HDP 301: Lecture #2

*Immune Pathology
*Pain

Jeanine Harrison BScN MN NP

Seneca College
Pathophysiology HDP 301
Immune System
 Recall the structures of the immune system:
1. Skin and mucous membranes

2. Monocytes and macrophages

3. Lymphoid system (spleen, thymus gland,

lymph nodes)
4. Bone marrow

*WBCs (leukocytes) mediate inflammation and

immunity.
 WBCs are attracted to pathogens and foreign
molecules, then activated to neutralize or
destroy them
Immune System continued
 The immune system is usually categorized into two
defense types:
1. Innate – no previous exposure to pathogen/antigen;
natural killer (NK) cells and phagocytic cells
(neutrophils and macrophages) are able to respond
to infection by a variety of antigens
2. Specific – more effective on 2nd exposure to an
antigen; recognize specific antigens; B cells and T
cells responsible for this type of immunity
Review these defense systems and immune system
structure using your text book
Dendritic Cells (DC)
 DCs are phagocytes found all over the body
but especially in the skin and mucous
membranes. They “recognize” non-self cells
with their pattern recognition receptors
(PRRs) and become antigen-presenting cells
(APCs) when they display new markers on
their cell membranes for presentation to
Helper T cells in lymph nodes to link the
innate immune system with the adaptive
one.
Inflammation
 Inflammation occurs when cells are injured
no matter the cause; protective mechanism
and begins healing process
 Purpose of Inflammation:
1. To neutralize/destroy harmful invading
agents
2. To limit the spread of harmful agents to
other organs
3. To prepare damaged tissue for repair
Signs of Inflammation
1. Redness
2. Swelling

3. Heat

4. Pain

5. Loss of function

“-itis” is used to describe inflammation ex.

Tendonitis, appendicitis etc.
*Infection is usually accompanied by
inflammation; but inflammation is not always
caused by infection
Inflammation

 Inflammation can be caused by exogenous

sources (surgery, trauma, burns etc) or
endogenous sources (ex. tissue ischemia
from MI)
 Acute inflammation is short in duration, lasts
<2 weeks; chronic inflammation is usually
widespread, lasts longer and can result in
scar tissue and/or deformity
Process of Inflammation
 Regardless of the cause, the inflammatory
response includes the same events:
1. Increased vascular permeability

2. Recruitment and emigration of leukocytes

3. Phagocytosis of antigens and debris

*Note, immediately after an injury, precapillary

arterioles around the injury vasoconstrict
briefly (possible mechanism to reduce blood
loss)
Inflammation
1. Increased Vascular Permeability
 Vasodilation is caused by the release of
chemical mediators (histamine,
prostaglandins, bradykinin and leukotrienes)
from mast cells at the injured area.
 These chemicals cause vasodilation  more
blood flow to the area  increased hydrostatic
pressure  increased capillary permeability
 More fluid is pushed out of blood vessels into
surrounding tissues  local swelling
 The increased build-up of blood and fluid in the
injured area contributes to the redness, pain,
heat and swelling
1. Increased Vascular Permeability
 Histamine is a strong
vasodilator – if released in
high amounts  significant
reductions in BP
 Prostaglandins and
leukotrienes contribute to
vasodilation, increased
permeability and pain by
enhancing the sensitivity of
pain receptors
 The fluid that accumulates
during inflammation is called
“exudate”
1. Increased Vascular Permeability
 In the early phases of inflammation, platelets
move into the site and release fibronectin to
form a meshwork/net/trap, as well as
stimulating clotting to help reduce bleeding
 Platelets release growth factor to stimulate
cell proliferation
 Blood begins to coagulate and development
of fibrin clot occurs (usually within minutes)
 Fibrin also develops in lymph vessels to “wall
off” the area of injury (reduces spread of
toxins)
2. Emigration of Leukocytes
 As blood travels to the injured area, neutrophils stick
to receptors called selectins along the injured
capillary wall
 Another group of receptors called integrins help
neutrophils stick and roll along the capillary
endothelial surface
 Chemokines are molecules that enhance the
binding affinity of integrins so that neutrophils can
attach firmly to vessel walls
 Once a neutrophil arrives at the area of injury, it can
squeeze through the spaces between endothelial
cells and “emigrate” to the inflamed tissue. This
process is called diapedesis (di- a –pe – dee –sis).
Emigration
2. Emigration
 Chemotaxis – the process by which
neutrophils are attracted to inflamed tissue
 Neutrophils are guided to damaged tissue by
chemicals (bacterial toxins, degenerative
products etc.)
 Neutrophils immediately begin phagocytosis
and production of collagenase to break down
dead tissue
 Monocytes, eosinophils and NK cells also
arrive at the area to contribute to
inflammation and to destroy infected tissues.
Diapedesis

Image from: Gordon, Joe Lecture Notes

 3. Phagocytosis
 Neutrophils and monocytes (macrophages) begin the
process of phagocytosis at the injured tissue
 Both cells produce enzymes that digest proteins;
lysozymes, neutral proteases, collagenase, elastase,
and acid hydrolases.
 Once a neutrophil leaves blood circulation to fight an
infection, it will eventually stop working and die at the
site
 Pus may form at the injury site – a collection of dead
neutrophils, bacteria, and cellular debris
 Macrophages last longer than neutrophils and thus
have the role of removing old neutrophils and preparing
the site for healing
Acute Inflammation
 Acute inflammation can cause tissue
damage; degradative enzymes and oxidative
agents can attack local tissues
 Inflammatory inactivators called “α-
antiprotease” inhibit the destructive proteases
released from activated neutrophils
 They are made in the liver and circulate
continuously in the bloodstream
 Individuals with antiprotease deficiencies are
at risk for inflammatory tissue destruction
Immune Response
 Alterations in Immune Function

 Remember: the purpose of the immune

system is to defend the body against
invasion or infection by foreign substances
called antigens
 Immune disorders are divided into 2
categories:
1. Excessive Immune Response (autoimmune
and hypersensitivity)
2. Deficient Immune Response
Excessive Immune Responses
 Immune system is hyperfunctioning
 Autoimmunity- immune system attacks its own tissue;
recognizes a persons’ own cells as foreign and
mounts an immune response that injures self tissues
 Causes are largely unknown
 Hypersensitivity - normal immune response that is
inappropriately triggered/excessive/produces
undesirable effects on the body
 Many autoimmune reactions toward self-tissues are
mediated through hypersensitivity mechanisms;
therefore, many autoimmune diseases are also
considered hypersensitivity reactions.
 Treatments for autoimmunity
 Immunosuppressive therapy is most often used
 individualized depending on disease
expression
 Corticosteroids and cytotoxins inhibit excessive
immune responses, but also limit the positive
and protective functions of the immune system
 Corticosteroids decrease the number of
lymphocytes and alter their function; also
decrease antibody formation
 Cytotoxins, such as methotrexate, kill actively
proliferating lymphocytes (reduces the number
of white blood cells)
Hypersensitivity

 There are 4 types of hypersensitivity:

1. Type I – immediate allergic or anaphylactic
reaction; mediated by mast cells 
vasodilation, increased vascular
permeability, hypotension,
bronchoconstriction, hives, increased
mucus secretion, itching (pruritis)
-usually occurs 15-30mins after exposure to
antigen/allergen
Type I

 Examples are seasonal allergic rhinitis,

eczema, bee stings, peanut allergic
reactions, food allergies
 Treatments – antihistamines, Epinephrine
(beta-adrenergic) to reduce bronchospasm
and bronchoconstriction, corticosteroids to
decrease inflammation, anticholinergics allow
bronchodilation
Hypersensitivity
2. Type II – tissue-specific, antibodies that
attack antigens on the surface of specific
cells; immediate reaction within 15-30mins
after exposure
-an example is a blood transfusion reaction 
person with blood type A receives blood
type B  antibodies will attack and destroy
large numbers of red blood cells
-fever, chills, flushing, tachycardia,
hypotension, nausea, anxiety, and can
progress to anaphylaxis, shock and death.
Hypersensitivity

3. Type III – immune complex reaction; failure

of the immune and phagocytic systems to
effectively remove antigen-antibody immune
complexes from tissues  long-lasting and
ongoing inflammatory reaction
-caused by persistent low-grade infections or
autoimmune production of antibodies
(production of antibodies against red blood
cells for example)
Hypersensitivity

4. Type IV – delayed hypersensitivity, T-cells

react with altered or foreign cells and initiate
inflammation; no antibody involvement
 Reaction is slow to develop, beginning 24
hours after exposure and lasting up to 14
days
 Most common: contact hypersensitivity;
immune or inflammatory response to
chemicals, ointments, clothing, cosmetics,
dyes and adhesives
Deficient Immune Responses
 Result from a functional decrease in one or more
components of the immune system
 Two types:
1. Primary Immunodeficiency Disorders (PID) –
congenital (abnormal development or maturation of
immune cells) or acquired such as HIV/AIDS;
directly affect immune cell function
2. Secondary Immunodeficiency Disorders – caused
by non-immune system disorders/treatments such
as poor nutrition, stress or drugs, that secondarily
suppress immune function
UNDERSTANDING
PAIN
 Pain
Pain is difficult to define and
assess because it is largely
a subjective experience
 Physiological mechanisms
involved in pain are called
nociception.
(no-sis-cep- tion)
 4 stages of nociception:
1. Transduction
2. Transmission
3. Perception
4. Modulation
 Nociception: Transduction
 Transduction is the process of converting
painful stimuli to neuronal action potentials at
the sensory receptor.
 Pain receptors, nociceptors, in the periphery
are stimulated by noxious stimuli
 Nociceptors are found in the skin, muscle,
connective tissue, circulatory system and in
abdominal, pelvic and thoracic organs
 Nociceptors convert negative stimuli into action
potentials that progress to the spinal cord and
brain
Transduction

 Nociceptors can be stimulated by damage to

nerve endings, or by the release of chemicals
at the injury site
 Chemicals can be released as a result of
injury or inflammatory response; pain
chemicals include K+, H+, lactate, histamine,
serotonin, bradykinins, and prostaglandins
 Chemicals depolarize the membrane
potential of the nociceptor to fire a pain signal
NSAIDs
 Prostaglandin inhibitors such as aspirin and
non-steroidal anti-inflammatory drugs (NSAIDs)
are commonly used to manage pain
 Prostaglandins are formed when cells are
damaged. Phospholipase A breaks down cell
membrane phospholipids into arachidonic acid
 Arachidonic acid is then converted to
prostaglandins by the enzyme cyclo-oxygenase
 Prostaglandins increase the sensitivity of
nociceptors  pain is felt faster and easier
 NSAIDs inhibit the action of cyclooxygenase =
no prostaglandin production!!
Transmission
 Transmission is the movement of action
potentials along sensory neurons from
peripheral receptors to the spinal cord and
centrally to the brain (collectively the CNS)
 Primary sensory fibers involved in transmission
are A-delta fibers (Aδ) and C fibers
 Aδ fibers are larger, myelinated, carry pain info
faster and represent the initial response to
injury
 Aδ fibers carry sharp, stinging, highly localized
and acute pain signals
Transmission

 C fibers are smaller, unmyelinated and

transmit pain slowly
 Pain from these fibers is poorly localized,
feels dull and achy and lasts longer
 C fibers typically carry pain info to areas of
the brain that evoke emotional responses
(displeasure, anxiety)
 Transmission
 Sensory afferent pain fibers enter the spinal cord by
posterior nerve roots; cell bodies of pain neurons are in
the dorsal root ganglion
 In the dorsal horn , collateral branches spread up and
down the spinal cord by the Tract of Lissauer  result
in reflex postural adjustments when a painful body part
is suddenly withdrawn from the stimulus
Transmission  Sensory afferent fibers
synapse with interneurons,
anterior motor neurons, and
sympathetic preganglionic
neurons in specific regions
of the spinal cord
 Neurotransmitters and
neuropeptides are released
at this synapse; Substance
P, glutamate, GABA,
cholecystokinin
 These neurotransmitters
bind to the next neuron in
the pathway  new action
potential
 Transmission to brain
 Pain signals transmitted by spinal interneurons are then
conducted to the brain via ascending spinal pathways
 Anterolateral tract – the major pathway for pain signal
transmission to brain; travels up the anterolateral
portion of the spinal cord white matter
 Also called the “spinothalamic tract
 Signals cross to the opposite side of the spinal cord
and carry signals up the contralateral side of the cord
 Nociceptor information from the left side of the body
travels up the right anterolateral tract and vice versa.
 Anterolateral tract
 Two divisions:
1. Neospinothalamic division – Aδ fibers travel up this
tract to the thalamus; signals reach brain quickly,
provide brain with location of pain, no real emotional
connection
2. Paleospinothalamic division – C fibers travel up this
tract slowly and projects to widespread brain areas;
lots of emotional response; pain lasts for a long time
*C fibers are sent to the thalamus, but also the reticular
formation, mesencephalon (midbrain), cerebral cortex,
limbic system and basal ganglia.
 Pain identification
 The brain can localize pain
sensation because
nociceptor pathways lead
to specific anatomical
regions in the cord and
somatosensory cortex
 Sensory Dermatome –
each spinal nerve contains
the nociceptor fibers for a
particular area of the body
surface
 If a certain nerve is
injured/pinched, pain will
follow a typical pattern
Perception
 Perception occurs when the brain receives
pain signals and interprets them as ‘painful’
 Is the result of neural processing of pain
awareness and interpretation of the meaning
of the sensation
 Pain is influenced by attention, distraction,
anxiety, fear, fatigue, previous experience
and expectations.
 Primary somatosensory cortex and
association region, frontal lobe and limbic
structures all participate in pain processing
Perception of pain

 “pain threshold” – the level of painful

stimulation required to be perceived; very
similar in everyone
 “pain tolerance” – the degree of pain that one
is willing to bear before seeking relief; varies
widely among individuals
 “pain expression” – the way in which the pain
experience is communicated to others; ex.
Facial grimacing, crying, moaning etc.
 Modulation
 Modulation is the complex mechanism whereby
synaptic transmission of pain signals is altered
 Modulation occurs at multiple sites along the
pathway
 Rubbing, shaking, pressing are attempts to
decrease the perception of painful stimuli
 The “gate control theory” suggests that impulses
carried by large myelinated cutaneous fibers
can ‘close the gate’ on nociceptor impulse 
pain signals would be blocked in the spinal cord.
Modulation  Descending pathways from
the brain, more specifically
from the brainstem nucleus
called “raphe magnus”, can
project to the dorsal horn and
inhibit transmission of pain
signals
 Opioids such as endorphins
and opioid drugs like
morphine produce analgesic
effects by inhibiting
Substance P release from
nociceptor neurons
Nociceptive inhibition
 During periods of pain and stress, the body
can modulate pain
 Serotonin, endorphins and norepinephrine all
produce analgesic effects
 “stress-induced analgesia” – brain secretes
endogenous opioids
 Binding of the endogenous opioids, such as
enkephalin, inhibit the release of substance P
at the synapse, and thus block the
transmission of pain
Pain Transmission
Acute vs. Chronic pain
 Acute pain – resolves
when tissue injury heals,
usually less than 3 months,
signs and symptoms typical
for stimulation of SNS
(tachycardia, increase
breathing rate etc)
 Short term therapy with
nonopioid or opioid drugs is
helpful
 Most common causes of
acute pain is headache
and/or migraines
 Chronic pain – lasts longer
than several months beyond
expected healing time, not
associated with SNS activity
 body becomes
accustomed to pain and
desensitized to noxious input
 Symptoms are often
psychological (lack of sleep,
disruption of routine, irritability
etc.
 Common chronic pain
syndrome is fibromyalgia
collection of symptoms
without a clear physiologic
cause
 Other types of pain
 Cancer-related pain – subcategory of chronic pain but
may involve acute pain episodes
- Pain is a result of infiltration of organs, compression of

structures by tumor, or as a result of treatment that

damage tissues
 Neuropathic pain – complex, disabling chronic pain that
results from damaged or dysfunctional nerves (not
stimulation of pain receptors)
- Can result from surgery, elevated blood glucose, viral
infection, trauma and is characterized by constant
aching sensations with bursts of burning or shock-like
pain
Other types of pain

 Ischemic pain – resulting from sudden or

profound loss of blood flow to the tissues in a
particular body part (common in MI)
-lowered perfusion  tissue hypoxia and injury
 release of inflammatory and pain-
producing chemicals
-aching, burning or prickling pain until blood
flow is improved
 Referred Pain – pain that is perceived in an area
other than the site of the injury
 Common in MI  pain is often felt in the jaw or left
arm
 Often pain is referred to other structures in the same
sensory dermatome
 Sometimes the brain cannot differentiate between
two sources of pain
Week 4

 Fluid Electrolyte
 Chapter 24 -25
 GI Chapter
 Chapter 36