Chapter 6

Innate Immunity: Inflammation

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 Immunity
 First line of defence
 Innate (natural or native) immunity
• Physical, mechanical, biochemical barriers
 Second line of defence
 Inflammation
 Third line of defence
 Adaptive (acquired or specific) immunity

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 Immunity Two Types
 Innate
 Acquired

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 INNATE
 First line of defense
 Non Specific

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 First Line of Defence
 Physical barriers:
 Skin
 Linings of the gastro-intestinal, genitourinary, and
respiratory tracts
• Sloughing off of cells
• Coughing and sneezing
• Flushing—urine
• Vomiting
• Mucus and cilia

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 First Line of Defence (Cont.)
 Epithelial cell–derived chemical barriers:
 Secrete saliva, tears, earwax, sweat, and mucus
 Antimicrobial peptides
• Cathelicidins, defensins, collectins, and mannose-binding
lectin
 Normal microbiome
 Each surface colonized by bacteria and fungi that is
unique to the particular location and individual

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 Internal Defenses
 Cell - certain types that protect us
 Chemical
 Physiological Response
 None of these are adaptive or acting like they
know what to do.

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 Non Specific Cellular Responses
 Phagocytes

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 Phagocytes
 Neutrophils
 Also referred to as polymorphonuclear neutrophils
(PMNs)
 Predominate in early inflammatory responses
 Ingest bacteria, dead cells, and cellular debris
 Cells are short lived and become a component of the
purulent exudate

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 Phagocytes (Cont.)
 Eosinophils
 Mildly phagocytic
 Defence against parasites and regulation of vascular
mediators
 Basophils
 Least prevalent granulocytes
 Primary role unknown

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 Phagocytes (Cont.)
 Monocytes and macrophages
 Monocytes are produced in the bone marrow, enter
the circulation, and migrate to the inflammatory site,
where they develop into macrophages.
 Macrophages typically arrive at the inflammatory site
24 hours or later after neutrophils.

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 Phagocytes (Cont.)
 Dendritic cells
 In peripheral organs and skin
 Migrate through lymph vessels to lymph tissue and
interact with T lymphocytes to generate an acquired
immune response

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 Phagocytosis
 Process by which a cell ingests and disposes of
foreign material
 Production of adhesion molecules
 Margination (pavementing)
 Adherence of leukocytes to endothelial cells
 Diapedesis
 Emigration of cells through the endothelial junctions

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 Phagocytosis (Cont.)
 Steps:
 Adherence
 Engulfment
 Phagosome formation
 Fusion with lysosomal granules
 Destruction of the target

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 Adaptive Immunity
 Immunological memory
 Calls in T-Cells and B-cells

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 Natural Killer Cells
 Recognize and eliminate cells infected with
viruses
 Inhibitory and activating receptors to allow
differentiation between normal and abnormal
cells
 Produce cytokines and toxic molecules
 Apoptosis

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 Plasma Protein Systems
 Protein systems:
 Complement system
 Clotting system
 Kinin system

 Support all the other immune processes. Promotes

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 Plasma Protein Systems (Cont.)
 All contain inactive enzymes (proenzymes)
 Sequentially activated
• First proenzyme is converted to an active enzyme
• Substrate of the activated enzyme becomes the next
component in the series (cascade)

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 Plasma Protein Systems (Cont.)
 Complement system
 Produces biologically active fragments that recruit phagocytes,
activate mast cells, and destroy pathogens
 Activation of C3 and C5
• Opsonins
• Chemotactic factors
• Anaphylatoxins
 Pathways:
• Classical
• Alternative
• Lectin

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 Plasma Protein Systems (Cont.)
 Clotting (coagulation) system
 Forms a fibrinous meshwork at an injured or inflamed
site
• Prevents the spread of infection
• Localizes micro-organisms and foreign bodies
• Forms a clot that stops bleeding
• Provides a framework for repair and healing
 Main substance is an insoluble protein called fibrin
 Extrinsic pathway
 Intrinsic pathway

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 Plasma Protein Systems (Cont.)
 Kinin system
 Functions to activate and assist inflammatory cells
 Primary kinin is bradykinin
 Causes dilation of blood vessels and smooth muscle
contraction, induces pain, and increases vascular
permeability

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 Plasma Protein Systems (Cont.)
 Control and interaction of plasma protein
systems
 Tight regulation is essential
 Multiple mechanisms are available to either activate
or inactivate (regulate) these plasma protein systems

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 Cytokines
 Responsible for activating other cells and
regulating inflammatory response
 Chemokines
• Synthesized by many cells (macrophages, fibroblasts,
endothelial cells) in response to proinflammatory cytokines
• Induce chemotaxis to promote phagocytosis and wound
healing
• Examples:
 Monocyte/macrophage chemotactic proteins
 Macrophage inflammatory proteins
 Neutrophils

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 Cytokines (Cont.)
 Interleukins (IL)
• Produced primarily by macrophages and lymphocytes in
response to stimulation of PRRs or by other cytokines
• Many types
• Examples:
 IL-1 is proinflammatory
 IL-10 is anti-inflammatory

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 Cytokines (Cont.)
 Tumour necrosis factor-alpha (TNF-α)
 Secreted by macrophages in response to PAMP and
toll-like receptor recognition
• Induces fever by acting as an endogenous pyrogen
• Increases synthesis of inflammatory serum proteins
• Causes muscle wasting (cachexia) and intravascular
thrombosis
 Very high levels can be lethal

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 Cytokines (Cont.)
 Interferon (IFN)
 Protects against viral infections
 Produced and released by virally infected host cells in
response to viral double-stranded RNA
• Protects neighboring healthy cells
 Types:
• IFN-α and IFN-β
 Induce production of antiviral proteins
• IFN-
 Increases microbiocidal activity of macrophages

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 Second Line of Defence
 Inflammatory response (first immune response
to injury)
 Nonspecific
 Caused by a variety of materials
• Infection, tissue necrosis, ischemia, trauma, physical or
chemical injury, foreign bodies, immune reaction
 Local manifestations
• Redness, heat, swelling, pain, loss of function

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 Second Line of Defence (Cont.)
 Inflammatory response
 Vascular responses:
• Vasodilation
• Increased vascular permeability and leakage
• White blood cell adherence to the inner walls of the vessels
and migration through the vessels

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 Inflammation
 Goals:
 Prevent and limit infection and further damage
 Limit and control the inflammatory process
 Initiate adaptive immune response
 Initiate healing
 4 signs of inflammation - Redness, pain, heat and
swelling, loss of function

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 Cellular Components
of Inflammation
 Cellular components:
 Erythrocytes
 Platelets
 Leukocytes
• Granulocytes
• Monocytes
• Lymphocytes

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 Cellular Components of
Inflammation (Cont.)
 Cellular receptors:
 Pattern recognition receptors (PRRs)
 Pathogen-associated molecular patterns (PAMPs)
 Damage-associated molecular patterns (DAMPs)
 Toll-like receptors (TLRs)
 Complement receptors
 Scavenger receptors
 NOD-like receptors (NLRs)

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 Mast Cells and Basophils
 Mast cells are cellular bags of granules located
in the loose connective tissues close to blood
vessels.
 Skin, digestive lining, and respiratory tract
 Contain histamine, cytokines, and chemotaxic factors
 Basophils are found in blood and probably
function in same way as mast cells.

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 Mast Cells and Basophils (Cont.)
 Chemical release in two ways
 Degranulation
• Release of the contents of mast cell granules
 Synthesis
• New production and release of mediators in response to a
stimulus

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 Mast Cell Degranulation
 Histamine
 Vasoactive amine that causes temporary, rapid
constriction of the large blood vessels and the dilation
of the postcapillary venules
 Retraction of endothelial cells lining the capillaries
causing increased vascular permeability

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Mast Cell Degranulation (Cont.)

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 Histamine
 Receptors:
 H1 receptor
• Proinflammatory
• Present in smooth muscle cells of the bronchi
 H2 receptor
• Anti-inflammatory
• Present on parietal cells of the stomach mucosa
 Induces the secretion of gastric acid

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 Degranulation
 Chemotactic factors:
 Neutrophil chemotactic factor (NCF)
• Attracts neutrophils
 Eosinophil chemotactic factor of anaphylaxis (ECF-A)
• Attracts eosinophils

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 Synthesis of Mediators
 Leukotrienes
 Product of arachidonic acid from mast cell membranes
 Similar effects to histamine in later stages
 Prostaglandins
 Similar effects to leukotrienes; they also induce pain
 Aspirin and some other nonsteroidal anti-inflammatory
drugs (NSAIDs) block the synthesis of prostaglandins,
thereby inhibiting inflammation and pain
 Platelet-activating factor
 Similar effect to leukotrienes and platelet activation

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 Endothelium
 Endothelial cells adhere to underlying
connective tissue matrix
 Interact with circulating cells, platelets, plasma
proteins
 Regulate circulating inflammatory components
 Damage to these initiates platelet adherence

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 Platelets
 Activated by tissue destruction and inflammation
 Activation leads to interaction with coagulation
cascade to stop bleeding
 Degranulation with serotonin release (acts like
histamine)

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 Acute and Chronic Inflammation
 Acute
 Self-limiting
 Local manifestations—result from vascular changes
and corresponding leakage of circulating components
into the tissue
• Heat, swelling, redness, pain
• Exudative fluids

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 Exudative Fluids
 Serous exudate
 Watery exudate: indicates early inflammation
 Fibrinous exudate
 Thick, clotted exudate: indicates more advanced
inflammation
 Purulent exudate (suppurative)
 Pus: indicates a bacterial infection
 Hemorrhagic exudate
 Exudate contains blood: indicates bleeding

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 Systemic Manifestations
of Acute Inflammation
 Fever
 Caused by exogenous and endogenous pyrogens
• Act directly on the hypothalamus
 Leukocytosis
 Increased numbers of circulating leukocytes

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 Systemic Manifestations of
Acute Inflammation (Cont.)
 Increased plasma protein synthesis
 Acute-phase reactants:
• C-reactive protein
• Fibrinogen
• Haptoglobin
• Amyloid
• Ceruloplasmin, etc.

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 Chronic Inflammation
 Inflammation lasting 2 weeks or longer
 Often related to an unsuccessful acute
inflammatory response
 Characterized by pus formation, suppuration, and
incomplete wound healing

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 Chronic Inflammation (Cont.)
 Other causes of chronic inflammation:
 High lipid and wax content of a micro-organism
 Ability to survive inside the macrophage
 Toxins
 Chemicals, particulate matter, or physical irritants

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Chronic Inflammation (Cont.)

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 Chronic Inflammation (Cont.)
 Characteristics:
 Dense infiltration of lymphocytes and macrophages
 Granuloma formation
 Epithelioid cell formation
 Giant cell formation

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 Wound Healing
 Regeneration
 Resolution
 Returning injured tissue to the original structure and
function
 Repair
 Replacement of destroyed tissue with scar tissue
 Scar tissue
• Composed primarily of collagen to restore the strength of the
tissue but not its function

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 Wound Healing (Cont.)
 Healing
 Filling in the wound
 Sealing the wound (epithelialization)
 Shrinking the wound (contraction)

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 Wound Healing (Cont.)
 Primary intention  Secondary intention
 Wounds that heal  Wounds that require a
under conditions of great deal more tissue
minimal tissue loss replacement
• Open wound

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 Wound Healing (Cont.)
 Inflammation phase
 Coagulation
 Infiltration of wound-healing cells
 Angiogenesis

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 Wound Healing (Cont.)
 Proliferative phase
 Granulation
 Epithelialization
 Requires fibroblast proliferation, collagen formation,
wound contraction

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 Wound Healing (Cont.)
 Remodelling and maturation phase
 Continuation of cellular differentiation
 Scar tissue formation
 Scar remodelling

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 Wound Healing (Cont.)

From Roberts, J.R., & Custalow, C.B. (2013). Roberts and Hedges’ clinical procedures in emergency
medicine (6th ed.). Philadelphia, PA: Saunders.

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 Dysfunctional Wound Healing
 May occur during any phase of wound healing
 Ischemia
 Excessive bleeding
 Excessive fibrin deposition
 Predisposing disorders
• Diabetes
• Obesity
• Wound infection
• Inadequate nutrients
• Numerous medications
• Tobacco smoke

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 Dysfunctional Wound
Healing (Cont.)
 Dysfunction during reconstructive phase
 Dysfunctional collagen synthesis
• Keloid scar
• Hypertrophic scar
 Wound disruption
• Dehiscence (increases risk of infection)
 Impaired contraction
• Contracture

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 Dysfunctional Wound
Healing (Cont.)
 Keloid scar formation

From Damjanov, I., & Linder, J. (1996). Anderson’s pathology (10th ed.). St Louis, MO:
Mosby.

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 Chapter 7

Adaptive Immunity

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 Secretory (Mucosal)
Immune System
 Lymphoid tissues that protect the external
surfaces of the body.
 Antibodies present in tears, sweat, saliva,
mucus, and breast milk.
 IgA is the dominant immunoglobulin.
 Small amounts of IgG and IgM are present.

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 Secretory (Mucosal)
Immune System (Cont.)

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 Adaptive Immunity
 Purposes:
 Destruction of infectious micro-organisms that are
resistant to inflammation
 Long-term, highly effective protection against future
exposure to the same micro-organism
 Inducible
 Specific
 Long-lived
 Has memory

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 Adaptive Immunity (Cont.)
 Elements:
 Antigens
 Lymphocytes (T cells, B cells)
 Components:
 Humoral—immunoglobulins (antibodies)
• Bind to antigens on bacteria and viruses
 Cellular—T cells
• Subpopulations (effector T cells)
 Kill target directly
 Stimulate other leukocytes
 Both produce memory cells
 Interact

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 Antigens and Immunogens
 Antigens
 Bind with antibodies, receptors on T and B cells
 Not necessarily immunogens
 Immunogens
 Induce production of antibodies, T and B cells
 All immunogens are antigens but not all antigens are
immunogens
 Haptens
 Too small to be immunogens by themselves but become
immunogenic after combining with larger molecules that function
as carriers for the haptens

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 Antibodies
 Immunoglobulins (antibodies)
 Classes:
• IgG
• IgA
• IgM
• IgE
• IgD
 Characterized by differences in structure and function

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 Antibodies (Cont.)

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 Antibody Functions
 Antibody functions:
 Direct
• Neutralization
• Agglutination
• Precipitation
 Indirect
• Inflammation
• Phagocytosis
• Complement

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 Adaptive Immunity (Cont.)
 Active acquired immunity
 Exposure to antigen
 Immunization
 Passive immunity
 Preformed antibodies or lymphocytes are
administered

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 Antigen–Antibody Binding
 Antigenic determinant (epitope)
 Area of the antigen recognized by an antibody
 Antigen-binding site (paratope)
 Matching portion on the antibody
 The antigen fits into the binding site of the
antibody like a “key into a lock”
 Held in place by noncovalent chemical interactions

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 Immunoglobulin G (IgG)
 Most abundant class (80 to 85%)
 Accounts for most of the protective activity
against infections
 Transported across the placenta
 Four classes:
 IgG-1
 IgG-2
 IgG-3
 IgG-4

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 Immunoglobulin A (IgA)
 Two classes:
 IgA molecules are found predominantly in the blood
 IgA-2 (secretory IgA) molecules are found
predominantly in bodily secretions (most important)

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 Immunoglobulin A (IgA) (Cont.)
 Secretory IgA is a dimer anchored by a J chain
and a “secretory” piece
 Secretory piece may function to protect IgAs against
enzyme degradation

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 Immunoglobulin M (IgM)
 Largest of the immunoglobulins
 Pentamer stabilized by a J chain
 First antibody produced during the primary
response to an antigen
 Synthesized early in neonatal life

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 Immunoglobulin D (IgD)
 Low concentration in the blood
 Function as one type of B-cell antigen receptor

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 Immunoglobulin E (IgE)
 Least concentrated of the immunoglobulin
classes in the circulation
 Mediator of many common allergic responses
 Defender against parasites

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 IgE Function
 Provides protection from large parasites.
 Initiates an inflammatory reaction to attract
eosinophils.
 When produced against innocuous
environmental antigens, they are a common
cause of allergies.
 Fc portions of IgEs are bound to mast cells.

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 Clonal Diversity
 B-cell development:
 Production, proliferation, differentiation in bone
marrow
 Travel to lymphoid tissue and reside there as
immunocompetent cells
 Each cell responds to only one specific antigen
 Central tolerance

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 Clonal Diversity (Cont.)
 T-cell development:
 Thymus is the central lymphoid organ of T-cell
development
 Development of antigen-specific T-cell receptors
(TCRs)
 Leave thymus, travel to and reside in secondary
lymphoid tissue as mature immunocompetent cells
 Central tolerance

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Primary and Secondary Responses
 Primary response
 Initial exposure
 Latent period or lag phase
• B-cell differentiation is occurring
 After 5 to 7 days, an IgM antibody for a specific
antigen is detected
 An IgG response equal or slightly less follows the IgM
response

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 Primary and Secondary
Responses (Cont.)
 Secondary response
 Subsequent exposure
 More rapid
 Larger amounts of antibody are produced
 Rapidity is the result of memory cells that require less
further differentiation
 IgM may be transiently produced, but IgG is produced
in considerably greater numbers

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 Antigen Processing
and Presentation
 Initiated when T and B cells interact with an
antigen
 Must first be processed and then presented by
antigen-processing (antigen-presenting) cells
(APCs)
 Results:
 Differentiation of B cells into active antibody-
producing cells (plasma cells)
 Differentiation of T cells into effector cells, such as T-
cytotoxic cells

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 Antigen Processing and
Presentation (Cont.)
 Major histocompatibility complex (MHC)
 Glycoproteins on the surface of all human cells
(except RBCs)
 Also referred to as human leukocyte antigens (HLAs)
 Class I
• Present endogenous antigens
 Class II
• Present exogenous antigens

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 Antigen Processing and
Presentation (Cont.)

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 Antigen Processing and
Presentation (Cont.)
 Antigen processing

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 Cellular Interactions
in the Immune Response
 Intercellular collaborations resulting in the
production of effector cells and memory cells
 Requires three complementary intracellular
signalling events:
 Antigen-specific recognition through the TCR complex
 Activation of intercellular adhesion molecules
 Response to specific groups of cytokines

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 T-Helper Lymphocytes
 “Help” the antigen-driven maturation of
B and T cells
 Facilitate and magnify the interaction between
APCs and immunocompetent lymphocytes

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 Superantigens (SAGs)
 Bind the variable portion of the TCR and the
MHC class II molecules outside of their antigen-
presentation sites
 Activate a large population of T-lymphocytes
regardless of antigen specificity

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 Superantigens (SAGs) (Cont.)
 SAGs induce an excessive production of
cytokines.
 Causes fever, low blood pressure, and potentially
shock.

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 B-Cell Clonal Selection
 B-cell activation
 When an immunocompetent B cell encounters an
antigen for the first time, B cells with specific BCRs
are stimulated to differentiate and proliferate
 Differentiated B cell becomes a plasma cell
 Plasma cell is a factory for antibody production
 Single class or subclass of antibody
 Class switch

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 B-Cell Clonal Selection (Cont.)
 T-cell activation
 Binding antigen to specific T-cell receptors
 Allows:
• Direct killing of foreign or abnormal cells
• Assistance or activation of other cells
 T-regulatory cells (Tregs)
• Regulate the immune response to avoid attacking “self”
 Memory T cells

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 T-Cytotoxic (Tc) Cells
 Destroy cancer cells or cells infected with virus
 Perforin, granzymes, or direct receptor
interactions

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 Other Cells
 Natural killer (NK) cells
 Complement Tc-cell mechanisms
 Lymphokine-secreting T cells
 Amplify inflammation
 T-regulatory lymphocytes (Treg cells)
 Provide peripheral tolerance
 Suppress immune response

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 Pediatric Immunity
 Fetus has sufficient IgM but deficient IgG, IgA
responses
 Maternal antibodies provide protection within the
fetal circulation and during the first months of life
 Immunologically immature when born with
deficiencies in antibody production, phagocytic
activity, and complement activity

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 Aging and Immune Function
 Decreased T-cell activity
 Thymus size is 15% of its maximum size
 Thymic hormone production drops, as
does the organ’s ability to mediate T-cell
differentiation
 Decreased antibody response to antigens

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 Chapter 8

Infection and Defects in

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 Factors for Infection
 Communicability
 Ability to spread from one individual to others and
cause disease: measles and pertussis spread very
easily; HIV is of lower communicability

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 Factors for Infection (Cont.)
 Infectivity
 Ability of pathogen to invade and multiply in the host
 Involves attachment to cell surface, release of
enzymes, escape of phagocytes, spread through
lymph and blood to tissues
 Virulence
 Capacity of a pathogen to cause severe disease; for
example, measles virus is of low virulence while
rabies virus is highly virulent

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 Factors for Infection (Cont.)
 Pathogenicity
 Ability of an agent to produce disease
 Success depends on communicability, infectivity,
extent of tissue damage, and virulence
 Portal of entry
 Route by which a pathogenic micro-organism infects
the host
• Direct contact
• Inhalation
• Ingestion
• Bites of an animal or insect

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 Factors for Infection (Cont.)
 Toxigenicity
 Ability to produce soluble toxins or endotoxins, factors
that greatly influence the pathogen’s degree of
virulence

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 Bacterial Disease
 Bacteria
 Prokaryocytes
 Aerobic or anaerobic
 Gram-positive or Gram-negative

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 Bacterial Disease (Cont.)
 Staphylococcus aureus
 Life threatening
 Major cause of nosocomial infection
 Common on normal skin and nasal passages
 Opportunistic
 Biofilms associated with colonization
 Secretes exotoxins
 Antibiotic resistance is a major problem

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 Bacterial Disease (Cont.)
 Toxin production
 Exotoxins
• Enzymes that can damage the plasma membranes of host
cells or can inactivate enzymes critical to protein synthesis
 Endotoxins
• Activate the inflammatory response and produce fever

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 Bacterial Virulence and Infectivity
 Bacteremia (presence) or septicemia (growth)
 Result of a failure of the body’s defence mechanisms
 Usually caused by Gram-negative bacteria
 Endotoxins released into the blood activate the
complement and clotting systems, leading to a degree
of capillary permeability sufficient to permit escape of
large volumes of plasma into surrounding tissue,
contributing to hypotension and, in severe cases,
cardiovascular shock

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 Viral Disease
 Most common affliction of humans
 Replication depends on ability to infect host cell
 Simple organism
 Usually self-limiting
 Transmission:
 Aerosol
 Infected blood
 Sexual contact
 Vector

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 Viral Replication
 Not capable of independent reproduction
 Need permissive host cell
• Attachment
• Penetration
• Uncoating
• Replication
• Assembly
• Release

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 Viral Replication (Cont.)
 Copies of genetic material made
 New virions released from cell to infect other
host cells
 Some remain latent in host cell until activated by
stress, hormonal changes, disease (e.g., herpes
virus and “cold sore”)

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 Cytopathic Effects of Viruses
 Inhibition of host cell DNA, RNA, or protein
synthesis
 Disruption of lysosomal membranes releases
enzymes that damage host cell
 Transformation of host cell to cancer cell
 Promotion of secondary bacterial infection

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 Cytopathic Effects of
Viruses (Cont.)
 Fusion of infected, adjacent host cells to
produce giant cells
 Alteration of antigenic properties of host cell
leading to immune system attack of cell as
foreign

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 Viral Disease
 Influenza
 Antigenic variation
• Antigens responsible for protection against influenza
undergo yearly change
 Minor change—antigenic drift
 Major change—antigenic shift

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 Viral Disease (Cont.)
 Antigenic shifts in influenza virus

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1. Which virus undergoes yearly “antigenic drift,”
allowing for emergence of new strains?

A. Influenza
B. Streptococcus
C. Staphylococcus
D. Herpes simplex

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 Fungal Infection
 Large micro-organisms with thick, rigid cell walls
without peptidoglycans (resist penicillin and
cephalosporins)
 Eukaryotes
 Exist as single-celled yeasts, multicelled molds,
or both
 Reproduce by simple division or budding

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 Fungal Infection (Cont.)
 Diseases caused by fungi are called mycoses
 Superficial, deep, or opportunistic
 Fungi that invade the skin, hair, or nails are
known as dermatophytes
 Diseases they produce are called tineas (ringworm)
• Tinea capitis, tinea pedis, and tinea cruris

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 Fungal Infection (Cont.)
 Pathogenicity
 Adapt to host environment
• Wide temperature variations, digest keratin, low oxygen
 Suppress the immune defences
 Usually controlled by phagocytes, T lymphocytes

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 Fungal Infection (Cont.)
 Candida albicans
 Most common cause of fungal infections
 Opportunistic
 Found in normal microbiome of skin, GI tract, and
vagina of many individuals
 Localized infection if overgrowth occurs
 Disseminated infection if immunocompromised
• May involve deep infection
• High mortality rates

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 Parasitic Infection
 Symbiotic
 Unicellular protozoa to large worms (helminths)
 Flukes, nematodes, tapeworms
 Protozoa include malaria, amoebae, flagellates
 More common in developing countries
 Spread human to human via vectors
 Usually ingested
 Tissue damage is secondary to infestation itself with
toxin damage or from inflammatory/immune response

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 Countermeasures
 Infection control measures
 Reemergence of some diseases due to lack of
implementation or breakdown in application
 Environmental measures include:
• Waste disposal
• Water treatment and contamination prevention
• Food safety
• Insect (vector) control
• Safe insecticides

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 Countermeasures (Cont.)
 Antimicrobials
 Bacteriocidal versus bacteriostatic
• Inhibit synthesis of cell wall
• Damage cytoplasmic membrane
• Alter metabolism of nucleic acid
• Inhibit protein synthesis
 Interfere with folic acid metabolism
• Modify energy metabolism

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 Countermeasures (Cont.)
 Antibiotic resistance
 Genetic mutations
 Inactivation of antibiotic
• Penicillin resistance
 Modification of target molecule
 Increasing active efflux of antibiotic
 Caused by:
• Lack of compliance with therapeutic regimen
 Allows selective resurgence
• Overuse
 Destruction of normal microbiome

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 Countermeasures (Cont.)
 Vaccines
 Biological preparations of weakened (attenuated) or
dead pathogens or recombinant viral protein
 Long-lasting immunity
 The Government of Canada publishes vaccine
schedules
 Development is expensive
 There is reluctance to vaccinate, but complications
are rare

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 Countermeasures (Cont.)
 Vaccines
 Induction of long-lasting protective immune responses
that will not result in disease in a healthy recipient
 Toxoids

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 Countermeasures (Cont.)
 Common problems
 Access in less developed countries
 Lack of compliance
 Unresponsiveness to vaccine
 Resistance
 Reluctance

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 Countermeasures (Cont.)
 Passive immunotherapy
 Preformed antibodies
• Human immunoglobulin for hepatitis
• Immunoglobulin and monoclonal antibodies for rabies
• Monoclonal antibody for respiratory syncytial virus (RSV)

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 Immune Deficiencies
 Failure of immune mechanisms of
self-defence
 Primary (congenital) immunodeficiency
 Genetic anomaly
 Secondary (acquired) immunodeficiency
 Caused by another illness
 More common

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 Immune Deficiencies (Cont.)
 Clinical presentation
 Development of unusual or recurrent, severe
infections
 T-cell deficiencies
• Viral, fungal, yeast, and atypical micro-organisms
 B-cell and phagocyte deficiencies
• Micro-organisms requiring opsonization
 Complement deficiencies

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 Primary Immune Deficiencies
 Most are the result of a single gene defect
 Generally not inherited
 May appear early or late in life
 Rare, but felt many cases are underdiagnosed
 Major groups:
 B and T lymphocyte deficient
 Antibody deficient
 Immune dysregulation
 Phagocytic defects
 Innate immunity defects
 Complement defects

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 Combined Deficiencies
 Results from underdevelopment of T and B
lymphocytes
 Severe combined immunodeficiency (SCID)
 Few detectible lymphocytes
 Underdeveloped thymus
 Absent or reduced IgM and IgA levels

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 Combined Deficiencies (Cont.)
 Bare lymphocyte deficiency
 Adequate B and T cells but defective cooperation
 Inability to produce MHC class I and II
 Wiskott-Aldrich syndrome
 Depressed IgM production with bleeding
 DiGeorge syndrome
 Thymic aplasia or hypoplasia
 Diminished parathyroid development
• Results in T-cell deficiency and calcium deficiency

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 Predominantly
Antibody Deficiencies
 Defective B-cell development
 May affect only one class of antibody or several
 Most common immune deficiencies
 Hypogammaglobulinemia or agammaglobulinemia
• Bruton agammaglobulinemia

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 Phagocyte Defects
 Chronic granulomatous disease (CGD)
 Defect in myeloperoxidase–hydrogen peroxide
system
• Causes deficient production of hydrogen peroxide and
oxygen products needed for phagocytic killing
 Results in recurrent pneumonia; tumour-like granulomata in
lungs, skin bones; and other infections

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 Defects in Innate Immunity
 Defect in capacity to produce immune response
 Chronic mucocutaneous candidiasis
 Severe recurrent candida infections due to defective
immune response to C. albicans

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 Complement Deficiencies
 C3 deficiency
 Most severe defect due to central role in compliment
cascade
 Results in recurrent life-threatening infections
 Mannose-binding lectin (MBL) deficiency
 Primary defect of lectin pathway of complement
activation
 Results in increased risk of infection with micro-
organisms that have polysaccharide capsules rich in
mannose

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 Secondary Deficiencies
 Also referred to as acquired deficiencies
 Far more common than primary deficiencies
 Often not clinically relevant

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 Evaluation of Immunity
 Complete blood count (CBC) with a differential
 Subpopulations of lymphocytes
 Quantitative determination of immunoglobulins
 Subpopulations of immunoglobulins
 Assay for total complement

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Treatment for Immunodeficiencies
 Gamma-globulin therapy
 Intravenous immune globulin (IVIg)
 Stem cell transplantation
 Transfusion of erythrocytes
 Bone marrow transplants
 Mesenchymal stem cell injection
 Gene therapy

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 Acquired Immune Deficiency
Syndrome (AIDS)
 Syndrome caused by a viral disease
 Human immunodeficiency virus (HIV)
 Depletes the body’s Th cells
 Incidence:
• Worldwide: 35.3 million (2013)
• Canada: 71 300 HIV/AIDS (2011)

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 Acquired Immune Deficiency
Syndrome (AIDS) (Cont.)
 Effective antiviral therapies have made AIDS a
chronic disease
 Epidemiology
 Blood-borne pathogen
 Heterosexual activity is most common transmission
route worldwide.
 Women are affected more often.

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 Acquired Immune Deficiency
Syndrome (AIDS) (Cont.)
 Pathogenesis
 Retrovirus
• Genetic information is in the form of RNA
• Contains reverse transcriptase to convert RNA into double-
stranded DNA
• Integrase
• Protease

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 Human Immunodeficiency
Virus (HIV)
 HIV life cycle and possible sites of therapeutic
intervention

Modified from Kumar, V., et al. (Eds). (2015). Robbins and Cotran pathologic basis of disease (9th ed.). Philadelphia, PA: Saunders.

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 Human Immunodeficiency
Virus (HIV) (Cont.)
 Structure
 gp120 protein binds to the CD4 molecule found
primarily on surface of helper T cells
• Destroys CD4+ Th cells
 Typically 800 to 1000 cell/mm3
 Reverses CD4:CD8 ratio

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 Human Immunodeficiency
Virus (HIV) (Cont.)
 Clinical manifestations
 Serologically negative, serologically positive but
asymptomatic, early stages of HIV, or AIDS
 Window period
 Th cells <200 cells/mm3 diagnostic for AIDS
 Diagnosis of AIDS is made in association with various
clinical conditions and laboratory tests:
• Atypical or opportunistic infections and cancer
• Presence of antibodies against HIV
• Western blot analysis

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 Human Immunodeficiency
Virus (HIV) (Cont.)
 Treatment and prevention
 Antiretroviral therapy (ART)—combination of the
following:
• Reverse transcriptase inhibitors
• Protease inhibitors
• Integrase inhibitors
• Fusion inhibitors
• CCR5 antagonist
 Death reduced significantly
 Resistance variance identified
 Not curative

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 Pediatric AIDS
 Transmitted during pregnancy, at delivery, or
through breastfeeding
 More aggressive in children
 If untreated, child will likely die by second
birthday
 Neurological involvement common
 HIV encephalopathy
 May be difficult to differentiate from other risk factors

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 Hypersensitivity
 Altered immunological response to an antigen
that results in disease or damage to the host

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 Hypersensitivity (Cont.)
 Allergy
 Deleterious effects of hypersensitivity to
environmental (exogenous) antigens
 Autoimmunity
 Disturbance in the immunological tolerance of
self-antigens
 Alloimmunity
 Immune reaction to tissues of another individual

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 Hypersensitivity (Cont.)
 Characterized by the immune mechanism:
 Type I
• IgE mediated
 Type II
• Tissue-specific reactions
 Type III
• Immune complex mediated
 Type IV
• Cell mediated

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 Hypersensitivity (Cont.)
 Immediate hypersensitivity reactions
 Anaphylaxis
 Delayed hypersensitivity reactions

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 Type I Hypersensitivity
 IgE mediated
 Against environmental antigens (allergens)
 IgE binds to Fc receptors on surface of
mast cells—“sensitized”
 Histamine release from mast cell degranulation
 H1 and H2 receptors
 Antihistamines

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 Type I Hypersensitivity (Cont.)
 Manifestations:
 GI allergy
• Nausea, vomiting, diarrhea, abdominal pain
 Skin manifestations
• Urticaria (hives)
 Mucosa allergens
• Conjunctivitis, rhinitis, asthma
 Lung allergens
• Bronchospasm, edema, thick secretions

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 Type I Hypersensitivity (Cont.)
 Genetic predisposition—atopic
 Tests:
 Food challenges
 Skin tests
 Laboratory tests

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Type I Hypersensitivity (Cont.)

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 Type II Hypersensitivity
 Tissue specific
 Specific cell or tissue (tissue-specific antigens) is the
target of an immune response

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 Type II Hypersensitivity (Cont.)
 Five mechanisms:
 Cell is destroyed by antibodies and complement
 Cell destruction through phagocytosis
 Soluble antigen may enter the circulation and deposit
on tissues; tissues destroyed by complement and
neutrophil granules
 Antibody-dependent cell-mediated cytotoxicity
(ADCC)
 Target cell malfunction (e.g., Graves’ disease—
targets thyroid)

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 Type III Hypersensitivity
 Immune complex mediated
 Antigen–antibody complexes are formed in the
circulation and are later deposited in vessel
walls or extravascular tissues
 Large release of lysosomal enzymes
 Not organ specific
 Serum sickness
 Raynaud phenomena
 Arthus reaction

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 Type IV Hypersensitivity
 Cell-mediated hypersensitivity reactions
 Does not involve antibody
 Cytotoxic T lymphocytes or lymphokine-producing
Th1 and Th17 cells
 Direct killing by Tc or recruitment of phagocytic cells
by Th1 and Th17 cells
 Examples:
 Graft rejection
 Tuberculosis skin test
 Allergic reactions from poison ivy or metals

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 Allergy
 Most common hypersensitivity and usually type I
 Environmental antigens that cause atypical
immunological responses in genetically
predisposed individuals
 Pollens, molds and fungi, foods, animals, cigarette
smoke, and components of house dust
 Often allergen is contained within a particle too
large to be phagocytosed or is protected by a
nonallergenic coat

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 Allergy (Cont.)
 Anaphylaxis
 Most rapid and severe immediate hypersensitivity
reaction
 Occurs within minutes of re-exposure to antigen
 Systemic or cutaneous
 Most severe reactions can lead to shock and death
 Bee stings, peanuts, shellfish, or eggs
 Desensitization
 May reduce the severity of the allergic reaction, but
could also cause anaphylaxis

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 Autoimmunity
 Genetic, environmental, and random factors
 Breakdown of tolerance
 Body recognizes self-antigens as foreign
 Self-antigens not normally seen by the immune
system
 Infectious disease (e.g., rheumatic fever,
glomerulonephritis)

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 Autoimmune Examples
 Systemic lupus erythematosus (SLE)
 Chronic multisystem inflammatory disease
 Autoantibodies against:
• Nucleic acids
• Erythrocytes
• Coagulation proteins
• Phospholipids
• Lymphocytes
• Platelets
• Other self components

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Autoimmune Examples (Cont.)
 Deposition of circulating immune complexes
containing antibody against host DNA
 More common in females

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 Systemic Lupus Erythematosus
 Clinical manifestations:
 Remissions and flares
 Arthralgias or arthritis (90% of individuals)
 Vasculitis and rash (70 to 80%)
 Renal disease (40 to 50%)
 Hematological changes (50%)
 Cardiovascular disease (30 to 50%)

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 Systemic Lupus
Erythematosus (Cont.)
 Eleven common findings:
 Facial rash (malar rash)  Hematological disorders
 Discoid rash  Immunological disorders
 Photosensitivity  Presence of antinuclear
 Oral or nasopharyngeal ulcers antibodies (ANA)
 Nonerosive arthritis
 Serositis
 Renal disorder
 Neurological disorder
 Serial or simultaneous presence of at least four
indicates SLE
 Laboratory diagnosis based on positive ANA screen

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 Alloimmunity
 Transfusion reactions
 ABO blood group
• A and B carbohydrate antigens
• Can be simultaneously expressed
 Blood types based on which erythrocytes expressed
– A
– B
– O (neither expressed)
– AB (both expressed)
• Example:
 Person with blood type A receives type AB or B blood, transfused
erythrocytes destroyed
 Type O—universal donor
 Type AB—universal recipient

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 Alloimmunity (Cont.)
 Rh blood group
 Antigens expressed only on RBCs
 Rh-positive
 Rh-negative
 Hemolytic disease of newborn

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 Transplant Rejection
 Classified according to time between transplantation
and rejection
 Hyperacute
• Immediate and rare
• Pre-existing antibody to the antigens of the graft
 Acute
• Cell-mediated immune response against unmatched HLA
antigens
 Chronic
• Months or years
• Result of a weak cell-mediated reaction against minor HLA
antigens

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 Chapter 9

Stress and Disease

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 Stress
 Perceived or anticipated threat that disrupts a
person’s well-being or homeostasis
 May stem from psychological/emotional (fear,
social rejection), physical (dramatic temperature
changes, abuse), or physiological (infection,
inflammation) stimuli that trigger the stress
response

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 Historical Background
 Walter B. Cannon
 “Fight-or-flight response”
 Hans Selye
 Work showed physiological stress involved:
• Enlargement of adrenal gland
• Decreased lymphocyte levels
• Development of bleeding ulcers
 Concluded that physiological stress impairs ability to
resist future stressors

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 General Adaptation
Syndrome (GAS)
 Dr. Selye termed this general stress response
the general adaptation syndrome (GAS).
 He perceived it as primarily physiological.

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 General Adaptation
Syndrome (GAS) (Cont.)
 Alarm stage
 Stressor triggers the hypothalamic-pituitary-adrenal (HPA) axis
• Activates sympathetic nervous system
 Arousal of body defences
 Resistance/adaptation stage
 Begins with the actions of adrenal hormones
 Mobilization contributes to “fight-or-flight”
 Exhaustion stage (allostatic overload)
 Occurs only if stress continues and adaptation is not successful
 Leads to stress-related disorders

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 The Alarm Reaction

Adapted from Patton, K.T., & Thibodeau, G.A. (2016). Anatomy & physiology (9th ed.). St Louis: Mosby.

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 Psychological Mediators
 In the 1950s it was determined that the GAS
also responded to psychological factors
surrounding the stressors:
 Reactive response
 Anticipatory response

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 Psychoneuroimmunology (PNI)
 Psycho
 Consciousness
 Neuro
 CNS
 Immune
 Immune modulation by psychosocial stressors leads
directly to health outcomes

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 Allostasis
 “Stability through change”
 Brain continuously monitors for future events
and anticipates what is required from
neuroendocrine and autonomic systems
 Allostatic overload
 Overactivation of adaptive systems
 Highly individualized

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 Hypothalamic-Pituitary-
Adrenal (HPA) Axis
 Hypothalamus secretes corticotropin-releasing
hormone (CRH)
 Pituitary releases adrenocorticotropic hormone
(ACTH)
 Adrenals secrete cortisol and catecholamines

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Neuroendocrine Regulation
via HPA Axis

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 Cortisol
 Secreted during stress
 Reaches all tissues
 Stimulates gluconeogenesis
 Elevates the blood glucose level
 Affects protein metabolism
 Powerful anti-inflammatory and
immunosuppressive agent

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 Cortisol (Cont.)
 Abnormal elevations linked to obesity, sleep
deprivation, lipid abnormalities, hypertension
(HTN), diabetes, atherosclerosis, and loss of
bone density
 Secretion during stress inhibits initial
inflammatory effects
 Promotes resolution and repair
 Shown to induce T-cell apoptosis

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 Cortisol Effects
 Used therapeutically as powerful anti-
inflammatory/immunosuppressive agents
 Influence virtually all immune cells
 Elevated levels may decrease innate immunity
and increase autoimmune responses

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 Catecholamines
 Released from the adrenal medulla
 Epinephrine released
 α-adrenergic receptors
 α1 and α2
 β-adrenergic receptors
 β1 and β2
 Mimic direct sympathetic stimulation
 Increases proinflammatory cytokine production

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 Histamine and Other Hormones
 Peripheral (immune) CRH
 Proinflammatory
 Mast cells are targeted
• Histamine release
• Induces acute inflammation and allergic reaction while
suppressing Th1 and promoting Th2 activity
 Neuropeptide Y (NPY)
 Sympathetic neurotransmitter
 Growth factor

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 Stress Response
 Innate and adaptive immunity

Redrawn from Elenkov, I.J., & Chrousos, G.P. (1999). Trends Endocrinol Metab, 10[9], 359-368.

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1. A patient experiences a stressor that activates
the stress response. What is a physiological
effect seen related to the release of
catecholamines into the bloodstream?

A. Increased heart rate

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 Role of Immune System
 Stress directly related to proinflammatory
cytokines
 Link between stress, immune function, and
disease/cancer
 Immune system affected by neuroendocrine
factors
 Stress response decreases T-cell cytotoxicity
and B-cell function

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 Stress, Personality,
Coping, and Illness
 Stress is a system of interdependent processes
moderated by nature, intensity, and duration of
the stressor and perception, appraisal, and
coping ability of the affected individual.
 Higher perception of stress associated with
reduced Tc-cell cytotoxicity.

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 Stress, Personality, Coping,
and Illness (Cont.)
 Psychosocial distress
 Manifests as physiological, emotional, cognitive, and
behavioural changes
 Individual at risk for immunological deficits
 Aggression associated with changes in T- and
B-cell numbers
 Linked to chronic disorders if severe
 Identifying and reducing stress in the clinical setting
may help in disease prevention and illness
management

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 Stress, Personality, Coping,
and Illness (Cont.)
 Coping
 May be adaptive or maladaptive
 Strategies beneficial when problem focused and when
social support is sought
 Maladaptive coping may contribute to adverse health
effects

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Stress, Personality, Coping,
and Illness (Cont.)

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2. What behaviour is an example of an adaptive
coping response to stress?

A. Sleeping less
B. Increased smoking
C. Seeking social support
D. Change in eating habits

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 Aging and Stress
 Stress–age syndrome
 Excitability changes in the limbic system and
hypothalamus
 Increased catecholamines, ADH, ACTH, and cortisol
 Decreased testosterone, thyroxine, and other
hormones
 Alterations of opioid peptides

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 Aging and Stress (Cont.)
 Immunosuppression and pattern of chronic
inflammation
 Alterations in lipoproteins
 Hypercoagulation of the blood
 Free radical damage of cells

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