Immunity: Pathophysiology

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How are the defenses of immunity divided?
The defenses of immunity are divided into:
1. 1st line of defense
2. 2nd line of defense
3. 3rd line of defense
First Line of Defense
Innate resistance
Second Line of Defense
Inflammation
Third Line of Defense
Adaptive (acquired immunity)
-normal immune response
What does the first line of defense consist of?
1st line of defense=innate resistance
-via physical and chemical barriers
1. skin
2. lining of GI, genitourinary and respiratory tract.
Skin
Part of the 1st line of defense of immunity
-keeps a lot of things in our environment from getting into the internal organs.
-skin also keeps fluid inside body and prevents dehydration
A burn victim will also have leaky skin. Why?
The skin, part of the first line of defense, has been removed.
-Increased risk of pathogens entering body
-Increased risk of dehydration (fluid volume deficiency)
-need for decrement of necrotic tissue
It is better to kill off some epithelial cells than noneptitheial cells, because epithelial cells will divide rapidly, while non epithelial cells don’t.
Lining of the GI tract, respiratory tract and genitourinary
First line of defense (physical barriers)
-sloughing off of cells
-coughing and sneezing (particles out of respiratory tract)
-flushing (UTI with water)
-vomitting (stomach)
-mucus and cilia (respiratory tract)
If you have a UTI, you are recommended to drink a lot of water. Why?
A lot of water will help to flush the bacteria out of the body and allow infection to heal faster.
Biochemical barriers of first line of defense
-synthesized and secreted saliva, tears, earwax, sweat, sebum
-antimicrobial peptides (cathelicidins, defensins collectins)
-normal bacterial flora
Why does sweat contain salt?
The more salt concentration, the less amount of microbial growth. This is why sweat contains a lot of salt, to keep microbial growth at bay.
All first line defense of immunity is (specific or nonspecific)
nonspecific
Earwax
biochemical barrier for the first line of defense. keeps insects out of the ear. earwax must be synthesized
What is the second line of defense?
Inflammatory response is the second line of defense
Inflammatory response-what causes it?
Inflammatory response is caused by many materials:
-infection
-mechanical damage
-ischemia
-nutrient deprevation
-temp. extremes
-radiation
Inflammatory response is a _____ manifestation
local
What is the vascular response of inflammatory response?
-blood vessels dilate
-increased vascular permeability and leakage
-white blood cells adhere to the inner walls of vessels and migrate through the vessels
What are the goals of inflammation?
-limit and control the inflammatory process
-prevent and limit infection and further damage
-interact with components of the adaptive immune system
-prepare the area of injury for healing
What are the major steps of inflammation?
Major steps of inflammation include:
1. Increased vascular permeability
2. Emigration of neutrophils
3. antigen destruction and phagocytosis
increased vascular permeability
involves chemical mediators
emigration of neutrophils to site of damage
involves
1. chemotaxis
2. margination
3. diapedesis
antigen destruction and phagocytosis
involves
-neutrophil
-macrophage activation
outside the vessel, and within the surrounding connective tissue
extravascular
where are mast cells found?
Mast cells are ALWAYS found in connective tissue. YOU WILL NEVER find a mast cell in the blood stream.
what are the cellular mediators in inflammatory response (i.e. the first step)?
The cellular mediators in inflammatory response include:
1.
Tissue injury will cause production of inflammatory mediator molecules–>
1. vascular factor(cause increased vascular permeability, vasodilation and edema)
2. chemokines attract leukotrienes
(actue inflammation and chronic inflammation)
What are the cellular components of cell mediators in inflammation?
Cellular components of cell mediators:
-granulocytes
-platelets
-monocytes
-lymphocytes
Cell Surface Receptors
PRP (pattern recognition receptors)
PAMPS (pathogen associated molecular patterns)
complement receptors
scavenger receptors
How do the WBC know to go to the site of injury?
Every WBC contains a number of surface cell receptors.
Cellular mediators of inflammation
1. Cellular components
-granulocytes
-platelets
-monocytes
-lymphocytes
2. Cell Surface Receptors
-PRP
-PAMP
-complement receptors
-scavenger receptors
chronic inflammatory cells
lymphocytes, monocytes, macrophages, and plasma cells are all referred to as chronic inflammatory cells
lymphocytes, monocytes, macrophages, and plasma cells
chronic inflammatory cells
acute inflammatory cells
neutrophils (PMN’s, eosinophils) are the acute inflammatory cells.
Lymphocyte: acute or chronic inflammatory cell
chronic
monocyte: acute or chronic inflammatory cell
acute
PMN
polymorphonuclear neutrophils
-WBC (called polymorphous because 2-5 lobed nucleus)
PMN’s count
PMN’s during inflammation have a much higher count.
When would a PMN count in the blood be high?
PMN’s count in the blood often increases greatly during a inflammatory process, ESPECIALLY TO A BACTERIAL INFECTION
Neutrophil
primary phagocyte that arrives early at the site of inflammation, usually within 90 minutes of injury.
aka pmn’s
How long do PMN’s last?
PMN’s are released from the bone marrow and circulating PMN’s have a 10 hour life span, so they must be constantly replaced if their numbers are to remain adequate.
Once you have injury extravascular, outside the vessel, what occurs?
WBC (neutrophils or PMN’s) will begin to:
1. marginate to the site of injury
2. adhesion of platelets
3. pavementing of neutrophils
4. emigration
In response to acute bacterial infection in the periphery, more PMN, often less mature, are released into the circulation (leukocytosis). Recruited cells die in inflamed tissues; but PMN have a short half life, perhaps less than a day, even in normal tissue. PMN are programmed to undergo apoptosis and are then phagocytosed by tissue macrophages.
Marginate to the site of injury
leukocyte (PMN’s) begin to slow their movement and begin to accumulate along the endothelial surface
Why does margination of neutrophils occur?
In response to injury, chemical mediators and cytokine are released that affect the endothelial cells and cause the leukotrienes to increase expression of adhesion molecules. The leukocytes begin to slow their movement and accumulate along the endothelial surface.
As leukocytes (PMN’s) accumulate, they begin to adhere to the endothelial vessel.
2nd step of PMN’s in inflammation
After adhesion of platelets, _____ occurs.
PAVEMENTING
Pavementing
strong adhesion of PMN’s to the endothelial wall
After pavementing, _____ occurs
emigration of PMN’s
mechanism by which leukocytes change shape, insert pseudopods into junctions between endothelial cells and squeeze through the junctions.
emigration (of PMN’s)
PMN’s in inflammation:
1. Margination
2. Adhesion
3. Pavementing
4. Emigration
Emigration of leukocytes (PMN’s causes)
1. Increased permeability of vessel wall and increased hydrostatic pressure–>transudate
2. Emigration of leukocytes–>exudate
3. Diapedesis of leukocytes and movement by chemotaxis.
Exudate
after leukocytes has moved out into the extravascular considered exudate
chemotaxis
movement along the gradient of chemical attractants released by bacteria (Receptor mediated)
Once PMN’s get into extravascular tissue, how do they know where to go?
PMN’s once they get out, their movement is dictated by chemotaxis. Chemotaxis is the process which movement is followed along the gradient of chemical attractants that are released by bacteria. PMN’s go to the greatest concentration of chemical attractions, receptor mediated.
Mast cells are found in ________
extravascular tissue only!!!!

You will never find a mast cell circulating in the blood.

Mast cells stay in the tissues.
Cellular bags of granules that are located in the loose connective tissues close to the blood vessels
mast cells
where are mast cells found?
mast cells are found everywhere in connective tissue and epithelium: skin, digestive lining and respiratory tract.
How are mast cells activated?
Mast cells are activated upon:
-physical injury, chemical agents, immunologic process and toll-like receptors (receptor mediated)
How is chemicals released from mast cells?
There are two ways in which chemicals may be released from mast cells:
1. degranulation
3. synthesis of lipid-derived chemical mediators
Mast cells are the 1st responders and start releasing quite amount of secretory granules.
What is the main chemical released from mast cells?
Histimine is the main chemical released from mast cells.
a vasoactive biogenic amine (protein) that causes temporary, rapid dilation of blood vessels and post capillary venules
histamine
Histamine is one of the first mediators in inflammatory response
causes dilation of arterioles, increased permeability of venules.
What are the two receptors found on histamine?
histamine has two types of receptors:
1. H1 receptor (found in two places)
2. H2 receptor
H1 receptor
found in both:
1. (smooth bronchial muscle cells) to constrict them
2. vessels->causes dilation and relaxation.
In H1, there are two sites for histamine…
but each has the opposite effect!
H2 receptor
predom. on parietal cells of the stomach mucosa
-induces gastric acid secretion and food allergies.
Is histamine the only thing released from mast cells?
No histamine is not the only thing released from mast cells.
-Chemotactic factors are also released:
1. Neutrophil chemotactic factor
2. eosinophil chemotactic factor of anaphylaxis (ECF-A)
Neutrophil chemotactic factor
released by mast cells upon degranulation.
Attracts more neutrophils to the site of injury.
ECF-A
Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A)
-released by mast cells upon degranulation
-attracts eosinophils
proteins that attract or signal for other certain types of cells
chemotactic factor
Derived from phospholipids through the action of phospholipases
arachidonic acid
Acarchidonic acid may be further metabolized…how?
2 pathways to further metabolize arachidonic acid:
1. lipoxygenase pathway
2. cyclooxygenase pathway
Where is arachidonic acid found?
Release of arachidonic acid from membrane phospholipids in mast cells through enzymatic action of phospholipases.
Mast cells also synthesize mediators of inflammation:
1. leukotrienes
2. prostaglandlins
3. platelet-derived factor
product of arachidonic acid from mast cell membranes, similar effects to histamine except occurs at a later stage. It serves to maintain the inflammatory response.
Leukotrienes
Function: chemotaxis, vascular permeability, bronchospasm
-arachidonic acid derivative
leukotrienes
produce of arachidonic acid from mast cell membranes, similar effects to leukotrienes, but it may also induce pain.
prostraglandins
Function: smooth muscle contraction and trigger pain receptors
-arachidonic acid derivative
prostaglandins
similar effect to leukotrienes and platelet activation
platelet-activating factors
Function: vasodilation, inhibition of neutrophil chemotaxis and monocyte adhesion
Serves to control inflammation
-arachidonic acid derivative
lipoxins
Function: Platelet aggregation to form clots and thromosis
-arachidonic acid derivative
thromboxane
Function:Opposite effect as thromboxane
-arachidonic acid derivative
prostacyclin
Monocytes are the garbage cleaners, the after party and clean up before healing may occur.
If you don’t remove damage with monocyte, then you won’t obtain the proper healing
secondary responders
arachidonic acid derivatives
-leukotrienes
-lipoxones
-thromboxones
-prostaglandins
-prostacyclin
What to corticosteroid/steroids do?
Corticosteroids will inhibit the phospholipase enzyme, which prevents production of arachidonic acid from membrane phospholipids. The inflammation will be reduced and joint will be movable. Less pain and more free movement will occur.
Danger of steroids
The area won’t undergo a true healing until inflammation can occur. If you continually downplay inflammation, healing won’t occur.
What are the secondary mediators in inflammation? Where did they come from?
arachidonic acid derivatives
-leukotrienes
-lipoxones
-thromboxones
-prostaglandins
-prostacyclin
How do mast cells move?
Mast cells move up the [] gradient to the site of injury, via chemotaxis.
Chemotaxis vs. chemotaxins
chemotaxis is the process
chemotaxins are the factors
Where will you have the greatest concentration or amount of chemotaxtic factors?
The site of damage or injury will prove the greatest amount of chemotaxtic factors.
hormone-like proteins secreted by cells that enhance inflammatory actions
cytokines
when are cytokines secreted?
cytokines are secreted after histamine to continue the inflammatory response.
polypeptide products synthesized in many cell types
cytokines
What is the function of cytokines?
Cytokines are secreted to enhance the inflammatory response:
1. leukocytic attraction-continue to attract PMN’s to the site of injury
2. phagocytosis stimulation
3. vasodilation
What are the primary cells that secrete cytokines?
Cytokines are secreted by many cell types but mainly:
1. lymphocytes
2. macrophages
subset of cytokines more specifically involved in chemotaxis; attract monocytes and leukocytes (PMN’s) to the site of injury
chemokines
IL
interluekins
produced primarily by macrophages and lymphocytes to response to a pathogen or stimulation by other products of inflammation; usually indicate the end of acute inflammation and start of chronic inflammation
interleukins (a subset of cytokines)
usually indicate the end of acute inflammation and the start of chronic inflammation
interleukins (a subset of cytokines)
white blood cell count is high…what does this mean?
WBC count is high when inflammation is occurring, because PMN (WBC) are leaving the vascular system into CT and site of injury. SO you need to replace the ones that are leaving
Protein derived protein systems
proteins that are circulating in plasma (blood) and when plasma leaks out are involved in inflammation.
What are protein systems involved in inflammation?
Protein systems:
1. complement system
2. coagulation system
3. kinnin system
What is an important feature of the protein systems involved in inflammation?
All the protein systems:
contain inactive enzymes (proenzymes)
-sequentially activated
1. proenzyme–>active enzyme
2. substrate of active enzyme becomes next component in series
Complement system
Unique: a protein system that may destroy something directly
opsinization (complement)
enhanced binding of antigen to antibody or complement
IT flags thing down for destruction
MAC in complement
may function for cell lysis
coagulation system
a protein system that forms a fibrinous meshwork at the injured or inflamed site.
Why is coagulation system important?
The fibrin acts as a net over site of inflammation to keep it contained:
1. prevents spread of infection
3. keeps microorganisms and foreign bodies at the site of greatest inflame. cell activity
4. forms a clot that stops bleeding
5. provides a framework for repair and healing
main substance in coagulation system, which is an insoluble protein
fibrin
acts as a net over the site of inflammation to keep it contained locally, produces a chicken wire frame so we can heal later.
fibrin (product of coagulation system)
Kinin system
a protein system involved in inflammation:
function to activate and assist inflammatory cells
-primary kinin is bradykinin
Function of bradykinin
primary kinin of the kinin protein system involved in inflammation (protein from plasma).

Activates pain receptors

What are the only two molecules associated with pain?
1. Bradykinin-from kinin system (protein system from plasma)
2. prostaglandin- from archaiconic acid, secondary mediator
Function of bradykinin (important)
Bradykinin functions to cause:
1. dilation of blood vessels
2. pain
3. smooth muscle contraction
4. vascular permeability
5. leukocyte chemotaxis
FIRST STUDIED HOW CELLS GOT TO INFLAMMATION, NOW STUDY HOW CELLS WORK TO DESTROY AT THE SITE OF INFLAMMATION
process by which a cell ingests and disposes of foreign material
phagocytosis
describe the movement of a phagocytic cell to the site of injury:
Movement of phagocyte to site of injury:
1. phagocytes are in circulation
2.magination
3. adhesion and pavementing
4. diapedesis
5. exudation into inflamed tissue
any fluid that filters from the circulatory system into lesions or areas of inflammation.
exudate
What are the steps of phagocytosis?
Phagocytosis steps:
1. Opsonization
2. Recognition by the phagocyte
3. Adherence (receptor mediated)
4. Engulfment
5. Phagosome formation
6. Fusion with lysosomal granules-release all the hydrolytic enzymes
7. destruction of the target.
What occurs when phagocytosis is unsuccessful??
When lysosomes are unsuccessful at killing and more and more lysosomes bind and then the higher content of hydrolytic enzymes in the cytoplasm. The phagocyte will eventually rupture due to high enzyme concentration. This will cause the enzymes and bacteria to be released from the phagocyte to the cytoplasm. Bacteria is not killed and will be able to infect another cell, while cells around phagocyte are affected.
Phagocytosis. The figure shows ingestion, digestion, and destruction of foreign particulate matter (a bacterium, in this example). A, Cell membrane receptors bind to antibody and complement molecules previously attached to the bacterial surface. B, The cell membrane creeps around the bacterium and envelopes it. C, The bacterium is trapped in a special space, the phagocytic vacuole, into which lysosomes discharge oxidants to kill it and digestive enzymes to dissolve it.
The purpose of inflammation is to limit the extent and severity of injury, eliminate or neutralize the offending agent, and to initiate the repair process.
What cells serve as phagocytes in the inflammatory response?
Main phagocytes:
1. PMN (neutrophils)
2. Monocytes and macrophages
Are neutrophils phagocytes?
Neutrophils (PMN’s) are phagocytes in early inflammatory response
-Function to inject bacteria, dead cells and cellular debris.
How long to neutophil phagocytes last?
Neutrophil phagocytes last very short period of time and become component of purulent exudate.
Monocytes vs. macrophages.
monocytes=in circulation in vascular system
same thing, just different location
macrophages=in tissues inflammatory site
Are monocytes or macrophages phagocytes?
Macrophages are phagocytes in the inflammatory response.
-takes 3-7 days to arrive after PMNS and initial tissue damage
Once macrophages (phagocytes) get to the site of injury, 3-7 days later what occurs?
Macrophage activation results in:
-increased size
-plasma membrane area
-glucose metabolism
-number of lysosomes
-secretory products
Once they get to the site, they basically explode
Uncoiled chromatin
indicates DNA is being transcribed into RNA
Do eosinophils have phagaocytic activity?
Eosinophils have some phagocytic activity.
-defense against parasites and regulation of vascular mediators (viral infection)
Basophils and lymphocytes have little to no phagocytic activity
NK cells
Natural killer cells
function is to recognize and eliminate cells infected with the viruses and some function in eliminating cancer cells
Natural killer cells
cells that recognize something that is similar to self but has changed a little bit…i.e. cancer cells in the tissues
NK cells
______ cells are more tissue regulating than circulatory regulating.
NK cells
Platelets: ARe they phagocytes?
Platelets are NOT phagocytes
-activation results in degranulation and interaction with components of the coagulation system
thrombocytes
aka platelets
Activation of platelets always stimulates…
a small-scale of coagulation cascade
In cancer, natural killer cells may be used….
and stimulated to activate and recognize cells similar to self-cells but has changed a little. Overstimulate to kill in cancer.
Pathogenesis of acute inflammation:
1. Vasodilation (0-24 hours)
2. Edema (escadate and transdate) (24-34 hours is top swelling)
3. Peak of PMN’s at 24-48 hours
4. Monocytes and macs begin to peak at days 3-4 to come for clean-up
Cardinal signs of inflammation (local)
1. Rubor=reddness
2. Tumor=swelling or inflammation
3. Calor=measurement of heat
4. Dolor=pain
rubor
reddness
tumor
swelling or inflammation
calor
measurement of heat
dolor
pain
An exudate is any fluid that filters from the circulatory system into lesions or areas of inflammation.
There is an important distinction between transudates and exudates. Transudates are caused by disturbances of hydrostatic or colloid osmotic pressure, not by inflammation. They have a low protein content in comparison to exudates. Medical distinction between transudates and exudates is through the measurement of the specific gravity of extracted fluid
Transudate=caused by hydrostatic pressure

Exudate=caused by inflammation

For a clinical standpoint, one ma classify the exudative fluids:
1. serous exudate
2. fibrinous exudate
3. purulent exudate
4. hemorrhagic exudate
watery exudate, which indicates early inflammation because it hasn’t become more complex or matured
serous exudate
(early in the inflammatory response)
thick, clotted exudate, which indicates a more advanced inflammation; contains more fibrin deprevation
fibrinous exudate
exudate that contains pus; indicating a bacterial infection
purulent exudate
exudate that contains blood; indicated bleeding
hemorrhagic exudate
pus almost always indicates…
a bacterial infection
A local manifestation of inflammation (redness, pain, swelling and heat) may spill over into a systemic manifestation of inflammation.
systemic manifestation of inflammation.
1. fever
2. leukocytosis (Increase in # WBC)
3. increased plasma protein synthesis
4. malaise
caused by exogenous and endogenous pyrogens of bacteria, which act directly on the hypothalmus
fever
increased # of circulating leukocytes
leukocytosis
increased plasma protein synthesis
acute-phase reactants
malaise
down in the dumps bc inflammatory mediators in circulation they are going to change the function in the body
Inflammatory response to infection
a lot of inflammation is due to infections, which may be caused by:
-bacteria
-parasites
-viruses
Anatomic characteristics of acute inflammation
1. Swelling
2. Edema
3. Reddness
4. Heat

Useful in diagnositc

Anatomic characteristics of systemic inflammation
Not always visible, acute inflammation has much more visible and define anatomical characteristics.
Collection of fluid on leg may be due to a lot of things.
If fluid is not clear, no pain and no heath may be edema caused by congestive heart failure.

If it is acute inflammation, you will expect to see heat, pain, swelling and reddness

Triple Response of Lewis
Intradermal effects of histamine:
1. Flush
2. Flare
3. Wheal
Flush
compression enough to cause cells injury. dull red line, indicates vasodilation due to local release of histamine
flare
red halo–>scratch expands and further dilation and increased flow. Fluid begins to move
wheal
swelling and blanching-edema
blanching
turn white in the middle of a wheal=
What are anatomical characteristics of acute inflammation?
In fibrinous pericarditis, acute inflammation:
1. tend to be swollen
2. may appear wet looking
3. fibrin meshwork caused by

actute inflammation is pretty noticeable in organs

absess
localized pocket of inflammation
sinus and fissure are open, while an abbess is closed, a pustule and somewhat isolated
Categories: Pathophysiology