Download Disorders of Immunity, Inflammation

The Immune Response:
• Introduction to Immunity
• Part I: Innate Immunity: Major Cells
• Part II: Innate Immunity: The Inflammatory
Response
• Part III: Treatment of Inflammation
• Part IV: Adaptive Immunity
1
Introduction to
Immunity
2
Functions of the Immune
Response
3
The Immune Response
The Immune Response: A collective and coordinated
response of cells of the immune system
1. Protects host from invasion of anything foreign
• Ex. foreign pathogens, bacteria, parasites, viruses, the environment in general
2. Distinguishes “self” from non-self
• Ex. cancer, autoimmune reactions
• The immune system has a surveillance mechanism to identify itself
– When it recognizes something that is nonself, the immune system has mechanisms to
kill the cell
– When the surveillance system breaks down or is over-challenged, disease occurs
3. Mediates healing
• Modulate inflammatory process and wound repair
• Immunity and inflammation are wrapped up together to make healing more
efficient
4
Results of Immune
Dysfunction or Deficiency
5
Results of Immune Dysfunction
or Deficiency
• Immunodeficiency
– Do not have the requisite amount of immunological ability
• Cannot keep up with what is going on
• Allergies/Hypersensitivities
– The response to something is exaggerated
• Transplantation pathology
• Autoimmunity
6
Innate Immunity
7
Innate Immunity
• Natural resistance that a person is born with
– Do not need anything else special
• Comprises physical, chemical, and cellular barriers that
keep the self and the nonself apart
• First line of defense
• Ex. skin, mucosa
– When radiator heat comes on, it dries out the mucosal
membranes and makes you more susceptible to microorganisms
– A person in the healthcare system needs to take care of the skin
because dry skin makes a person more susceptible to invasion
8
Adaptive Immunity
9
Adaptive Immunity
• Acquired
– When you are born and come into contact with antigens in the
environment, your body mounts a response
• Are able to recognize the pathogen in the future
• Specific
• Amplified response with memory
– Has a recognition system
– There is a molecular memory in the body about what happened
– Able to respond more quickly to the pathogen when interact with
it in the future
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Components of the Adaptive
Immune Response
11
Components of the Adaptive
Immune Response
• Divided into two major components:
1. Cell-mediated adaptive immunity
- T cells
2. Antibody-mediated (humoral immunity)
- Circulating antibodies
- B cells produce the antibodies for humoral immunity
a. Antibody-mediated immunity is triggered by encounters with
Antigens (Ags)
b. Antibodies are also known as Immunoglobulins (Igs)
12
Part I:
Innate Immunity
13
Primary Immune Cells of
Innate Immunity
14
Primary Immune Cells of Innate
Immunity
•
•
•
•
•
•
Monocytes, macrophages, dendritic cells
Neutrophils
Eosinophils
Basophils
Mast cells
Natural killer cells
15
Monocytes, Macrophages,
and Dendritic cells
16
Monocytes, Macrophages, and
Dendritic cells
•
•
Phagocytic cells that are located in different areas of the body
While macrophages are important cells of the innate immunity, they also
play key role in adaptive immunity
•
Monocytes in blood  Macrophages in tissues:
•
Dendritic cells are phagocytic cells in the nervous system
•
Include Kupffer, Langerhans, alveolar, peritoneal oligodendrocytes etc
•
Phagocytize antigen  present antigen (APC-antigen presenting cell)
•
–
–
•
Takes the antigen, sticks it outside of itself, and presents it
When activated, secrete cytokines (tumor necrosis factor, interleukin-1, and
others), oxygen radicals, proteolytic enzymes, arachidonic acid metabolites,
prostaglandins
–
•
Internalize and consume pathogens with lysosomes and peroxisomes
Process the antigen out of the substance that is foreign
Release molecules that are very important in inflammation
Macrophages are phagocytes
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Neutrophils
18
Neutrophils
• AKA Polymorphonuclear leukocytes (PMN)
• Antigen binding and non-specific phagocytosis
• Inflammatory response: First-line defender
against bacterial invasion, colonization, and
infection
• Important in innate immunity
– Responsible for antigen binding and phagocytosis
19
Eosinophils
20
Eosinophils
• Inflammatory response
• Fight parasites (worms especially)
• May release chemicals in respiratory tract during
allergic asthma
– Release chemical mediators
21
Basophils
22
Basophils
• Release potent mediators during allergic
responses (e.g. histamine)
• Have binding sites for IgE antibodies (Type 1
Hypersensitivity)
– The antibody will bind to antigen, and the basophil will release
the inflammatory substances
• Reside in blood
23
Mast Cells
24
Mast Cells
• Also from bone marrow and share
characteristics with basophils
• Located in tissues; not blood
• Releases histamine which is the hallmark
of tissue inflammatory response.
25
Natural Killer Cells
26
Natural Killer Cells
Natural Killer Cells: an effector cell important in innate immunity.
• Small % of lymphocytes
– Part of the lymphocyte population but are a small amount
• Can bind with antibody coated target cell  Antibody
dependent cell-mediated cytotoxicity (ADCC)
– Can recognize the antibody and destroy the cell
• Can attack virus-infected cells or cancer cells without help or
activation first
– Important in immunosurveillance
• Can recognize antigen without MHC restrictions
– Major histamine compatibility
• NO MEMORY
– Lives by the minute by doing what it does
• Regulated by cytokines, prostaglandins and thromboxane
• Release NK perforins, enzymes, and toxic cytokines to
destroy target cells
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Outline of Immunity
28
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Cytokines and the Immune
Response
30
Cytokines and the Immune
Response
• Small, low molecular weight proteins (hormone-like) which are
produced during all phases of the immune response.
– They are released form one area, move, and act on another area
– Short half-life
– Work in a parocrine system (acts locally) rather than an endocrine
system
• This is characteristic of many of the immunological cytokines
• Primarily made by T cells and macrophages (lymphokines/
monokines) and act primarily on immune cells
– Lymphokines – a cytokine released from a lymphocyte (T cell)
– Monokines – a cytokine released from a macrophage
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Processes that Cytokines are
Involves in
32
Processes that Cytokines are
Involves in
• Innate immunity
• Adaptive immunity
• Hematopoiesis
33
Cytokines and Innate
Immunity
34
Cytokines and Innate Immunity
• IL-1, IL-6, TNF (tumor necrosis factor) are
important in the early inflammatory response.
• Derived mainly from macrophages,endothelial,
and dendritic cells, and lymphocytes (T cells)
• Processes
– Stimulate acute phase protein production by the liver
– Stimulate the hypothalamus for a fever response
– Increase adhesion molecules on the vascular
endothelium
35
Acute Phase Protein
Production by the Liver
36
Acute Phase Protein Production
by the Liver
• Overlaps with the ESR
• Increases cytokine release in the bodysensed by the liver-liver increases amount
of acute-phase proteins (complement,
clotting factors)
– Increased cytokines due to inflammation
causes liver to produce more proteins, which
increases ESR
37
Stimulate Hypothalamus for
Fever Response
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Stimulate Hypothalamus for
Fever Response
• Hypothalamus in the base of the brain
thermoregulates the body
• One of the main reasons that you get a fever is
because a cytokine burden increases enough to
pass through the vasculature of the hypothalamus
and resets the temperature of the body
– Reason why anti-inflammatory decrease fever –
decrease the burden of the cytokine production,
which decreases the reason that the hypothalamus
causes fever
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Increase in Adhesion
Molecules
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Increase in Adhesion Molecules
• Cytokines trigger the endothelium to put out
adhesion molecules so that when a macrophage
comes by it sticks to it and squeezes between
the endothelium cells out into the tissue to fight
infection
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Cytokines and Adaptive
Immunity
42
Cytokines and Adaptive
Immunity
• Activate immune cells to proliferate and
differentiate into effector and memory
cells.
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Cytokines and Hematopoiesis
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Cytokines and Hematopoiesis
• Cytokines that stimulate bone marrow
pluripotent stem cells, progenitor cells and
precursor cells to produce large numbers
of platelets, erythrocytes, lymphocytes,
neutrophils, monocytes, eosinophils,
basophils and dendritic cells are termed
Colony Stimulation Factors (CSFs)
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PART II
Innate Immunity:
THE INFLAMMATORY
RESPONSE
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Inflammation
47
Inflammation
Reaction of vascularized tissue to local injury (cellular) manifesting as
redness, swelling, heat, pain, loss of function
•
Non-specific, chain of events similar regardless of injury type and extent
•
Includes vascular and cellular changes
•
Triggered when FIRST LINE OF Defense's integrity has been breached
– Stereotypic no matter the size of the injury
(skin, mucus membranes and damaged the endothelium or gotten to a vessel)
– May be from the outside into the body or from the inside of the body out (ex.
vacularitis)
•
•
Unpleasant and uncomfortable, but essential for survival
May lead to inflammatory diseases
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Acute Inflammation
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Acute Inflammation
• 1. vascular phase
• 2. cellular phase
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Acute Inflammation
Vascular Phase
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Acute Inflammation
Vascular Phase
After injury or insult, inflammation initiates a rapid vasoconstriction
of small vessels in the local area
•
–
The same thing as the rapid vasoconstriction that occurs in hemostasis
•
This vasoconstriction is then followed by a rapid vasodilatation of
arterioles and venules (vasoactive hyperemia) that supply the
local area.
–
Results in the erythema (redness) and warmth in the area due
to the increased blood flow to the area
•
Capillary permeability increases and fluid moves into the tissues
(edema) causing swelling and pain.
–
–
Due to cytokines that are released
The capillaries become more permeable – cells that make up the cell wall
become looser, allowing fluids and proteins to move out of the capillaries and
into the tissue
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Vascular Phase
Possible Scenarios
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Vascular Phase
Possible Scenarios
1. Immediate transient response to minor injury
•
Ex. very small, sterile cut (ex. razor cut, paper cut)
•
At first you do not notice the blood because of the rapid vasoconstriction
but then after rapid vasoconstriction the vasodilation occurs
2. Immediate sustained response (several days; results in damaged vessels)
•
More of a traumatic event and possibly a less sterile field
•
Ex. step on a garden hose
•
The issue cannot resolve quickly and due to the hemostasis and clotting
necessary, the several day response results in extra damage to the skin
and vessels
3. Delayed hemodynamic response (increase in capillary permeability 4-24 hours
after injury ; e.g., radiation burns, sun burns)
•
Have an insult but do not realize an effect until 4-24 hours after an injury
•
Ex. sunburn cooks the cells and damages them but they take a while to
build up the response and the damage so that the response takes a while
to show
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•
Redness is the vasodilation, vascular permeability leads to the edema
Acute Inflammation
Vascular Phase
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Acute Inflammation
Cellular Phase
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Acute Inflammation
Cellular Phase
•
•
•
•
Ex. step on a garden rake and bacteria enters the site of injury
Characterized by the movement of phagocytic cells into the site of
injury
•
Need to remove them by recycling them
Release of chemical mediators by sentinel cells in the tissue
(mast cells, basophils, macrophages)
•
Sentinel cells in the tissues release cytokines, the endothelial
cells recognize them, stick out adhesion molecules to allow
phagocytic cells to stick to them
•
Chemotaxis of the phagocytic cells from the vessels to
the tissue because the cells of moving to the area of high
signaling
Increases capillary permeability and allows leukocytes to migrate
to the local area.
•
Water wants to leave the vasculature, making it easier for the
cells to get out of the blood and into the tissue where they can
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fight infection
Acute Inflammation
Cellular Phase
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Inflammatory Mediators
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Inflammatory Mediators
•
•
•
•
•
Histamine
Plasma proteases
Arachidonic acid metabolites
Platelet aggregating factors
Cytokines
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Histamine
61
Histamine
• One of the first mediators of inflammation
causing dilatation and increased capillary
permeability.
• Histamine high concentration in platelets,
basophils, and mast cell
– Allows there to be a cross talk between the
clotting cascade and platelet plug
• In mast cells histamine is released in
response to binding of IgE Antibodies
62
Plasma Proteases
63
Plasma Proteases
• Kinins, activated complement, clotting
proteins
• Bradykinin causes increased capillary
permeability and pain.
– Byproduct of plasma proteases
– Causes pain by binding to nociceptors
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Arachidonic Acid Metabolites
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Arachidonic Acid Metabolites
•
Metabolism of arachidonic acid into prostaglandins
via the cyclooxygenase pathway
•
Metabolism of arachidonic acid into leukotrienes via
the lipoxygenase pathway
66
Metabolism of Arachidonic
Acid into Prostaglandins via
the Cyclooxygenase Pathway
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Metabolism of Arachidonic Acid into
Prostaglandins via the Cyclooxygenase Pathway
•
Arachidonic metabolics are very, very important inflammatory
mediators
•
PGE1(prostaglandin E1) and PGE2, prostaglandin intermediates,
are important in inducing inflammation
–
–
–
–
–
–
•
–
•
–
Promoting the inflammatory pathways
Induces vasodilation and bronchoconstriction
Inhibits inflammatory cell function
Prostaglandins released during the pulsatile flow are important in making blood
not stick
Control of acid production in the stomach
Some are pro-inflammatory and some are pro-other things that are important
and beneficial to the body
TXA2 (Thromboxane A2) promotes platelet aggregation and
vasoconstriction
Promotes branchoconstriction
Non-steroidals (aspirin etc) inhibit the first enzyme in the
cyclooxygenase pathway.
Used pharmacologically to reduce inflammation
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Metabolism of Arachidonic
Acid into Leukotrienes via
the Lipoxygenase Pathway
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Metabolism of Arachidonic Acid into
Leukotrienes via the Lipoxygenase Pathway
•
Leukotrienes are critically important in
the generalized response of anaphlaxis
•
•
C4, D4, E4: the slow releasing substances of anaphylaxis
(SRA’s). They cause slow sustained contraction of
bronchiole smooth muscle. Are important in asthma and
anaphylaxis.
Target of the newer anti-asthma drugs,
e.g., montelukast (Singulair), which act as
leukotriene inhibitors
70
Arachidonic Acid
Diagram
71
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Platelet Aggregating Factor
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Platelet Aggregating Factor
• Induced platelet aggregation
– Pathways that are important for hemostasis are also important in
the immune and inflammatory pathways
• Neutrophil activation
• Eosinophil chemotaxis
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Complement System
75
Complement System
• Functionally analogous to the clotting cascade in
hemostasis
• Primary mediator of the innate and adaptive
humoral immune response. Produce inflammatory
response, lyse foreign cells, increase
phagocytosis
• About 20 plasma proteins. Circulate in inactive
form much like clotting factors (C1, C4, C2, C3,
C5C9). Proteins must be activated in the proper
sequence in order to have their end effect (as with
the clotting factors)
• Non-specific and no memory
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Complement Pathways for
Activation
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Complement Pathways for
Activation
• Classical pathway depends on:
1. Binding of IgG or IgM to invading organisms
- antibodies bind to invading organisms
2. Binding of complement to circulating antigen-antibody complex
(complement fixation)
- undergoes molecular change that promotes the activation
complement
- complement sees this and there is a molecular recognition
• Alternate pathway is triggered by interactions between complement
and polysaccharides on microbes
• Lectin pathway is activated by binding proteins interacting with cell
surface proteins in bacteria and yeast
– Lectin can be recognized by complement and activates it
– Lection is located inside cells and is seen when cells lyse
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Results of Complement
79
Results of Complement
• MAC (membrane attack complex) insertion into target cell
membrane  holes in cell membrane (lysis)
– Form a pore that sticks into a cell and causes the cell to die through
membrane depolarization
• Opsonization - C3b coats Ag-Ab complexes
– Helps out neutrophils and macrophages with phagocytosis
– Opsonization is when an antibody binds to bacteria
• Complement binds to the antigen-antibody complex and opsonizes it so that the
phagocytes want to phagocytize the complex even more
• Chemotaxis - C3a stimulates mast cells and basophils to
release histamine and attract neutrophils and others
• C3a and C5a produce anaphylatoxin inducing histamine
release in mast cells and basophils:
•
•
Leads to contraction of smooth muscle,  vascular permeability, edema
Complement, if activated, will bind to these cells and cause them to release histamine
80
Complement Pathways
Diagram
81
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Chronic Inflammation
Persistent Irritants
83
Chronic Inflammation
Persistent Irritants
• Ex. talc, silica, asbestos that are breathed deeply into the
respiratory tract, surgical sutures
– The chronic inflammation causes persistent problems that results in
disease
• Some bacteria (tuberculosis, syphilis)
– Can be in the body for a long time, escape surveillance, and cause
inflammation
• Injured tissue surrounding healing fracture
– Keep stressing the healing fracture, leading to inflammation
• Inflammatory process lasts a prolonged amount of time
– Sustained types of response
84
Chronic Inflammation
Patterns
85
Chronic Inflammation
Patterns
•
Non-specific diffuse accumulation of macrophages and lymphocytes leading
to fibroblast proliferation and scar tissue formation
– Relsease cytokines and mediators that lead to the fibroblast proliferation
and scar tissue formation
– Ex. in the respiratory tract of smokers the epithelium begins dying and
as the body goes to replace it, it says that the epithelium is difficult to
replace so it replaces it with less ciliated, good cells, and then a scar
tissue and fibroblasts
•
Granulomatous lesion  epitheloid cells form granuloma:
– Lesions are very discrete
• Ex. splinters, foreign bodies
• After a couple of days, a granulomatous lesion forms and
encapsulates the splinter
• Eventually fibroblasts form around it and the nodule stays there for
a long time
– Ex. Tuberculosis tubercle
• Waiting for the immune system to decrease so that the tuberculosis
can come back
86
Chronic Inflammation
Causes and Characteristics
87
Chronic Inflammation
Causes and Characteristics
Due to:
• Recurrent or progressive acute inflammation
(smoking), OR
• Low-grade responses that fail to evoke acute
responses (talc, silica, asbestos, tb)
Characteristics:
• Infiltration by mononuclear cells (Macs and Lymphs);
not Neutrophils like in acute inflammation.
• Proliferation of fibroblasts ( scarring) ; not exudates
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Manifestations of Inflammation
Exudation
89
Manifestations of Inflammation
Exudation
• Local manifestation of inflammation
• Extra vascular influx of fluid with high concentration of
proteins, salts, cells (WBC) and cell debris
– The fluid from the vessel leaves the vessel and enters into the
tissues
• Fluid dilutes injurious chemicals
• Fluid brings in complement, Abs, and other chemotactic
substances to injured areas in the tissues due to osmotic
gradient
• The extra vascular proteins also act to pull water out of
plasma   blood viscosity  clotting because water is taken
out and cells are left behind (increase hemotocrit);
containment of pathogens  cellular phase begins
90
Manifestations of Inflammation
Types of Exudate
91
Manifestations of Inflammation
Types of Exudate
• Serous watery; low in protein
– Early exudate
• Fibrinous large amounts of fibrinogen in the exudate
• Membranous necrotic debris in fibrinous matrix on
mucus membrane surfaces
– Forms a muscosy sheen on certain membranous surfaces
• Purulent
degraded white cells, protein, tissue debris
– Ex. white looking acne blemish
• Hemorrhagic severe leakage of red cells from
capillaries
– Blood leaves the vasculature and enters the tissue
– Ex. petechiae, purpura
92
Systemic Manifestations of
Inflammation
93
Systemic Manifestations of
Inflammation
• Most all of the inflammatory mediators have very short
half lives so autocrine and paracrine signaling
predominates.
– Mechanisms whereby cells secrete substances and they act very, very
locally
• Compared to endocrine systems
• If the site of inflammation is large enough or robust enough of if the
inflammation is in the circulation, systemic manifestations can be
evident in addition to the local manifestations
• Acute phase response
• Lymphadenitis
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Acute Phase Responses
95
Acute Phase Responses
Acute-Phase Response (hours-days after onset)
• Increase in plasma proteins (e.g., C-reactive protein)
– Increased erythrocyte sedimentation rate (ESR)
• Fever (IL-1, IL-6 and TNF effects on hypothalamus)
– Drive the hypothalamus to increase body temeprature
• Leukocytosis (presence of immature neutrophils; “band cells”)
– Are consuming leukocytes to significant amounts and are trying to
replace them
– Similar to the reticulocytes in red blood cells
– Band cells are indicative are immature neutrophils
• Skeletal muscle catabolism (mobilize amino acids for protein
synthesis)
– When there is active inflammation, individuals do not feel well, lose the
drive to eat, do not take in enough nutrition, ask the liver to make a
bunch of proteins
• Break down the skeletal muscle to increase amino acid pool and make more
proteins
–
Negative nitrogen balance
–
Skeletal muscle is wasting
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Lymphadenitis
97
Lymphadenitis
• Regional swelling of lymph nodes, painful upon
palpation
• A swollen lymph node is indicative of an
inflammatory event in a local area or regional
area
– The regional swelling is an indication of systemic inflammation
98
Part III:
Treatment of Inflammation
99
Types of Treatment of
Inflammation
100
Types of Treatment of
Inflammation
• Focus: Prevent the synthesis and release
of pro-inflammatory mediators, such as
prostaglandins
• NSAIDs
• Steroids
101
Treatment of Inflammation
Diagram
102
Treatment of Inflammation
Diagram
103
Treatment of Inflammation
NSAIDs
104
Treatment of Inflammation
NSAIDs
• NSAIDS: nonsteroidal anti-inflammatory drugs
inhibit cyclooxygenase (COX), the enzyme that
converts arachidonic acid to prostaglandins and
thromboxane (e.g., aspirin, et al.) through the
cyclooxygenase pathway
•
Inhibit the enzymatic conversion
105
Treatment of Inflammation
Steroids
106
Treatment of Inflammation
Steroids
• Steroids: given systemically or topically
• Have a multiplicity of actions, many of which
impair immune cell proliferation or cytokine
release.
• Stop the metabolism of arachidonic acid from
cell membrane phospholipids
107
COX-1 and COX-2
108
COX-1 and COX-2
• Both produce prostaglandins and
thromboxane (TXA) and convert
arachidonic acid into prostaglandins
109
COX-1
110
COX-1
•
Found in many different tissues
•
Inhibition of COX-1 is responsible for the adverse effects of
NSAID’s because the drug works on all COX-1 tissue types
•
COX-1 inhibition impairs the gastrointestinal mucosal barrier and
gastric erosion and ulceration may result
•
COX-1 inhibition impairs renal function so that sodium and water
retention can result
•
•
Leads to edema and hypertension
COX-1 inhibition decreases the creation of thromboxane, which
prevents platelet aggregation, which may produce bleeding.
•
Such inhibition may also prevent myocardial infarction or ischemic (thrombotic)
111
stroke in patients with overactive coagulation pathways.
COX-2
112
COX-2
• COX-2 is predominantly in immune cells.
•
•
Inhibiting COX-2 results in the therapeutically desirable effects of
NSAID’s:
•
If you are targeting inflammation, you should really be targeting COX-2
because it is more specific
•
Suppression of inflammation
•
Decreasing systemic side effects
•
Alleviation of pain
•
Reduction of fever
However, many of the non-steroidals inhibit both COX-1 and COX-2
113
Contraindications
114
Contraindications
• NSAIDs
• Hypersensitivity syndrome
115
NSAIDs
116
NSAIDs
•
NSAIDs should be avoided in mid to late pregnancy
since:
•
They may cause premature closure of the ductus
arteriosus.
•
•
•
A shunt in the heart in the developing fetus that allows proper blood flow
Important in maternal-fetal circulation and oxygenation of the fetus
They might also cause prolonged bleeding following
delivery because of their effects on platelets.
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Hypersensitivity Syndrome
118
Hypersensitivity Syndrome
•
Hypersensitivity syndrome caused by COX inhibition:
•
This is not an allergic response because there are no
antibodies to the NSAID; in susceptible individuals,
any NSAID can trigger the reaction.
•
Certain people are more sensitive to NSAIDs just because
•
Symptoms are similar to those of anaphylaxis.
•
Susceptible individuals should avoid all NSAIDS
119
Aspirin
120
Aspirin
•
An irreversible inhibitor of both COX-1 and COX-2 (it is
nonselective).
•
Metabolized (with a half-life of ~20 minutes) to salicylic
acid, which inhibits both COXs reversibly and has a
longer half-life than aspirin
•
The anti-inflammatory activity is due to both the
irreversible inhibition of both COXs by aspirin and
reversible inhibition by salicylic acid.
121
Uses of Aspirin
122
Uses of Aspirin
•
•
•
Anti-inflammatory
Anti-pyretic (suppression of fever)
Analgesic
•
Dysmenorrhea
•
•
Menstrual cramps are due to the production of prostaglandins
•
Aspirin decreases smooth muscle cramping
Suppression of platelet aggregation
123
Uses of Aspirin
Suppression of Platelet
Aggregation
124
Uses of Aspirin
Suppression of Platelet Aggregation
•
•
This use is usually accomplished by administration of an 81-mg
enteric-coated tablet each morning.
–
Allows the drug to pass through the stomach and be absorbed in the intestine
–
Do not want aspirin to dissolve in the stomach because it affects gastric pH
The aspirin irreversibly inhibits COX-1 in platelets it encounters in the
portal circulation, but in its 81 mg form it is completely metabolized on
first pass and has no systemic effects.
–
When aspirin is taken, any platelets in circulation are irreversibly inhibited but on
the second time, the aspirin is converted to salicyclic acid and reversibly inhibit
platelets
•
•
Taking the small dose allows it to be that only the platelets in the circulation
are irreversibly affected (because of the short life of the platelets)
Over time, a substantial portion of platelets are affected by the low
dose aspirin without undue systemic side effects.
125
Adverse Effects
Common to all Aspirin Formulations
126
Adverse Effects
Common to all Aspirin Formulations
•
Salicylism: tinnitus, headache and dizziness caused by high
doses such as the doses that are used in rheumatoid arthritis.
Respiratory alkalosis may also result.
•
Reye’s syndrome: a fatal syndrome of liver failure in children
suffering from chickenpox or influenza who use aspirin. For this
reason, it is recommended that children be only given
acetaminophen or ibuprofen for febrile illness. With this
recommendation, the incidence of Reye’s syndrome has
plummeted.
•
Poisoning: before childproof caps were mandated by law,
aspirin poisoning was a common cause of illness and death in
children. This is no longer such a problem
•
The toxicity of aspirin in children is what prompted the mandation of
childproof safety caps
127
Aspirin Formulation
128
Aspirin Formulation
•
Plain aspirin tablets.
•
Buffered aspirin: includes sodium bicarbonate to neutralize
stomach acid and prevent gastric irritation.
•
The sodium bicarbonate acts as the buffer
•
Inhibit the prostaglandins, allowing the gastric mucosa to temporarily go
down but you are also buffering the aspirin so you are helping it out
•
Enteric coated aspirin: remains intact in the stomach and
dissolves in the duodenum; prevents gastric irritation.
•
Timed released: makes no sense for an irreversible drug that is
completely metabolized on first pass
•
Rectal suppositories: Not recommended due to inconsistent
absorption and rectal ulceration.
129
Aspirin Dosage
130
Aspirin Dosage
•
Is commonly available in:
•
•
•
regular strength (327 mg)
extra-strength (500 mg)
low-dose (81 mg) tablets
•
•
•
Used by adults for the inhibition of platelets
There is no evidence that taking more than 81 mg leads to further
platelet aggregation
Adults: 650-1000 mg in one dose can be repeated every 4
hours.
•
Children: aspirin is not recommended unless specifically requested by the
•
Inhibition of platelets: 81 mg per day.
child’s physician.
131
Other Non-Selective NSAIDs
132
Other Non-Selective NSAIDs
• Non-specific COX-1 and COX-2 inhibitors
• Specific COX-2 inhibitors
133
Non-specific COX-1 and COX2 Inhibitors
134
Non-specific COX-1 and COX-2
Inhibitors
•
Nonspecific COX-1 and -2 inhibitors
(aspirin, Ibuprofen, naproxen, etc.):
•
All have interactions with warfarin
(Coumadin); they may potentiate bleeding
tendencies produced by warfarin
•
Coagulation studies should be obtained
frequently and warfarin dosage adjusted in
patients who take both an NSAID and
warfarin
135
Specific COX-2 Inhibitors
136
Specific COX-2 Inhibitors
•
Have recently been associated with increased risk of heart attacks.
•
•
A result of clinical trials but many of the reasons are not known
Could inhibit prostacycline, which is a positive mediator
•
Purported to produce fewer adverse effects in some individuals, such
as GI irritation, bleeding, and sodium/water retention. However, data
in the general population to support this contention is shaky.
•
Much more expensive than nonselective NSAIDS
•
•
A nonselective NSAID is equally effective as a COX-2 inhibitor
Include:
–
–
–
Rofecoxib (withdrawn from the market)
Valdecoxib (withdrawn from the market)
Celecoxib (Celebrex) is still available
137
Acetaminophen
138
Acetaminophen
•
Does not inhibit COX in the periphery; MOA is unclear
•
•
Is not a COX inhibitor
Has no anti-inflammatory activity.
•
Does not decrease inflammatory mediators
•
No side effects of gastric ulceration, sodium and water
retention.
•
No effect on platelets or coagulation.
•
Uses
–
Antipyretic
–
Analgesic
139
Acetaminophen
Adverse Effects
140
Acetaminophen
Adverse Effects
•
Adverse effects: Hepatoxicity
•
Usually occurs because of overdose
•
Decreases liver function and may
increase toxicity
•
Greatly exacerbated by concurrent alcohol
use; so, hepatoxicity may occur at
therapeutic doses in heavy drinkers.
•
Hepatotoxicity from acetaminophen has
resulted in deaths from liver failure.
141
Acetaminophen
Drug Interactions
142
Acetaminophen
Drug Interactions
• May affect warfarin metabolism because it
is metabolized by the liver to increase
levels of warfarin and increase its
anticoagulant effects.
143
Acetaminophen
Dosages
144
Acetaminophen
Dosages
•
Available in 327 mg and 500 mg tablets.
•
Adult dose is 650 mg to 1000 mg every
4-6 hours with a daily limit of 3 g (3000
mg).
•
Dosage is reduced depending on the age
of the child
145
Formulations of NSAIDs and
Acetaminophen
146
NSAIDS and acetaminophen are found in
many formulations
Be careful !
147
Part IV:
Adaptive Immunity
148
Active Adaptive Immunity
149
Active Adaptive Immunity
• Active passive immunity - Through
immunizations
• Active natural immunity - Through having
the disease
• Present for a life-time
150
Passive Adaptive Immunity
151
Passive Adaptive Immunity
• Transferred from another source (in utero,
breast milk, antibodies)
• Short-term
– It is only around as long as we are given the
substances
152
Characteristics of the Adaptive
Immune Response
153
Characteristics of the Adaptive Immune
Response
• Self tolerance: Discrimination of self and non-self
• Self-regulation: the immune system can initiate,
maintain, and down-regulate without help of the
nervous system (NS) or other systems
– This is one of the only body systems that can do this
• Specificity: Targets very specific antigens
• Diversity: Can invoke specific immune response to
an indefinite number of different antigens
• Memory: Makes memory cells (only IS and CNS
have memory)
154
Major Functional Cells of the
Adaptive Immune Response
155
Major Functional Cells of the
Adaptive Immune Response
B-Cell Lymphocytes including:
• Plasma B Cells
• Memory B Cells
T-Cell Lymphocytes including:
• T-Helper Cells
• Cytotoxic T Cells
156
Antigens
157
Antigens
Antigens: Initiators of Immune response and
Adaptive Immunity
Antigens (aka immunogens) are:
• Substances foreign to the host which stimulate an immune response
• Antigens are ligands that are recognized by receptors on immune
cells and by antibodies (immunoglobulin's; Igs)
• Often proteins or polysaccharides and less often lipids or nucleic
acids.
– Your DNA can actually act as an antigen in some instances, but it is not as
common
158
Locations of Antigens
159
Locations of Antigens
Antigens are found on:
• Bacteria, fungi, protozoa, parasites or nonmicrobial agents such as pollens, plant
resin, insect venom, transplanted organ.
160
Antigens
Diagram
161
Antigens
Diagram
162
Immunity Antigens
163
Immunity Antigens
• Many antigens are large molecules.
– The antigen may be recognized by multiple antibodies at a number
of locations
• Small fragments, often single sites, can be immunologically
active. These sites are called epitopes.
• Antigens or epitopes are what is recognized by a specific Ig
receptor
• Often a single antigen can have several antigenic sites. A
distinct lymphocyte clonal population will recognize each
distinct site
• Certain small molecules are unable to stimulate an immune
response (Haptens) .
– Too small to stimulate a response
– These molecules can become immunologically active when bound to a carrier
protein (e.g., penicillin hypersensitivity)
• The body is now able to recognize the body as foreign and can
recognize the antigen as foreign
164
Major Histocompatibility
Complex
165
Major Histocompatibility
Complex
• Cell surface molecules which provide a mechanism to
differentiate “self” from “non-self”
– The portion of your DNA that encodes for your MHC molecules is
what makes you unique
• This becomes important when we want to transplant organs because one
person’s MHC may not match the other person’s MHC
• Region of genetic information that makes each individual of
one and the same species different:
•
aka Human Leukocyte Antigens (HLA) since these were first identified
on white blood cells.
•
Cytotoxic T cells and helper T cells both recognize MHC complexed
with antigen
•
Because these molecules (MHC) play a big role in transplant rejection,
they are also termed antigens in this instance.
166
MHC-II Complex
167
MHC-II Molecules
• Found primarily on antigen-presenting cells (APC’s) such as
macrophages, dendritic cells, and B lymphocytes.
• MHC-II molecule contains a groove in them that contains a
recognition site which binds a peptide fragment of an antigen from
pathogens engulfed/digested during phagocytosis.
• The APC comes into contact with a virus, recognizes an antigen on
the virus, activates complement, opsonizes the virus, which
increases the phagocytic action, the phagocytic cell ingests the
virus, takes the foreign antigen and then presents it on itself
– Holds the antigens out to a T helper cell and the T cell agrees that it is
foreign
– The T cell then calls in other players to become immune to it and calls
cytokines to destroy the cell
• Helper T cells (Th) recognize these complexes on APC’s and they
become activated.
168
MHC-II Molecules
169
MHC-I Molecules
170
MHC-I Molecules
•
•
Found on cell surface glycoproteins on most nucleated cells of body.
They Interact with antigen receptor and CD8 molecule on cytotoxic T
lymphocytes (Tc)
– Tc cells are responsible for direct cell killing
•
The virus enters a cell and the cell presents the virus on the outside
– Indicates that the cell has been infected with the virus
•
Cytotoxic T-cells (Tc) become activated only when they are presented with
an antigen associated with a Class I MHC.
•
MHC has the ability to present antigens on our body cells
– Distinguishes self from non-self
•
Antigen peptides associate with MHC-I in cells that are infected with
intracellular pathogen
– E.g., as virus multiplies, small degraded peptides associate with MHC-I and are
transported to the membrane.
– This antigen-MHC complex communicates with the Tc cell and the host cell is
destroyed.
171
MHC-I Molecules
Diagram
Virus particles
172
Comparison of MHC-II and
MHC-I
173
174
Humoral vs. Cell-Mediated
Immunity
175
Humoral vs. Cell-Mediated
Immunity
• Lymphocyte stem cells are located in the
bone marrow
1. Lymphocytes which migrate through lymphoid
tissue  B cells (make antibodies)
2.
Lymphocytes which migrate through the thymus 
T lymphocytes (cell-mediators)
176
Development of B
Lymphocytes and T
Lymphocytes
177
Development of B Lymphocytes
and T Lymphocytes
• If the bone marrow lymph cell matures in the thymus, it
is called a T cell
– T cells can become memory, cytotoxic, or helper T cells
– Cell mediated immune response
• If the cell leaves the bone marrow and goes to the
bursal equivalent tissue (lymphoid tissue), it becomes
a B cell
– Can become a memory cell or antibodies (plasma cell)
– Produce cells that make antibodies
• A part of the humoral immune system
178
Development of B
Lymphocytes and T
Lymphocytes
Diagram
179
180
B Lymphocytes
181
B Lymphocytes
Responsible for antibody production (humoral immunity)
Function
• Identified by the presence of surface immunoglobulin (antibody)
bound to them permanently that functions as an antigen receptor,
particular CD proteins and complement receptors
• Plasma cells are antibody factories
• Manufactures specific antibodies that target bacteria, neutralize
bacterial toxins, prevent viral infection, and produce immediate
allergic response
• Formed from bone marrow stem cells
--Pre-maturation in the bone marrow to immature precursor cells
--Genetic rearrangement results in a unique receptor and type of effector
antibody (IgM or IgD)
- shown an antigen by a presenting cell
- the plasma cell recognizes the cell with the antigen and
inside the cell itself, a genetic rearrangement is made so that 182
the antibody will only ever recognize the specific antigen
Differentiation of B
Lymphocytes
183
Differentiation of B
Lymphocytes
•Mature B Lymphocytes leave the bone marrow, enter the
blood and travel to peripheral tissues
• B lymphocytes bind antigens with help of Th and then
differentiate into
1. Plasma cells (large # of cells: which are responsible for antibody
secretion)
2. Memory cells (small # of cells: pre-programmed to become
plasma cells from that clonal line)
184
B Lymphocytes
Diagram
185
186
B Lymphocytes
Description
187
B Lymphocytes
Description
• Helper T cell can present cell to B cell and the B cell
can recognize the antigen from then on
– Later, if the B cell recognizes the antigen it can do
something about it
• A mature B cell produces a memory B cell and a
plasma cell
• A memory just remembers what antigen it should
recognize and then goes dormant
• Plasma cells are not dormant like memory cells
– Produce antibodies
– Look for the foreign antigen
188
Activation of B Lymphocytes
189
190
Antibodies
Primary Immune Response
191
Antibodies
Primary Immune Response
• Sensitization
– Antigen is first introduced into the body
– Antigen is processed by Antigen Presenting Cells (APCs)
• Activation
– MHC complexed Antigen is recognized by Th cells
• Differentiation
– Activated Th cells release cytokines and trigger B
lymphocytes to proliferate into a clonal line of plasma cells
and memory cells
– Plasma cells release antibody
• This time course has a significant lag time.
192
Antibodies
Secondary Immune Response
193
Antibodies
Secondary Immune Response
• Once re-challenged with antigen at a later
time, the memory cells recognize antigen
and respond quickly to the antigen.
• Immunization boosters (e.g., tetanus) take
advantage of this response.
194
Primary and Secondary B
Lymphocyte Immune Response
Diagram
195
Primary and Secondary B Lymphocyte Immune Response
Diagram
196
Primary and Secondary B
Lymphocyte Immune Response
Description
197
Primary and Secondary B Lymphocyte
Immune Response
Description
• A B cell that has never been exposed to an antigen but is
mature is naïve
– A naïve B cell does not know what it wants to be yet
• The first time that a B cell sees the antigen, the antigen has to
be injected, complement binds to it, presented to helper T
cells, B cell is sensitizes and becomes a memory B cell or a
plasma cell
– Takes about two weeks
– Creates a bunch of memory B cells that remember the antigen
and can mount a quicker response
• The second exposure is very quick because the memory B
cell is present
– Secondary immune response
198
Antibody Types
(Immunoglobulins)
199
Antibody Types
(Immunoglobulins)
•
•
•
•
•
IgA
IgM
IgD
IgE
IgG
200
IgA Antibodies
201
IgA Antibodies
•Secretory (saliva, colostrum, bronchial,
pancreatic, GI,prostatic, vaginal).
•Prevents viral and bacterial binding to
epithelial tissues.
•IgA is first line of defense in mucosal
tissues
–Secretions can bind the pathogen so that it
does not enter the vasculature
202
IgM Antibodies
203
IgM Antibodies
•Large macromolecular Ig complex.
•First Ig made in response to an antigen.
•First antibody type made by a newborn
–During fetal development, the fetus is
receiving Igs passively
204
IgD Antibodies
205
IgD Antibodies
• Found primarily on cell membranes of B
Lymphocytes.
• Acts as antigen receptor.
206
IgE Antibodies
207
IgE Antibodies
• Involved in inflammation, allergic
responses and combating parasitic
infections.
• Antigen binding to IgE on mast cells or
basophils causes histamine release
• Important in inflammation and allergies.
208
IgG Antibodies
209
IgG Antibodies
• Most abundant circulating antibody in blood
• Only Ab that can cross the placenta.
• Ig in fetus/newborn is passed from mother
until new Ig’s are formed by newborn.
• Targets bacteria, virus and toxins.
• Can activate complement.
210
Maternal vs. Fetal/newborn
IgG Contributions
211
Maternal vs. Fetal/newborn IgG
Contributions
212
T Lymphocytes
213
T Lymphocytes
Responsible for cell mediated immunity
• Formed from bone marrow stem cells which migrate to the
thymus (T) for maturation. Mature T-cells then migrate to
peripheral lymphoid organs
•
Genetic modification to form a unique T-cell antigen
receptor (clonal selection)
•
•
Produce a specific receptor (T cell receptor) which
recognizes the antigen
TCR: two polypeptide grooves that recognize
processed antigen-peptide MHC complexes.
-TCR is associated with CD3 cell surface molecules,
which is a protein
•
•
•
The TCR is bound to the CD3 protein
Subpopulations of CD proteins offer further cell
specificity:
•
•
1. CD4+: T-helper cells (have CD3 and CD4)
2. CD8+: T-cytotoxic (have CD3 and CD8)
214
Types of T Lymphocytes
215
Types of T Lymphocytes
• CD4 cells: T helper cells
• CD8 cells: Cytotoxic T cells
216
Helper T Cell
217
Helper T Cell
• Helper T cell (Th or CD4+ cell): Regulatory cells
Master switch of immune system
• Do not do direct cell killing
• Recognizes Ag-MHC-II complex
• Once activated by APC, they release cytokines that
affect most other cells of immune system
– Orchestrate the immune response by telling the B cells
what to become and by secreting cytokines
• Activated Th cell can differentiate into
distinct sub-populations based on cytokines secreted
by the APC.
218
Cytotoxic T Cell
219
Cytotoxic T Cell
Cytotoxic T cell (Tc or CD8+ cell): Effector
• Get activated by Th cells
• Recognize Ag-MHC-I complex on infected cells
• Destroy infected cells by releasing cytolytic enzymes,
toxic cytokines, Perforins
• Important in controlling intracellular pathogens (bacteria
and viruses)
• Do a lot of self vs. nonself checking
• Natural killer cells do not check the MHC, like the
cytotoxic cells do
– Tc cells are much more selective
220
Types of T Lymphocytes
Diagram
221
222
Cell-mediated Immunity
223
Cell-mediated Immunity
• Provide protection from viruses, bacteria, cancer cells
• T lymphocytes and macrophages predominate
• APC cells present MHCII-Ag to Th cells
– Th cells become activated by antigen recognition and by
interleukin-2.
– Th cells then produce IL-2 and IL-4 to drive clonal expansion of
Th cells and Interferon-gamma which activate Tc cells (cytotoxic
T cells).
• Tc cells and macrophages form the basis of the cellmediated cell destruction in the immune response, while
224
Th cells modulate the process.
Cell-mediated and Humoral
Immunity
Diagram
225
226
Cell-mediated and Humoral
Immunity
Description
227
Cell-mediated and Humoral Immunity
Description
• T helper cell recognizes the antigen that becomes
activated, releases cytokines, sensitizes B cell, helper
T cell recruits Tc cell, Tc cell can kill cells that
recognize the MHC-1 antigen
• When B cells are sensitized, they either make memory
cells or plasma cells
• T helper cells orchestrate virtually the entire process
• Both the memory cells and the other cells all have
specific genetic memory for the certain antigen
228
Natural Killer Cells
229
Natural Killer Cells
Natural Killer Cells: an effector cell important in innate immunity.
• Small % of lymphocytes
• Can bind with antibody coated target cell  Antibody
dependent cell-mediated cytotoxicity (ADCC)
• Can attack virus-infected cells or cancer cells without help or
activation first
• Can recognize antigen without MHC restrictions
– Difference between NK and T cells
• NO MEMORY
• Activity is regulated by cytokines, prostaglandins and
thromboxane locally
• Release NK perforins, enzymes, and toxic cytokines to
destroy target cells
– They do not phagocytize
230
Cytotoxic C vs. Natural Killer
Cells
231
Cytotoxic C vs. Natural Killer
Cells
Cytotoxic T Cells
• T lymphocyte
• Do phagocytize
• Do have memory
• Do require MHC-1
restrictions
Natural Killer Cells
• Small percentage of
lymphocytes
• Do not phagocytize
– Release NK perforins,
enzymes, and toxic
cytokines to destroy target
cells
• Do not have memory
• Do not require MHC
restrictions
• Activity is regulated by
cytokines, prostaglandins
and thromboxane locally
232
Secondary Lymphoid Organs
233
Secondary Lymphoid Organs
• Connected by blood and lymphatic vessels
• The secondary lymphoid organs provide an
environment for lymphocytes to circulate, meet and
fight antigens, spread antigens, encounter
information
• Lymphocytes circulate constantly between blood 
tissuelymphatic ducts  lymph nodes  thoracic
duct –bloodstream
– This is a good place for immunosurveillance
234
Lymph Nodes
235
Lymph Nodes
• Localize and prevent the spread of infection
• Contain both B and T cells
• Discrete locations of concentration of the
lymphatic system
• Good place to aggregate and look for
antigens
236
Spleen
237
Spleen
• Filters and processes antigens from blood
• Contains both B and T cells
• Functions as a reservoir for blood (red
pulp)
• RBC “graveyard”  Hb released
• Macrophages and other phagocytic cells in
white pulp
• Some parts innervated by sympathetic NS
238
MALT
239
MALT
MALT (Mucosa –Associated Lymphoid Tissue):
• Major portion of secondary lymphoid tissues
• Non-encapsulates areas of lymphoid tissue
• Around mucosal membranes of respiratory,
digestive, and urogenital tract.
– Located at the interface of the environment and your
body
• Contains T and B lymphocytes.
• E.g. tonsils, Peyer’s Patches (intestine),
appendix
240
Secondary Lymphoid Organs
Diagram
241
242
Immunodeficiency
243
Immunodeficiency
• Abnormality in one or more branches of the Immune
System (IS)
1. Antibody-mediated (aka Humoral)
2. Cell mediated
3. Complement
4. Phagocytosis
– Increased vulnerability to opportunistic disease
(infections and malignancies)
– Diseases may cross or more of these branches
244
Normal Immunity in Infancy
245
Normal Immunity in Infancy
• After 6 months, maternal
Igs 
• Between 1-2 years adult
levels of all Igs are
reached
• First Ig to be produced by
maturing plasma cells is
IgM
• IgM can transform into
other Igs after antigenic
stimulus
246
Primary Immunodeficiency
247
Primary Immunodeficiency
• Transient hypogammaglobulinemia
• Defective congenital or inherited genes
are rare and include
– X linked agammaglobulinemia – Bruton’s=
– DiGeorge Syndrome – lack of thymus
development
– Severe combined immunodeficiency
syndrome (SCID)
248
Transient
Hypogammaglobulinemia
249
Transient
Hypogammaglobulinemia
Transient Hypogammaglobulinemia of
Infancy (B cell) involves:
•
•
•
•
The transient lack of antibodies in infancy
Delay in maturation process of B cells
Prolonged deficiency in IgG levels
Fewer B cells = fewer Antibodies
•
More prone to opportunistic infections
–
Increased amount of upper respiratory and middle ear
infections
• Resolves at ± 2-4 yrs old
•
Many children are not specifically tested for this
because it resolves
250
X-Linked Agammaglobulinemia
Bruton’s
251
X-Linked Agammaglobulinemia
Bruton’s
• Impaired ability of B lymphocytes to
produce antibodies
• More common in males
• Have much less or no humoral immunity
252
DiGeorge Syndrome
253
DiGeorge Syndrome
• Affects T cells
– Problems with the development of the thymus
• Impaired ability of T-helper lymphocytes
(Th cells) to orchestrate an immune
response or Cytotoxic T- lymphocytes (Tc
cells) to mount a cytotoxic response
254
Severe Combined
Immunodeficiency Syndrome
(SCID)
255
Severe Combined Immunodeficiency
Syndrome (SCID)
• No T or B cells !!!
• Tends to be in the stem cell lineage of
these cells
• Need a bone marrow transplant
256
Secondary Immunodeficiency
257
Secondary Immunodeficiency
Acquired later in life due to:
• Selective loss of Igs through GI and/or GU tracts
- e.g. Nephrotic Syndrome
- the kidney is not able to obtain protein, so it passes into the urine
- loss of the protein leads to a loss of antibodies
• Chronic or recurrent infections with:
–
–
–
AIDS
Viruses, Fungi, Intracellular bacteria (TB)
Burden the immune system
• Neoplasia (e.g. Lymphoma)
•
– Lead to an inability to produce cells in the bone marrow
Iatrogenic causes (e.g. immunosuppressive therapy with
cyclosporine)
– You are treating one issue by suppressing the immune system but are creating
another problem
• Stress and aging
• Drug abuse and maternal alcoholism
– Due to alterations in the nervous system and the liver’s ability to
produce proteins
258
Hypersensitivity Disorders
259
Hypersensitivity Disorders
•Exaggerated immune responses to allergens (Ags)
–Ex. pollen
•Leads to inflammation and tissue injury caused by
inhalation (depends on the amount of antigen and how we
come into contact with the antigen), ingestion, skin contact,
or injection
•Sensitization depends on:
–Allergen
–Exposure
–Person’s genetic make-up
260
Types of Hypersensitivity
Disorders
261
Hypersensitivity Disorders
• Four Types
Type I: IgE-mediated hypersensitivity
Type II: Antibody-mediated hypersensitivity
Type III: Immune Complex Allergic Disease
Type IV: T-cell mediated Hypersensitivity
262
Type I Hypersensitivity
IgE Mediated
263
Type I Hypersensitivity
IgE Mediated
• Appears within few minutes; fades within few hours
• Minor symptoms : localized, pruritic (itchy), skin wheal
• Severe symptoms: vasodilation and
bronchoconstriction (=anaphylactic shock)
• Triggered by the binding of an antigen (allergen) to mast cell
or basophil with attached IgE, leading to degranulation:
– The antigen-antibody complex binds to a mast cell or basophil and
that cell degranulates
• Release a lot of histamine
• Ex. pollen allergy in the spring
264
Type I Hypersensitivity
Primary Response
265
Type I Hypersensitivity
Primary Response
Primary Phase: Fast-acting or primary
mediators:
• Histamine
• Complement
• Acetylcholine causes bronchoconstriction
and vasodilation of small vessels
• Eosinophil chemotactic factor (ECF)
causes chemotaxis
• Kinins: Prepared from inactive form
• Can result in a significant, localized event
266
Type I Hypersensitivity
Secondary Response
267
Type I Hypersensitivity
Secondary Response
Secondary Phase: Slow-reacting or
secondary substances of anaphylaxis:
• Leukotrienes: lipid based; cause
vasodilation, chemotaxis,
bronchioconstriction
• Cytokines: ( Interleukins and Tumor
Necrosis Factor)
• Platelet activating factor (PAF)
• Prostaglandins (PGs) : lipid based
268
Type I Hypersensitivity
Diagram
269
270
Types of IgE-mediated
Hypersensitivity Disorders
271
Types of IgE-mediated
Hypersensitivity Disorders
• Atopic
• Non-atopic
272
Types of IgE-mediated
Hypersensitivity Disorders
Atopic Disorders
273
Types of IgE-mediated
Hypersensitivity Disorders
Atopic Disorders
• Atopic = Local Anaphylaxis:
• Local reaction to common allergens
– Ex. allergic rhinnitus
– Organ specific
– High IgE serum levels and high basophil and
mast cell numbers
– Allergic rhinitis, allergic asthma, atopic
dermatitis (eczema), certain food allergies,
certain aspects of latex allergy
– Diagnosis needs careful history, identification
of nasal eosinophilia and skin testing.
274
Types of IgE-mediated
Hypersensitivity Disorders
Non-atopic Disorders
275
Types of IgE-mediated
Hypersensitivity Disorders
Non-atopic Disorders
• Non-atopic = Systemic Anaphylaxis:
– Not organ specific
– Can be lethal (anaphylactic shock)
– Common allergens are : Nuts, shellfish,
penicillin, insect stings, etc.
– Urticaria (hives) , pruritis (itching) ,
bronchospasm (asthma), angioedema,
contraction of GI and uterine muscles,
laryngeal edema  asphyxiation and
erythema
276
Antihistamines (H1 blockers)
277
Antihistamines (H1 blockers)
• Two types of histamine receptors – H1
and H2
– H1 receptor blockers block the effects of
histamine that are responsible for allergy
symptoms (Type 1 hypersensitivity)
– H2 blockers block the secretion of stomach
acid (to be covered in a later lecture)
278
H1 Blockers
279
H1 Blockers
• See Table 66-1 in Lehne
• Most first generation H1 blockers also
block muscarinic receptors and have
sedating properties
• Second generation H1 blockers (nonsedating antihistamines) do not cross the
BBB very well.
– Also do not block muscarinic receptors very
well.
• More tolerated with fewer side effects
280
H1 Blockers Block Histamine
Receptors
281
H1 Blockers Block Histamine
Receptors
• Block symptoms of allergies that are due
to histamine
– Remember, histamine is only one of the
mediators of Type 1 hypersensitivity
• Symptoms of a cold are caused by viral
infection, not Type 1 hypersensitivity
– H1 blockers are probably not useful for cold
symptoms.
– However, in many combination cold pills, you
will find an antihistamine.
282
Type II Hypersensitivity
Antibody-Mediated
283
Type II Hypersensitivity
Antibody-Mediated
• Have preformed reactions to an antigen and then when
you come into contact with the antigen, you have a
reaction
Types of Type II Antibody-mediated Disorders:
• ABO antigens in blood transfusion reactions
• Rh Antigens of fetus (erythroblastosis fetalis)
• Drug Reactions (e.g., penicillin)
– Binds to a carrier in the body and then is recognized
• Autoimmune hemolytic anemia: Antibodies against own
RBCs
• Graft rejections, parasites (lysis without phagocytosis)
– Mount a hypersensitivity reaction to the antigens in the
graft
284
Type II Hypersensitivity
Antibody Cytotoxicity
285
Type II Hypersensitivity
Antibody Cytotoxicity
• IgG and IgM antibodies interact with antigens on
cell surfaces. This activates complement and/or
Antibody-dependent cell-mediated cytotoxicity:
e.g., the activation of Natural Killer Cells (NK)
– Involves antigens on RBCs, neutrophils,
platelets, basement membranes
– Involves stimulation or inhibition of cellular
function
286
Type II Hypersensitivity
Injuries
287
Type II Hypersensitivity
Injuries
• Complement fixation  inflammation,
opsonization with phagocytosis, or cell lysis
– Antibody-dependent cell-mediated
cytotoxicity: Null or NK cells recognize
antibodies and release toxins causing cell
lysis
288
Type III Hypersensitivity
Complex Allergic Disease
Triggers and Injuries
289
Type III Hypersensitivity
Complex Allergic Disease
Triggers and Injuries
Triggered by:
• Formation of insoluble Antigen-antibody
complexes in blood circulation or extravascular
sites, leading to:
- Precipitate formation
- Complement activation
• Injuries due to:
– Change in blood flow
– Vascular permeability
– Inflammatory response
290
Type III Hypersensitivity
Antigen-Antibody Complexes
291
Type III Hypersensitivity
Antigen-Antibody Complexes
• Antigen-Antibody complexes are formed and
– Get deposited in the blood vessels, which activates
complement, which in turn causes vasculitis
(inflammation of the vessels), and leads to vessel wall
damage.
• Antigens bound to antibodies bind with one
another and become insoluble complexes, settle
down toward the endothelium, activate
complement, the MAC complex goes into the
endothelium and kills the endothelium
– Leads to a vasculitis secondary to lack of blood flow
292
Type III Hypersensitivity
Diagram
293
294
Immune Complex Disorders
Localized
295
Immune Complex Disorders
Localized
•
•
At site of injection, localized tissue
necrosis due to blockage by Ag-Ab
complexes that precipitate
Onset within 4-10 hrs
296
Results of Immune Complex
Disorders
297
Results of Immune Complex
Disorders
Vasculitis:
- If Blood vessel bursts  hemorrhage into surrounding tissue
- If Blood vessel becomes occluded  ischemia  necrosis
Immune complex pneumonitis (Allergic
Pneumonitis):
Probably involves Type IV hypersensitivity as well
E.g., Miner’s, farmer’s, pigeon breeder’s, mushroom lung
Individuals inhale the antigen that results in vasculitis in the
respiratory tract
-
Cough, malaise, fever, dyspnea, radiographic densities
298
Immune Complex Disorders
Systemic
299
Immune Complex Disorders
Systemic
• Systemic response
• Urticaria (hives), edema, rash, fever
• Antigen-antibody complexes precipitate in blood
vessels, joints, heart, kidneys. This leads to pain
and edema in these areas (rheumatoid arthritis)
• Usually temporary; symptoms go away when the
antigen is taken away
• Penicillin, foods, drugs, insect venoms can initiate
the response.
• Need preformed antibodies to drive this response
300
Type IV Hypersensitivity
T-cell Mediated
301
Type IV Hypersensitivity
T-cell Mediated
• Delayed: 24-72 hours after exposure
• Triggered by specifically sensitized T lymphocytes
(CD4 memory cells) and Not antibodies
• The T cell system is presensitized to the antigen
– When the antigen is present, there is an exaggerated
response
• T cell and Antigen combine and release
lymphokines which attracts macrophages.
Macrophages then release monokines which leads
to inflammation.
• Direct attack by Tc cells can also occur
• Not tissue specific
– Depends on where the antigen is and the route of the
administration
302
Type IV Hypersensitivity
T-cell Mediated
Diagram
303
304
Types of T-cell Mediated
Immunity
305
Types of T-cell Mediated
Immunity
Contact dermatitis:
– e.g. poison ivy  erythema, papules, vesicles, warm, swollen,
exudation, crusting
• Not immediate, have been sensitized where it came into contact with skin
• Takes a while to react because the T cells must be activated
– Latex allergy
Response to the Tuberculin test:
- Erythema and induration within 8-12 hours at site of injection
Granulomatous inflammation with large,
insoluble Antigens:
- e.g. splinter, silica, tuberculosis bacteria
306
Which type of hypersensitivity
disorder is related to ABO
antigen blood transfusion
reactions?
307
Which type of hypersensitivity
disorder is related to ABO antigen
blood transfusion reactions?
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1. Antibody
mediated
2. IgE-mediated
3. Immune Complex
Allergic Disease
4. T-cell mediated
ia
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25% 25% 25% 25%
Host vs. Graft Disease
309
Host vs. Graft Disease
•
Recipient attacks donor cells: e.g. you receive
•
Cell-mediated responses: Th  Tc (Type IV
Hypersensitivity)
liver and your body rejects it
–
Tc and Th severely respond to the graft
310
Results of Host vs. Graft
Disease
311
Results of Host vs. Graft
Disease
•
Th cells activate the production of antibodies
through B cells which circulate and target graft
vasculature. This causes:
1. Complement-mediated toxicity (Type II
reaction)
2. Antigen-antibody complexes (Type III
reaction)
3. Antibody-mediated cytolysis (Type II
reaction)
312
Autoimmunity
313
Autoimmunity
•
Breakdown of immune system  cannot differentiate between self and
non-self
–
Breakdown in the immunosurveillance
•
Can lead to localized or systemic injury depending on what you have an
autoimmune reaction to
•
Response may be T cell-mediated or involve Ag-Ab complexes that
precipitate Type III or even anaphylactic response depending on the
severity and type of reaction
•
More common in females and elderly
•
May be tissue specific: e.g. Graves’ disease (thyroid), myasthenia
gravis (neuromuscular junction)
•
May be system specific: e.g. systemic lupus erythematosis (SLE),
rheumatoid arthritis
•
Causes unclear:
– Possibly due to an inheritance in the alterations of MHC Genes.
– However, individuals may still need a trigger event
314
Rheumatoid Arthritis (RA)
315
Rheumatoid Arthritis (RA)
• Systemic, inflammatory disease
• Affects ± 0.3 – 1.5% of population
•
Affects all races
• Women 2-3 times more than men
• Prevalence  with age:
– Peak for women: 40-60 YOA
– Peak for men: 30-50 YOA
• Etiology of RA
– Not sure, but:
• Many patients (not all) have specific genes (although some people have
these genes and do not develop RA)
• Environment: virus, bacteria
316
Rheumatoid Arthritis (RA)
Diagram
317
318
Pathogenesis of Rheumatoid
Arthritis (RA)
319
Pathogenesis of Rheumatoid Arthritis (RA)
•
70-80% of patients have Rheumatoid Factor (RF): RF is an Antigen against
IgG that is found in blood, synovial fluid and synovial membrane
–
Antigen against protein in own body that is highly enriched in the synovial fluid and
membrane, it makes sense that you would get joint problems
•
•
Problems could also happen in similar membranes around the heart and lung
RF + IgG form immune complexes which leads to synovitis and the
development of PANNUS (granulation tissue)  swollen and puffy joint
–
Complex activates complement, settles in joints, recruits immune cells, inflammation, MAC
•
Cartilage and subchondral bone get destroyed
•
Surrounding muscles, ligaments and tendons weaken, and cannot function
well.
•
Reduced joint motion and possibly ankylosis (fusion of joint) due to
calcification and inflammation
•
Pannus differentiates RA from other arthritis (granulation tissue)
–
This is what separates RA from OA
320
Signs and Symptoms of
Rheumatoid Arthritis (RA)
321
Signs and Symptoms of
Rheumatoid Arthritis (RA)
•
Mild: May last only few months or 1-2 yrs
•
Moderate: Flares and remissions
•
Severe: Active most of time for many yrs;
causes serious joint damage and disability
322
Extra-articular Manifestations
in RA
Systemic
323
Extra-articular Manifestations in RA
Systemic
•
•
•
•
•
•
•
•
•
Fatigue
Anorexia
Weight loss
Aching of muscles and joints
Stiffness
 ESR due to significant burden
Anemia
Rheumatoid nodules: Bumps under skin close to
joints. There are Granulomatous lesions that develop
around small BVs ± ¼ of patients
Vasculitis, pleuritis, pericarditis
324
Emotional and Mental
Symptoms of RA
325
Emotional and Mental
Symptoms of RA
•
Depression
•
Anxiety
•
Feelings of helplessness
•
Can’t perform ADL or work (arthritis
self-management programs help
patients cope)
326
Diagnosis of RA
327
Diagnosis of RA
1. Morning stiffness for > 1 hour
2. Swelling of >3 joints for >6 weeks
3. Symmetric joint swelling
- because this is systemically based, it is
present bilaterally
4. Rheumatoid nodules present (around
small blood vessels)
5. Presence of serum rheumatoid factor
(RF) antibody
328
Evaluation of RA
329
Evaluation of RA
• History
• Physical exam
• Radiographs are NOT diagnostic
• Lab tests (RF is NOT diagnostic)
• Check for Cloudy synovial fluid
330
Goals of RA Treatment
331
Goals of RA Treatment
• Relieve pain
• Reduce inflammation (anti-inflammatories)
• Slow down or stop joint damage
• Improve a patient’s sense of well-being
and ability to function (Educate patient!)
332
Treatment of RA
Lifestyle
333
Treatment of RA
Lifestyle
•
•
•
•
Rest and exercise
Joint care
Stress reduction
Balanced diet
334
Treatment of RA
Medications
335
Treatment of RA
Medications
•
•
NSAIDs
DMARDs (Disease Modifying Anti-Rheumatic
Drugs) reduce joint destruction and retard
disease progression
• Reduced number of immune cells (methotrexate)
• Block cytokines (anti-TNF (anti-cytokine); Etanercept)
decreases inflammation
•
•
•
Immunosuppressants
Corticosteroids
New approach: Combination therapy
336
Treatment of RA
Surgery
337
Treatment of RA
Surgery
• Joint replacement
• Tendon reconstruction and
synovectomy
• Arthrodesis (joint fusion)
338
Osteoarthritis
339
Osteoarthritis
• Degenerative Joint Disease; Osteoarthrosis
• Most common form of arthritis
• Second to CV disease for chronic disability in
US
• 1/3 of all adults in US show OA on X-rays
• Only affects articular cartilage and
subchondral bone of diarthrotic joints
– Shows reduction of bone and calcification, not
pannus
340
Influences on Osteoarthritis
341
Influences on Osteoarthritis
• In age: Men affected at younger age
than women, but rate for affected
women exceeds that of men by
middle age
• Occupation
• Obesity
• Heredity (e.g. hand OA)
342
Causes of Osteoarthritis
343
Causes of Osteoarthritis
• Primary OA: Idiopathic; no identified risk factors
• Secondary OA: Associated with risk factors:
• Joint stress (obesity, sports injuries)
• Congenital abnormalities
• Joint instability leads to chronic stress of
a joint over time
• Trauma
344
Pathogenesis of OA
345
Pathogenesis of OA
•Joint cannot absorb mechanical stress.
– This leads chondrocytes to release cytokines which
causes release of enzymes and more joint damage.
–Articular cartilage breaks down and wears away.
–Bone wears on bone  Pain, swelling, loss of motion.
•Other results:
–Osteophytes
–Fragments
–Microfractures
–Loss of capability to secrete synovial fluid
–Joint immobility  lubrication  more cartilage atrophy
346
Signs of Symptoms of OA
347
Signs of Symptoms of OA
•Sudden or insidious
•Mild synovitis
•Mostly hips, knees, lumbar and cervical
regions, proximal and distal joints of hand, first
CMC joint and first MTP joint
•Joint enlargement
•Joint feels hard
348
Process of OA
Diagram
349
350
Warning Signs of OA
351
Warning Signs of OA
•
•
•
•
•
Steady or intermittent pain in a joint
Stiffness > bed
Joint swelling or tenderness in 1 or > joints
Crepitus (a grinding sound in the joint)
Hot, red, or tender?? No….. probably not
OA, maybe RA
• Not always pain
352
Diagnosis of OA
353
Diagnosis of OA
• No single test
• History
• X-rays
• Lab tests (usually normal)
354
Treatment Goals of OA
355
Treatment Goals of OA
• Control pain
• Improve joint care
• Maintain acceptable body weight
• Achieve healthy life style
356
Joint with OA
Diagram
357
358
Differences between RA and
OA
359
Differences between RA and
OA
OA is different because...
•
•
•
•
•
•
•
No or very little synovitis
No systemic signs and symptoms
Normal synovial fluid (no pannus)
Affects cartilage and subchondral bone only
Not always symmetric
Not always polyarticular
Hardness around joint
360
Differences between RA and
OA
Diagram
361
:
362
Congenital Immunodeficiency
363
Congenital Immunodeficiency
•
Congenital (primary)
–
Lymphocyte development disrupted in fetus or embryo (rare)
•
•
T cell
B cells
364
Acquired (Secondary)
Immunodeficiency
365
Acquired (Secondary)
Immunodeficiency
1. Immune /inflammatory deficiency after birth.
2. Not related to genetic defects:
•
Nutritional
•
•
•
•
•
•
Need folate in order to help properly dividing cells develop healthily
Iatrogenic Deficiencies
Medical treatment
- chemotherapy
- immunosuppression
Trauma:
- Burn victims
Stress
- sympathetic lymphoid innervation
- cortisol
Acquired Immunodeficiency Syndrome (AIDS)
366
Human Immunodeficiency
Virus (HIV)
367
Human Immunodeficiency Virus
(HIV)
A retrovirus unknown until early 1980s:
•
•
•
Contains only RNA; no DNA
Most infections caused by HIV-1 variant of the virus
Cannot replicate outside of living host cells
Infection leads to relentless destruction of immune system  AIDS:
One of leading causes of death in US and in other countries
Patients infected with HIV are at risk for illness and death from:
•
•
Opportunistic infections
Neoplastic complications
Mainly present in blood, genital secretions, breast milk
Presence in saliva, tears, urine, sweat is not important or a high risk for
transmission
368
Transmission of HIV
369
Transmission of HIV
• Sex: Semen, vaginal secretions, cervical secretions, and rectal secretions
• Blood: Open wound, injection with contaminated needle, blood transfusion
(<1985)
•
1.
2.
3.
Perinatally:
In utero
Inoculation during birth and delivery due to the mixing of blood
Breast-feeding
•
NOT TRANSMITTED BY:
1. Casual contact
2. Mosquitoes or other insects
• Occupational transmission is very rare
370
HIV Structure
371
HIV Structure
• Viral genome: Two short strands of RNA with
three major genes that encode enzymes:
– Reverse transcriptase (Makes mistakes 
mutations  HIV variants)
– Protease: breaks down proteins
– Integrase: incorporates viral DNA into host
genome to make more virus
• Outer lipid envelope with surface projections
containing gp120 antigen which binds to CD4
proteins of Th
– CD4 are part of the T cell receptor in T helper cells
– When the HIV virus gets into the body, it seeks out
cells with the CD4 receptor, and the virus
incorporates into contents into the host’s cell, lying
dormant and waiting for more virus to be made
372
Mechanism of HIV Infection
Description
373
Mechanism of HIV Infection
Description
•
•
•
•
•
•
Gp 120 antigen binds to CD4 cell
Fusion of HIV virus with cell membrane
RNA is incorporated
Reverse transcriptase makes DNA
Protease breaks down proteins
Integrase integrates proteins into host’s viral genome
• Cell lies dormant
• Cell at some time decides to make all of the proteins for HIV,
virus buds out of the host cell, killing the host cell (CD4) in the
process, the virus incorporates some of the host’s cell
markers with it, helping it to further evade detection
• Kills T helper cells, which orchestrate the immune system,
release cytokines
374
Mechanism of HIV Infection
Diagram
375
376
Mechanism of Infection
Detailed Description
377
Mechanism of Infection
Detailed Description
•
gp120 of virus binds to CD4 molecule
- virus and host membranes fuse
- virus enters host and sheds protein coat
•
Viral RNA is converted to viral DNA with reverse transcriptase
•
After integration of proviral DNA, virus may remain latent for
some time
•
Eventually, productive virus synthesis occurs  virions released
(protease)  T cell dies
•
Virions invade other CD4 cells  fast amplification  first few
years, destruction of millions of T cells  release of millions of
virions, but all T cells still get replaced
•
After several years, however, T cell numbers begin to crash to
very low levels.
378
Clinical Course of HIV
Infection
379
Clinical Course of HIV Infection
• Latest classification based on CD4 cell count rather than
signs and symptoms
• Primary or Initial Infection:
-Window Phase: Between time of exposure to time Abs are detectable
• Latent period 8-10 years
-Acute Phase
-Latent Phase
-Clinically Apparent Disease with Constitutional Symptoms
• Full-blown AIDS
380
Primary Infection with HIV
381
Primary Infection with HIV
• Immune response  HIV Abs (2 weeks to 6 months after infection) 
Patient will test positive for HIV Ab (seropositive)
• Acute phase that may go unnoticed or produce mild disease:
–
–
–
–
Acute mononucleosis-like syndrome (acute retroviral syndrome)
Fever, myalgia, sore throat, nausea, lethargy, lymphadenopathy, rash, headache
Symptoms  after 1-2 months
Burst of viral replication (viremia)  CD4 count  (as low as 200), but then immune
system tries to control viral replication  viremia   CD4 cells rebound, but not to
pre-infection levels
•
The individual is then asymptomatic because the CD4 cells increase
• Both humoral and cell mediated responses play role in the primary
infection phase
• Sometimes mistaken for flu or cold
382
Viral Load in the Blood
(Viremia)
383
Viral Load in the Blood (Viremia)
384
Clinical Latency of HIV
385
Clinical Latency of HIV
• May last 10 years
• Disease concentrates in lymph nodes
– Lymph nodes are areas where T cell congregate
• Asymptomatic and little detectable virus in blood
– There will not be an active viremia
• Gradual fall in CD4 count as more virus occurs
• Patient still tests seropositive for antibodies against HIV
386
Clinically Apparent HIV
Disease
387
Clinically Apparent HIV Disease
• Persistent generalized lymphadenopathy (PGL)
(>3mos.) : Lymph nodes swell; not life threatening
• Fatigue, weight loss, night sweats, diarrhea, fungal
infections of mouth and nails
– These occur because immunosurveillance is decreased
• CD4 count < 500 cells/l (normal 800-1000)
388
Full-Blown or Clinical AIDS
389
Full-Blown or Clinical AIDS
• CD4 count < 200 cells/l
• Confirmed by a variety of lab tests
• Opportunistic infections (risk correlated with CD4
count)
390
Full-Blown or Clinical AIDS
Lungs
391
Full-Blown or Clinical AIDS
Lungs
• PCP: Pneumocystis carinii pneumoni:
Fever, chest pain, sputum,
tachypnea
• TB: Mycobacterium tuberculosis
392
Full-Blown or Clinical AIDS
GI Tract
393
Full-Blown or Clinical AIDS
GI Tract
• Esophageal candidiasis, thrush: painful
swallowing; retrosternal pain
• Diarrhea or gastroenteritis
394
Full-Blown or Clinical AIDS
Nervous System
395
Full-Blown or Clinical AIDS
Nervous System
• Toxoplasmosis: Toxoplasma gondii
(parasite): affects CNS; fever, altered
mental status, seizures, motor deficits
• AIDS Dementia: Ataxia, tremor,
spasticity, paraplegia
• Cerebral atrophy
396
Full-Blown or Clinical AIDS
Neoplastic Malignancies
397
Full-Blown or Clinical AIDS
Neoplastic Malignancies
• Kaposi’s sarcoma
- Neoplasm of endothelium
- Opportunistic cancer
- Small discolored elevated tumors of skin
that invade viscera
• Lymphoma
398
Full-Blown or Clinical AIDS
Wasting Syndrome
399
Full-Blown or Clinical AIDS
Wasting Syndrome
Wasting syndrome (Cachexia):
– Emaciation, severe diarrhea, chronic weakness, fever, fatigue,
lethargy, severe negative nitrogen balance
400
Patients with HIV disease are
most likely to die from:
401
Patients with HIV disease are most
likely to die from:
1. Neoplastic
complications
2. Opportunistic
infections
3. Neurological disease
4. Wasting
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.
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..
33% 33% 33%
Diagnosis of HIV Infection
403
Diagnosis of HIV Infection
• HIV antibody test (ELISA: enzyme-linked
immunosorbent assay):
– Detects Abs produced in response to HIV
infection
• Western Blot (done if ELISA is positive):
– Identifies Abs specific to viral Ags
• CD4 count
• Based on symptoms
404
Treatment of AIDS
405
Treatment of AIDS
• No cure; no vaccine
• Treat opportunistic infections with drugs
• Therapeutic management:
–
–
–
–
–
Inhibit reverse transcriptase
Inhibit protease
Inhibit integrase
Prevent transcription from host DNA into viral RNA
Vaccine??
406
Treatment of HIV
Diagram
407
1.Fusion inhibitor
2.RT inhibitor
3.Protease inhibitor
4.Under development
5. Integrase inhibitor
408