The Immune Response:
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Transcript of The Immune Response:
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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
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Introduction to Immunity
Functions of the Immune Response
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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
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Results of Immune Dysfunction or Deficiency
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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
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Innate Immunity
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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
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Adaptive Immunity
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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
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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)
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Part I:
Innate Immunity
Primary Immune Cells of Innate Immunity
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Primary Immune Cells of Innate Immunity
• Monocytes, macrophages, dendritic cells
• Neutrophils
• Eosinophils
• Basophils
• Mast cells
• Natural killer cells
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Monocytes, Macrophages, and Dendritic cells
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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)– Internalize and consume pathogens with lysosomes and peroxisomes– Process the antigen out of the substance that is foreign
• 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
– Release molecules that are very important in inflammation
• Macrophages are phagocytes17
Neutrophils
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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
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Eosinophils
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Eosinophils
• Inflammatory response
• Fight parasites (worms especially)
• May release chemicals in respiratory tract during allergic asthma– Release chemical mediators
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Basophils
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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
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Mast Cells
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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.
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Natural Killer Cells
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Natural Killer CellsNatural 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
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Cytokines and the Immune Response
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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
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Processes that Cytokines are Involves in
• Innate immunity
• Adaptive immunity
• Hematopoiesis
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Cytokines and Innate Immunity
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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
endothelium35
Acute Phase Protein Production by the Liver
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Acute Phase Protein Production by the Liver
• Overlaps with the ESR
• Increases cytokine release in the body-sensed 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
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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
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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
Inflammation
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InflammationReaction 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– Stereotypic no matter the size of the injury
• Includes vascular and cellular changes
• Triggered when FIRST LINE OF Defense's integrity has been breached (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 InflammationVascular Phase
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Acute InflammationVascular 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 PhasePossible Scenarios
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Vascular PhasePossible 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
• Redness is the vasodilation, vascular permeability leads to the edema
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Acute InflammationVascular Phase
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Acute InflammationCellular Phase
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Acute InflammationCellular 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 fight infection
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Acute InflammationCellular 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
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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
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Plasma Proteases
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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
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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
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Arachidonic Acid Diagram
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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
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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, C5C9). Proteins must be activated in the proper sequence in order to have their end effect (as with the clotting factors)
• Non-specific and no memory76
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
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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
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Complement PathwaysDiagram
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Chronic InflammationPersistent Irritants
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Chronic InflammationPersistent 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
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Chronic InflammationPatterns
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Chronic InflammationPatterns
• 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
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Chronic InflammationCauses and Characteristics
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Chronic InflammationCauses 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 InflammationExudation
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Manifestations of InflammationExudation
• 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
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Manifestations of InflammationTypes of Exudate
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Manifestations of InflammationTypes 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
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Systemic Manifestations of Inflammation
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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
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Acute Phase ResponsesAcute-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
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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
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Part III:
Treatment of Inflammation
Types of Treatment of Inflammation
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Types of Treatment of Inflammation
• Focus: Prevent the synthesis and release of pro-inflammatory mediators, such as prostaglandins
• NSAIDs
• Steroids
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Treatment of InflammationDiagram
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Treatment of InflammationDiagram
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Treatment of InflammationNSAIDs
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Treatment of InflammationNSAIDs
• 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
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Treatment of InflammationSteroids
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Treatment of InflammationSteroids
• 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
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COX-1 and COX-2
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COX-1 and COX-2
• Both produce prostaglandins and thromboxane (TXA) and convert arachidonic acid into prostaglandins
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COX-1
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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)
stroke in patients with overactive coagulation pathways.111
COX-2
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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-2113
Contraindications
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Contraindications
• NSAIDs
• Hypersensitivity syndrome
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NSAIDs
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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
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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
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Aspirin
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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.
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Uses of Aspirin
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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
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Uses of AspirinSuppression of Platelet
Aggregation
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Uses of AspirinSuppression 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.
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Adverse EffectsCommon to all Aspirin Formulations
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Adverse EffectsCommon 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
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Aspirin Formulation
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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.
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Aspirin Dosage
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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 child’s physician.
• Inhibition of platelets: 81 mg per day.131
Other Non-Selective NSAIDs
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Other Non-Selective NSAIDs
• Non-specific COX-1 and COX-2 inhibitors
• Specific COX-2 inhibitors
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Non-specific COX-1 and COX-2 Inhibitors
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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
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Specific COX-2 Inhibitors
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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
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Acetaminophen
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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
AcetaminophenAdverse Effects
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AcetaminophenAdverse 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.
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AcetaminophenDrug Interactions
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AcetaminophenDrug Interactions
• May affect warfarin metabolism because it is metabolized by the liver to increase levels of warfarin and increase its anticoagulant effects.
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AcetaminophenDosages
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AcetaminophenDosages
• 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
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Formulations of NSAIDs and Acetaminophen
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NSAIDS and acetaminophen are found in many formulations
Be careful !
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Part IV:
Adaptive Immunity
Active Adaptive Immunity
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Active Adaptive Immunity
• Active passive immunity - Through immunizations
• Active natural immunity - Through having the disease
• Present for a life-time
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Passive Adaptive Immunity
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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
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Characteristics of the Adaptive Immune Response
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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)
Major Functional Cells of the Adaptive Immune Response
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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
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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 non-
microbial agents such as pollens, plant resin, insect venom, transplanted organ.
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AntigensDiagram
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AntigensDiagram
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
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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.
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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.
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MHC-I MoleculesDiagram
172
Virus particles
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
LymphocytesDiagram
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 the antibody will only ever recognize the specific antigen
182
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 LymphocytesDiagram
185
186
B LymphocytesDescription
187
B LymphocytesDescription
• 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
AntibodiesPrimary Immune Response
191
192
AntibodiesPrimary 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.
AntibodiesSecondary Immune Response
193
194
AntibodiesSecondary 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.
Primary and Secondary B Lymphocyte Immune Response
Diagram
195
196
Primary and Secondary B Lymphocyte Immune Response
Diagram
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
212
Maternal vs. Fetal/newborn IgG Contributions
T Lymphocytes
213
214
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)
Types of T Lymphocytes
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Types of T Lymphocytes
• CD4 cells: T helper cells
• CD8 cells: Cytotoxic T cells
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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 LymphocytesDiagram
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 cell- mediated cell destruction in the immune response, while Th cells modulate the process.
224
Cell-mediated and Humoral ImmunityDiagram
225
226
Cell-mediated and Humoral Immunity
Description
227
Cell-mediated and Humoral ImmunityDescription
• 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 CellsNatural 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
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Secondary Lymphoid Organs
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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 tissuelymphatic 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
NS238
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 OrgansDiagram
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
246
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
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 resolves250
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
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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
262
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
Type I HypersensitivityIgE Mediated
263
Type I HypersensitivityIgE 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 spring264
Type I HypersensitivityPrimary Response
265
Type I HypersensitivityPrimary 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
event266
Type I HypersensitivitySecondary Response
267
Type I HypersensitivitySecondary 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 HypersensitivityDiagram
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 (non-sedating 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 HypersensitivityAntibody-Mediated
283
Type II HypersensitivityAntibody-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 HypersensitivityAntibody Cytotoxicity
285
Type II HypersensitivityAntibody 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 HypersensitivityInjuries
287
Type II HypersensitivityInjuries
• 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 HypersensitivityComplex Allergic Disease
Triggers and Injuries
289
Type III HypersensitivityComplex Allergic Disease
Triggers and InjuriesTriggered 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 HypersensitivityAntigen-Antibody Complexes
291
Type III HypersensitivityAntigen-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 HypersensitivityDiagram
293
294
Immune Complex DisordersLocalized
295
Immune Complex DisordersLocalized
• 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 DisordersSystemic
299
Immune Complex DisordersSystemic
• 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 HypersensitivityT-cell Mediated
301
Type IV HypersensitivityT-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 HypersensitivityT-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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25% 25%25%25%1. Antibody
mediated
2. IgE-mediated
3. Immune Complex Allergic Disease
4. T-cell mediated
Host vs. Graft Disease
309
Host vs. Graft Disease
• Recipient attacks donor cells: e.g. you receive liver and your body rejects it
• Cell-mediated responses: Th Tc (Type IV Hypersensitivity)
– 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
320
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
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
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Emotional and Mental Symptoms of RA
• Depression
• Anxiety
• Feelings of helplessness
• Can’t perform ADL or work (arthritis self-management programs help patients cope)
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Diagnosis of RA
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Diagnosis of RA
1. Morning stiffness for > 1 hour2. Swelling of >3 joints for >6 weeks3. 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 fluid330
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 RALifestyle
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Treatment of RALifestyle
• Rest and exercise• Joint care• Stress reduction• Balanced diet
334
Treatment of RAMedications
335
Treatment of RAMedications
• 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 RASurgery
337
Treatment of RASurgery
• 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 OADiagram
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 OADiagram
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)
• Perinatally:1. In utero2. Inoculation during birth and delivery due to the mixing of blood3. Breast-feeding
• NOT TRANSMITTED BY:1. Casual contact2. Mosquitoes or other insects
• Occupational transmission is very rare 370
HIV Structure
371
372
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
Mechanism of HIV InfectionDescription
373
Mechanism of HIV InfectionDescription
• 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 InfectionDiagram
375
376
Mechanism of InfectionDetailed Description
377
378
Mechanism of InfectionDetailed 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.
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 AIDS380
Primary Infection with HIV
381
382
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
Viral Load in the Blood (Viremia)
383
384
Viral Load in the Blood (Viremia)
Clinical Latency of HIV
385
386
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
Clinically Apparent HIV Disease
387
388
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)
Full-Blown or Clinical AIDS
389
390
Full-Blown or Clinical AIDS
• CD4 count < 200 cells/l
• Confirmed by a variety of lab tests
• Opportunistic infections (risk correlated with CD4 count)
Full-Blown or Clinical AIDSLungs
391
Full-Blown or Clinical AIDSLungs
• PCP: Pneumocystis carinii pneumoni: Fever, chest pain, sputum,
tachypnea
• TB: Mycobacterium tuberculosis
392
Full-Blown or Clinical AIDSGI Tract
393
Full-Blown or Clinical AIDSGI Tract
• Esophageal candidiasis, thrush: painful swallowing; retrosternal pain
• Diarrhea or gastroenteritis
394
Full-Blown or Clinical AIDSNervous System
395
Full-Blown or Clinical AIDSNervous 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 AIDSNeoplastic Malignancies
397
Full-Blown or Clinical AIDSNeoplastic Malignancies
• Kaposi’s sarcoma - Neoplasm of endothelium
- Opportunistic cancer
- Small discolored elevated tumors of skin that invade viscera
• Lymphoma398
Full-Blown or Clinical AIDSWasting Syndrome
399
Full-Blown or Clinical AIDSWasting 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:
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33% 33%33%1. Neoplastic
complications
2. Opportunistic infections
3. Neurological disease
4. Wasting
All of the above
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 HIVDiagram
407
408
1.Fusion inhibitor
2.RT inhibitor
3.Protease inhibitor
4.Under development
5. Integrase inhibitor