture:
Inflammatory response local tries to contain infection from where organism
trying to enter
Hygiene hypothesis society is too clean thus asthma, etc. developing
When innate immune system overreacts
SEPSIS
oAKA SIRS
oResponse is inflammatory
oInnate immunity typically local
Inflammation occurs restricted to that site of infection
Contained
oIn sepsis, ALL cells in body react to bacterial products, producing
cytokines and inflammatory mediators
Thus massive inflammation at whole body level
Not restricted
oConsequences
Multiple organ dysfunction
Often death
Victims often children, immunocompromised individuals, elderly
Their immune systems not as effective as healthy adults
Mortality rate is approx 50%
Ex. Pope John Paul II
Incidence of sepsis versus more popular killers
Sepsis has higher incidence
Also for mortality, neck to neck with heart attacks
Viral triggers of this immune response
SARS
oCoronovirus virus resembles crown
oPandemic defined as spread of infectious disease worldwide
oCaused major problems
oSpread within a matter of weeks
Began in China
oSARS
Reservoir thought to be bats do not have overt disease symptoms
Bats transferred virus to civets, then to humans
Humans extremely susceptible to infection by this virus
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oFlu-like illness, shortness of breath lungs targeted pneumonia like
symptoms
oLung failure is COD
Avian flu
oBird-specific influenza
oTransmitted from infected birds
oHighly pathogenic in birds kills birds
oPassed to humans inefficiently
Current strain transmission to humans is inefficient
oAlso death due to lung failure
oHUGE mortality rate
These three diseases linked to same sort of response: innate immune-mediated
cytokine storm
Positive feedback loop that amplifies cytokine production
Cytokine amplify production of other mediators and other cytokines involved in
inflammatory response
oTriggering whole-body inflammation
Moves from local response to a systemic response
Key mediators of cytokine storm
oNormally involved in containment of infections
oBut when out of control, can cause lot of collateral damage
oIL-8 brings neutrophils to site
Initiation of septic shock
oHappening in all cells of body
oDifferent innate cells reacting to bacteria or bacterial or viral products,
producing massive amounts of idffernet cytokines that then trigger
activation of other mediators of inflammation
Complement
Chemokines and inflammatory factors that affect vascular system
and cause massive permeability of blood vessels
One of the key early componments of inflammation is
increase blood flow and increase permeability of vessels so
cells can come to site of infection
If occurring everywhere in body VERY ROBLEMATIC
Also increase expression of adhesion proteins, expressed by cells to
stick to vascular endothelium
Causes clot formation
Procoagulant affect
Clots restricting blood flow to different organs; other organs
flooded with blood
THUS multiple organ failure
Cannot cope with excess or restricted blood flow organs
oLike SARS and influenza
Restricted to lung
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Both affect epithelial cells releaseing coinflammatory mediators,
that result in storm that becomes systemic
Destruction of lung tissue
Restriction of blood flow to organs
Lungs are no longer functional die of respiratory failure
oHow do ppl die?
Cytokine production that on one hand lead to changes in vascular
permeability
Increased permeability and also clot formation because of
increased ability to stick to endothelium
Organ and in viral infection, ischemia
oHow are ppl treated?
Incidence of sepsis is quite high
Dampen the cytokine storm treat with steroids that are drugs
typically know to be anti-inflammatory
Restrict production of different cytokines
Also enhance bacterial or viral infection simultaneously
oCan grow
Get rid of clots
Activated protein C is a drug acting to decompose clotting
factors
To decrease clots forming within blood vessels
Vasopressors drugs that constrict blood vessels
Type I interferons in case of viral infections
Might limit cytokine storm
Innate immune mediators, cytokines that restrict infection
Interferons makes cells less susceptible to released viruses
from infected cells
Still 50% mortality in sepsis
oPREVENTION of viral infection
Cannot really prevent septic shock from happening
Tamiflu
Blocks viral propagation
Prophylactic for prevention and treatment
PART 2
Mutations in innate immune system
Specific mutations that occur within innate immune system
1.CGD
Caused by mutations affecting NADPH oxidase complex
oNeutrophils and macrophages ability to kill bacteria Because of ROS
oEnzyme within cells response for generating ROS is NADPH oxidase
oThis protein is mutated in patients with CGD
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